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15 September 2021, Volume 16 Issue 9 Previous Issue    Next Issue

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Effects of primary microglia and astrocytes on neural stem cells in in vitro and in vivo models of ischemic stroke Sheng-Jun Wen, Xi-Min Zheng, Li-Fen Liu, Na-Na Li, Hai-An Mao, Liang Huang, Qiong-Lan Yuan 2021, 16 (9):  1677-1685.  doi: 10.4103/1673-5374.306093 Abstract ( 181 )   PDF (5467KB) ( 152 )   Save Transplantation of neural stem cells (NSCs) can protect neurons in animal stroke models; however, their low rates of survival and neuronal differentiation limit their clinical application. Glial niches, an important location of neural stem cells, regulate survival, proliferation and differentiation of neural stem cells. However, the effects of activated glial cells on neural stem cells remain unclear. In the present study, we explored the effects of activated astrocytes and microglia on neural stem cells in vitro stroke models. We also investigated the effects of combined transplantation of neural stem cells and glial cells after stroke in rats. In a Transwell co-culture system, primary cultured astrocytes, microglia or mixed glial cells were exposed to glutamate or H2O2 and then seeded in the upper inserts, while primary neural stem cells were seeded in the lower uncoated wells and cultured for 7 days. Our results showed that microglia were conducive to neurosphere formation and had no effects on apoptosis within neurospheres, while astrocytes and mixed glial cells were conducive to neurosphere differentiation and reduced apoptosis within neurospheres, regardless of their pretreatment. In contrast, microglia and astrocytes induced neuronal differentiation of neural stem cells in differentiation medium, regardless of their pretreatment, with an exception of astrocytes pretreated with H2O2. Rat models of ischemic stroke were established by occlusion of the middle cerebral artery. Three days later, 5 × 105 neural stem cells  with microglia or astrocytes were injected into the right lateral ventricle. Neural stem cell/astrocyte-treated rats displayed better improvement of neurological deficits than neural stem cell only-treated rats at 4 days after cell transplantation. Moreover, neural stem cell/microglia-, and neural stem cell/astrocyte-treated rats showed a significant decrease in ischemic volume compared with neural stem cell-treated rats. These findings indicate that microglia and astrocytes exert different effects on neural stem cells, and that co-transplantation of neural stem cells and astrocytes is more conducive to the recovery of neurological impairment in rats with ischemic stroke. The study was approved by the Animal Ethics Committee of Tongji University School of Medicine, China (approval No. 2010-TJAA08220401) in 2010.  Related Articles | Metrics

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Oligodendrocyte precursor cell maturation: role of adenosine receptors Federica Cherchi, Anna Maria Pugliese, Elisabetta Coppi 2021, 16 (9):  1686-1692.  doi: 10.4103/1673-5374.306058 Abstract ( 109 )   PDF (716KB) ( 50 )   Save Oligodendrocyte-formed myelin sheaths allow fast synaptic transmission in the brain and their degeneration leads to demyelinating diseases such as multiple sclerosis. Remyelination requires the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes but, in chronic neurodegenerative disorders, remyelination fails due to adverse environment. Therefore, a strategy to prompt oligodendrocyte progenitor cell differentiation towards myelinating oligodendrocytes is required. The neuromodulator adenosine, and its receptors (A1, A2A, A2B and A3 receptors: A1R, A2AR, A2BR and A3R), are crucial mediators in remyelination processes. It is known that A1Rs facilitate oligodendrocyte progenitor cell maturation and migration whereas the A3Rs initiates apoptosis in oligodendrocyte progenitor cells. Our group of research contributed to the field by demonstrating that A2AR and A2BR inhibit oligodendrocyte progenitor cell maturation by reducing voltage-dependent K+ currents necessary for cell differentiation. The present review summarizes the possible role of adenosine receptor ligands as potential therapeutic targets in demyelinating pathologies such as multiple sclerosis. Related Articles | Metrics

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Inflammation induces zebrafish regeneration Maria Iribarne 2021, 16 (9):  1693-1701.  doi: 10.4103/1673-5374.306059 Abstract ( 75 )   PDF (1184KB) ( 134 )   Save Tissue or organ regeneration is a complex process with successful outcomes depending on the type of tissue and organism. Upon damage, mammals can only efficiently restore a few tissues including the liver, skin, epithelia of the lung, kidney, and gut. In contrast, lower vertebrates such as zebrafish possess an extraordinary regeneration ability, which restores the normal function of a broad spectrum of tissues including heart, fin, brain, spinal cord, and retina. This regeneration process is either mediated by the proliferation of resident stem cells, or cells that dedifferentiate into a stem cell-like. In recent years, evidence has suggested that the innate immune system can modulate stem cell activity to initiate the regenerative response to damage. This review will explore some of the newer concepts of inflammation in zebrafish regeneration in different tissues. Understanding how inflammation regulates regeneration in zebrafish would provide important clues to improve the therapeutic strategies for repairing injured mammalian tissues that do not have an inherent regenerative capacity. Related Articles | Metrics

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Astrocytes: a double-edged sword in neurodegenerative diseases Zhi-Bin Ding, Li-Juan Song, Qing Wang, Gajendra Kumar, Yu-Qing Yan, Cun-Gen Ma 2021, 16 (9):  1702-1710.  doi: 10.4103/1673-5374.306064 Abstract ( 121 )   PDF (1928KB) ( 113 )   Save Astrocytes play multifaceted and vital roles in maintaining neurophysiological function of the central nervous system by regulating homeostasis, increasing synaptic plasticity, and sustaining neuroprotective effects. Astrocytes become activated as a result of inflammatory responses during the progression of pathological changes associated with neurodegenerative disorders. Reactive astrocytes (neurotoxic A1 and neuroprotective A2) are triggered during disease progression and pathogenesis due to neuroinflammation and ischemia. However, only a limited body of literature describes morphological and functional changes of astrocytes during the progression of neurodegenerative diseases. The present review investigated the detrimental and beneficial roles of astrocytes in neurodegenerative diseases reported in recent studies, as these cells have promising therapeutic potential and offer new approaches for treatment of neurodegenerative diseases.  Related Articles | Metrics

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Chronic peripheral inflammation: a possible contributor to neurodegenerative diseases Patrick Süβ, Addison J. Lana, Johannes C. M. Schlachetzki 2021, 16 (9):  1711-1714.  doi: 10.4103/1673-5374.306060 Abstract ( 80 )   PDF (855KB) ( 227 )   Save The contribution of chronic peripheral inflammation to the pathogenesis of neurodegenerative diseases is an outstanding question. Sustained activation of the peripheral innate and adaptive immune systems occurs in the context of a broad array of disorders ranging from chronic infectious diseases to autoimmune and metabolic diseases. In addition, progressive systemic inflammation is increasingly recognized during aging. Peripheral immune cells could potentially modulate the cellular brain environment via the secretion of soluble molecules. There is an ongoing debate whether peripheral immune cells have the potential to migrate into the brain under certain permissive circumstances. In this perspective, we discuss the possible contribution of chronic peripheral inflammation to the pathogenesis of age-related neurodegenerative diseases with a focus on microglia, the resident immune cells of the brain parenchyma.  Related Articles | Metrics

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What do we know about the role of lncRNAs in multiple sclerosis? Viviana Nociti , Massimo Santoro 2021, 16 (9):  1715-1722.  doi: 10.4103/1673-5374.306061 Abstract ( 66 )   PDF (633KB) ( 70 )   Save Multiple sclerosis is a chronic, inflammatory and degenerative disease of the central nervous system of unknown aetiology although well-defined evidence supports an autoimmune pathogenesis. So far, the exact mechanisms leading to autoimmune diseases are still only partially understood. We know that genetic, epigenetic, molecular, and cellular factors resulting in pathogenic inflammatory responses are certainly involved. Long non-coding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides that play an important role in both innate and acquired immunity, so there is great interest in lncRNAs involved in autoimmune diseases. The research on multiple sclerosis has been enriched with many studies on the molecular role of lncRNAs in the pathogenesis of the disease and their potential application as diagnostic and prognostic biomarkers. In particular, many multiple sclerosis fields of research are based on the identification of lncRNAs as possible biomarkers able to predict the onset of the disease, its activity degree, its progression phase and the response to disease-modifying drugs. Last but not least, studies on lncRNAs can provide a new molecular target for new therapies, missing, so far, a cure for multiple sclerosis. While our knowledge on the role of lncRNA in multiple sclerosis has recently improved, further studies are required to better understand the specific role of lncRNAs in this neurological disease. In this review, we present the most recent studies on molecular characterization of lncRNAs in multiple sclerosis disorder discussing their clinical relevance as biomarkers for diagnosis and treatments. Related Articles | Metrics

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Considerations on the concept, definition, and diagnosis of amyotrophic lateral sclerosis Ren-Shi Xu, Min Yuan 2021, 16 (9):  1723-1729.  doi: 10.4103/1673-5374.306065 Abstract ( 88 )   PDF (290KB) ( 121 )   Save The concept, definition, and diagnosis of amyotrophic lateral sclerosis (ALS) currently present some problems. This article systematically reviews the literature on the history, current concepts, definition, and diagnosis of ALS, and discloses the present problems based on the retrieved literature and the authors’ clinical experience. The current concepts and definitions of ALS have not yet been unified or standardized in clinical practice, and are sometimes vague or inaccurate, which can cause difficulties for neurologists in the clinical treatment of ALS. The concept and definition of ALS need to be further ascertained, and the current diagnostic criteria for ALS require further development. The identification of effective and objective biomarkers may be a feasible method for the early and accurate diagnosis of ALS. Therefore, future research should focus on the identification of reliable biomarkers—especially neuroimaging biomarkers—through autopsy. Standardizing the concept and definition of ALS and formulating clear diagnostic criteria will largely avoid many uncertainties in the future clinical research and treatment of ALS, which will greatly benefit patients.  Related Articles | Metrics

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Promising drug targets and associated therapeutic interventions in Parkinson’s disease Sachchida Nand Rai, Payal Singh, Ritu Varshney, Vivek K. Chaturvedi, Emanuel Vamanu, M. P. Singh, Brijesh Kumar Singh 2021, 16 (9):  1730-1739.  doi: 10.4103/1673-5374.306066 Abstract ( 87 )   PDF (394KB) ( 108 )   Save Parkinson’s disease (PD) is one of the most debilitating brain diseases. Despite the availability of symptomatic treatments, response towards the health of PD patients remains scarce. To fulfil the medical needs of the PD patients, an efficacious and etiological treatment is required. In this review, we have compiled the information covering limitations of current therapeutic options in PD, novel drug targets for PD, and finally, the role of some critical beneficial natural products to control the progression of PD. Related Articles | Metrics

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Topical delivery of nerve growth factor for treatment of ocular and brain disorders Gemma Eftimiadi, Marzia Soligo, Luigi Manni, Daniela Di Giuda, Maria Lucia Calcagni, Antonio Chiaretti 2021, 16 (9):  1740-1750.  doi: 10.4103/1673-5374.306062 Abstract ( 89 )   PDF (952KB) ( 91 )   Save Neurotrophins are a family of proteins that support neuronal proliferation, survival, and differentiation in the central and peripheral nervous systems, and are regulators of neuronal plasticity. Nerve growth factor is one of the best-described neurotrophins and has advanced to clinical trials for treatment of ocular and brain diseases due to its trophic and regenerative properties. Prior trials over the past few decades have produced conflicting results, which have principally been ascribed to adverse effects of systemic nerve growth factor administration, together with poor penetrance of the blood-brain barrier that impairs drug delivery. Contrastingly, recent studies have revealed that topical ocular and intranasal nerve growth factor administration are safe and effective, suggesting that topical nerve growth factor delivery is a potential alternative to both systemic and invasive intracerebral delivery. The therapeutic effects of local nerve growth factor delivery have been extensively investigated for different ophthalmic diseases, including neurotrophic keratitis, glaucoma, retinitis pigmentosa, and dry eye disease. Further, promising pharmacologic effects were reported in an optic glioma model, which indicated that topically administered nerve growth factor diffused far beyond where it was topically applied. These findings support the therapeutic potential of delivering topical nerve growth factor preparations intranasally for acquired and degenerative brain disorders. Preliminary clinical findings in both traumatic and non-traumatic acquired brain injuries are encouraging, especially in pediatric patients, and clinical trials are ongoing. The present review will focus on the therapeutic effects of both ocular and intranasal nerve growth factor delivery for diseases of the brain and eye. Related Articles | Metrics

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The future of retinal gene therapy: evolving from subretinal to intravitreal vector delivery Maya Ross, Ron Ofri 2021, 16 (9):  1751-1759.  doi: 10.4103/1673-5374.306063 Abstract ( 74 )   PDF (1259KB) ( 44 )   Save Inherited retinal degenerations are a leading and untreatbale cause of blindness, and as such they are targets for gene therapy. Numerous gene therapy treatments have progressed from laboratory research to clinical trails, and a pioneering gene therapy received the first ever FDA approval for treating patients. However, currently retinal gene therapy mostly involves subretinal injection of the therapeutic agent, which treats a limited area, entails retinal detachment and other potential complications, and requires general anesthesia with consequent risks, costs and prolonged recovery. Therefore there is great impetus to develop safer, less invasive and cheapter methods of gene delivery. A promising method is intravitreal injection, that does not cause retinal detachment, can lead to pan-retinal transduction and can be performed under local anesthesia in out-patient clinics. Intravitreally-injected vectors face several obstacles. First, the vector is diluted by the vitreous and has to overcome a long diffusion distance to the target cells. Second, the vector is exposed to the host’s immune response, risking neutralization by pre-existing antibodies and triggering a stronger immune response to the injection. Third, the vector has to cross the inner limiting membrane which is both a physical and a biological barrier as it contains binding sites that could cause the vector’s sequestration. Finally, in the target cell the vector  is prone to proteasome degradation before delivering the transgene to the nucleus. Strategies to overcome these obstacles include modifications of the viral capsid, through rational design or directed evolution, which allow resistance to the immune system, enhancement of penetration through the inner limiting membrane or reduced degradation by intracellular proteasomes. Furthermore, physical and chemical manipulations of the inner limiting membrane and vitreous aim to improve vector penetration. Finally, compact non-viral vectors that can overcome the immunological, physical and anatomical and barriers have been developed. This paper reviews ongoing efforts to develop novel, safe and efficacious methods for intravitreal delivery of therapeutic genes for inherited retinal degenerations. To date, the most promising results are achieved in rodents with robust, pan-retinal transduction following intravitreal delivery. Trials in larger animal models demonstrate transduction mostly of inner retinal layers. Despite ongoing efforts, currently no intravitreally-injected vector has demonstrated outer retinal transduction efficacy comparable to that of subretinal delivery. Further work is warranted to test promising new viral and non-viral vectors on large animal models of inherited retinal degenerations. Positive results will pave the way to development of the next generation of treatments for inherited retinal degeneration.  Related Articles | Metrics

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New insights on the molecular mechanisms of collateral sprouting after peripheral nerve injury Dominique Lemaitre, Felipe A. Court 2021, 16 (9):  1760-1761.  doi: 10.4103/1673-5374.306069 Abstract ( 127 )   PDF (650KB) ( 290 )   Save Axonal regeneration after injuries to the nervous system has been extensively studied due to its implication in motor and sensory functional recovery. Distinct types of regeneration has been identified, such as canonical axonal regeneration, defined as the growth of axons from the transected axonal stump to reinnervate the original target, or regenerative sprouting, in which the growth occurs from a region of the damaged axon either close or far from the injury site (Tuszynski and Steward, 2012). Both types of axonal regeneration depend on cellular and molecular responses of the injured neuron. However, undamaged neurons can also react to an injury-induced environment by extending sprouts along their axons that functionally synapse with denervated targets, a process known as collateral sprouting (Collyer et al., 2014; Bao et al., 2016). Related Articles | Metrics

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Synaptic mechanisms of cadmium neurotoxicity Andrei N. Tsentsevitsky, Alexey M. Petrov 2021, 16 (9):  1762-1763.  doi: 10.4103/1673-5374.306067 Abstract ( 128 )   PDF (778KB) ( 55 )   Save Cadmium (Cd) is a toxic heavy metal ubiquitously distributed in the environment (water, air, food, smoke) with extreme ability to accumulate in the human body due to its delayed clearance (half-life time 15–30 years). Consequently, prolonged exposure to low doses of Cd causes multi-organ toxicity. Remarkably, the central and peripheral nervous systems are considered as one of the most vulnerable targets. Excessive Cd exposure can profoundly aggravate common neurodegenerative diseases and peripheral polyneuropathies as well as lead to mental deficits in children (Branca et al., 2020). Conceivably, that Cd-induced defects in communication between neurons could be triggering events in Cd neurotoxicity. Numerous studies have discovered the disturbances at the synaptic levels in response to both acute and chronic Cd administration. Furthermore, release of Cd, captured by neuronal tissue, into extracellular space is increased by stimulation of synaptic vesicle (SV) exocytosis (Minami et al., 2001), pointing to Cd accumulation within the SVs in presynaptic terminals. Being a divalent cation, Cd can enter cells through various ways (such as active transporters, carriers, channels, and endocytosis), which serve to transport physiologically essential cations (Ca, Mg, Cu, Mn, Zn). An important route for Cd penetration into neuronal cells relies on zinc transporters (ZnTs). Among them, ZnT3 is highly abundant in the membranes of the SVs and responsible for maintaining the vesicular Zn pool in brain (McAllister and Dyck, 2017). Presumably, presynaptic terminals containing from hundreds to thousands of SVs could be reservoirs for Cd accumulating in the SVs due to ZnT3 activity. Furthermore, SV membranes are enriched with anionic negatively-charged lipids that can electrostatically attract bivalent cations, including Cd. Likewise, voltage-gated Ca2+ channels (VGCCs), which are reversibly blocked by Cd, reside densely at the presynaptic site can concentrate Cd, facilitating its uptake. Moreover, Cd may slowly pass into the cytosol through some of the VGCCs. Inside the nerve terminals Cd could affect a plethora of processes, consequently disturbing various presynaptic functions, notably neurotransmitter release. The resulting synaptic defects can produce “devastating signals” which are propagated to the neuronal bodies. Such retrograde pattern of pathology spreading is observed in some neurodegenerative disorders. Recently, we have found that at very low concentrations Cd can desynchronize neurotransmitter release from motor nerve terminals (Tsentsevitsky et al., 2020). A focus on the mechanism behind this phenomenon (Figure 1) can delineate the early events in Cd neurotoxicity and reveal a bridge between Cd action and neurodegeneration. Related Articles | Metrics

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Sex, ApoE4 and Alzheimer’s disease: rethinking drug discovery in the era of precision medicine Manish D. Paranjpe, Jason K Wang, Yun Zhou 2021, 16 (9):  1764-1765.  doi: 10.4103/1673-5374.306070 Abstract ( 183 )   PDF (430KB) ( 42 )   Save Alzheimer’s disease (AD) is the most common cause of dementia and presents with an insidious onset and long prodromal period. Despite billions spent on clinical trials and decades of research, there are currently no disease modifying therapies approved for AD. Related Articles | Metrics

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Predictive models for mild cognitive impairment to Alzheimer’s disease conversion Konstantina Skolariki, Graciella Muniz Terrera, Samuel O. Danso 2021, 16 (9):  1766-1767.  doi: 10.4103/1673-5374.306071 Abstract ( 65 )   PDF (588KB) ( 64 )   Save Alzheimer’s disease (AD) is an irreversible and progressive neurodegenerative disease as well as the most common form of dementia. It usually affects the older population, but early onset AD is still possible (Ritchie et al., 2015). Recent studies propose that AD is a middle-life disease (Ritchie et al., 2015). Regardless the onset of the disease, it is important to note that it takes years for the symptoms to manifest. Specifically, it is believed that AD begins 20 years before the onset of symptoms. AD broadly includes three stages: preclinical AD, mild cognitive impairment (MCI) and dementia (Grassi et al., 2019). Researchers find it challenging to classify the MCI stage. This is partly because although MCI patients appear to have neurological deficits, their symptoms are not advanced enough to meet the AD criteria. MCI is also known as the stage between normal cognitive ageing and dementia and is often thought of as the prodromal stage of AD (Grassi et al., 2019). MCI patients can either remain stable at this stage of the disease or convert to AD. Approximatively 20–40% of MCI patients convert to AD (MCI converters-MCIc; Grassi et al., 2019). Like any other disease, early diagnosis is important. Therefore, identifying subtle brain changes that occur during the MCI-to-AD conversion as early as possible could be the key to the development of more effective treatment plans. Related Articles | Metrics

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Probiotics, prebiotics and their role in Alzheimer’s disease Valeria D’Argenio, Daniela Sarnataro 2021, 16 (9):  1768-1769.  doi: 10.4103/1673-5374.306072 Abstract ( 112 )   PDF (863KB) ( 59 )   Save Accumulation of amyloid and dysfunctional tau proteins in the brain, along with the development of dementia, characterizes Alzheimer’s disease (AD). Although the cause of AD is currently unknown, it has been shown that the onset of the disease, with amyloid-beta peptide (Aβ) accumulation, occurs 10–20 years before the development of the clinical signs; to date, several factors, including lifestyle habits (such as diet and exercise), chronic infection and inflammation, have been related to AD pathogenesis and progression (Sochocka et al., 2019). In addition, the gut microbial dysbiosis seems to be a critical feature able to characterize AD and regulate Aβ production. Indeed, imbalances in gut microbiota can induce aberrant immune responses which, in turn, can disrupt the local and systemic homeostasis of the host (Figure 1A). Moreover, it has been proposed that the gut microbiota, represented by intestinal microflora, may participate in the development of the disease through a network called “gut-brain axis,” that is a bidirectional signaling mechanism between the central nervous system and the intestinal tract. Gut has the largest nervous system, outside the central nervous system, that is in close interplay with the microbiome (MB), the other human genome. The extraordinary complexity of the intestinal ecosystem is represented by more than 100 trillion of microbial cells and their interaction with the intestinal epithelium can influence brain functionality and behavior. Likely, human MB is a promising target for prevention and therapeutic interventions. Indeed, several approaches have been employed with the aim to reduce age-related dysbiosis in both experimental model and in clinical studies. These include strategies to regulate MB via the administration of probiotics and prebiotics, and dietary interventions. The progress of research on the role of intestinal MB in the development of AD will dictate the future for the employment of pro- and prebiotics in the prevention/treatment of AD (D’Argenio and Sarnataro, 2019). Related Articles | Metrics

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Human stem cell-derived microglia will be an indispensable toolbox for Alzheimer’s disease research Tongfei Liu 2021, 16 (9):  1770-1771.  doi: 10.4103/1673-5374.306087 Abstract ( 79 )   PDF (510KB) ( 53 )   Save Alzheimer’s disease (AD) is the most common age-related dementia without cures. Between 2000 and 2017, deaths resulting from AD increased 145%. Based on the latest statistical data, more than 50 million people in the world suffered this devastating disease, which is one of major burdens in modern public health system (Alzheimer’s Association, 2020). Genetic mappings have uncovered numerous susceptibility genetic variants, the vast majority of which are located in noncoding regions of the genome.  Related Articles | Metrics

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Preventative medicine and Alzheimer’s disease: is Alzheimer’s disease risk reduction achievable? Benjamin Sinyor, Richard Isaacson, Christopher Ochner 2021, 16 (9):  1772-1773.  doi: 10.4103/1673-5374.306086 Abstract ( 55 )   PDF (423KB) ( 34 )   Save Alzheimer’s disease (AD) has a multifactorial etiology that has eluded scientists and clinicians for decades. This incomplete understanding of the causal factors likely contributes to the dearth of effective therapeutics available to treat this growing pandemic. Cholinesterase inhibitors such as galantamine, rivastigmine and donepezil are considered frontline treatments but these medications merely treat some of the symptoms associated with AD, rather than curing or even slowing the progression of the disease. This has caused some investigators and clinicians to start exploring the potential to prevent AD. However, the concept of AD has gained widespread acceptance in the clinical community, with many stating that the prevention of AD is impossible. While we would concede that reducing the likelihood of AD development to zero is impossible, these authors argue that significant reduction of the risk of developing AD, particularly in patients at an elevated risk for AD development, is achievable today, and can save many lives and life years.  Related Articles | Metrics

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The molecular implications of a caspase-2-mediated site-specific tau cleavage in tauopathies Peng Liu, Karen H. Ashe 2021, 16 (9):  1774-1775.  doi: 10.4103/1673-5374.306073 Abstract ( 64 )   PDF (231KB) ( 77 )   Save A major focus of current experimental therapies for neurodegenerative diseases is on modulating post-translational modifications (PTMs) of the microtubule-associated protein tau. Tau is a highly soluble, neuronal protein that is comprised of four domains – the N-terminal projection domain, the proline-rich region, the microtubule-binding domain, and the C-terminal tail. As a scaffold protein, tau dynamically interacts with numerous structural and functional biomolecules, such as cytoskeleton and motor proteins, chaperones, enzymes, DNA, RNA, and lipids. Over a dozen types of PTMs, combined with alternative splicing, confer upon tau its enormous structural heterogeneity, which subserves its many (patho-)physiological functions. Related Articles | Metrics

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Phenotypic heterogeneity in amyotrophic lateral sclerosis type 8 and modifying mechanisms of neurodegeneration#br# Danyllo Oliveira, Sergio Verjovski-Almeida, Mayana Zatz 2021, 16 (9):  1776-1778.  doi: 10.4103/1673-5374.303030 Abstract ( 148 )   PDF (487KB) ( 44 )   Save In his accounts “On longevity and shortness of life”, Aristotle considered how diseased states could be interchangeably associated with long and short lifespans. He believed that the presence of opposite elements and the environment were the sole determinants of this variability. Nowadays, also struck by the same phenomenon observed by the Greek philosopher, human geneticists are still trying to define the etiological basis of the phenotypic plasticity in neurodegenerative disorders. Among such diseases, amyotrophic lateral sclerosis (ALS) stands out as a highly heterogeneous condition. Patients affected by ALS commonly start manifesting symptoms such as weakness in the upper or lower limbs, difficulty in climbing stairs, fasciculations and loss of muscular mass. As the disease progresses, patients become wheelchair-bound and bulbar signs such as dysarthria and dysphagia become more pronounced. Death occurs on average after 3 years of onset, mainly due to respiratory failure (Renton et al., 2014). However, this canonical course is frequently variable, with a myriad of phenotypic alterations (Swinnen and Robberecht, 2014). Here, we describe different aspects of amyotrophic lateral sclerosis type 8 (ALS8) clinical variability, both in terms of clinical manifestations and in rate of disease progression. Then, we outline our recent work on ALS8 patients (Oliveira et al., 2020), in which we tried to address the molecular underpinnings of clinical progression variation in the patients we studied. We were able to rule out well-described genetic modifiers, such as EPHA4 and UNC13A, and potential copy number variation alterations. Interestingly, both cell death rates and energetic metabolism appeared to be different among the severe ALS8, mild ALS8 and controls, suggesting an attenuation of pathological process in the less affected patients. Whole transcriptomic analysis of induced pluripotent stem cells (iPSCs)-derived motor neurons pointed that both “mild patients” presented 43 upregulated and 66 downregulated genes, when compared to controls and the “severe” group. Interestingly, most of the identified genes were associated with protein synthesis and protein targeting to endoplasmic reticulum (ER). Expression of protein translation markers’ pMTOR, 4EBP1 and RPS6 were found to be high in the mild ALS8 individuals, when compared to both controls and the severe group. To sum up, our data point that mitigating factors are most likely preventing neurodegeneration in ALS8 through maintenance of protein synthesis. Further studies, assessing the relationship among these potential genetic modifiers and the pathophysiology in ALS8, are fundamental. They might shed light on venues for treatment of this devastating disease.  Related Articles | Metrics

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A central role for mitochondrial-derived vesicles in the innate immune response: implications for Parkinson’s disease Thomas A. Ryan, David A. Tumbarello 2021, 16 (9):  1779-1780.  doi: 10.4103/1673-5374.306074 Abstract ( 76 )   PDF (655KB) ( 69 )   Save Mitochondria are well known for their function in energy production; however they also play a crucial role in phospholipid transfer, inflammation, calcium balance and cell death, positioning them as a central regulator of cellular homeostasis. The cell therefore relies on quality control mechanisms to limit mitochondrial damage and the production of harmful reactive oxygen species (ROS). To date, numerous mitochondrial quality control (mitoQC) pathways have been defined, with mitophagy, the autophagic degradation of entire mitochondria, being the most extensively studied. Locally directed repair pathways also exist and we have recently elucidated key mechanisms of one of these mitochondrial stress response pathways regulated by the endosomal adaptor – Toll-interacting protein (Tollip) (Ryan et al., 2020). In this pathway, damaged mitochondrial proteins and lipids are selectively transported as mitochondrial-derived vesicles (MDVs) into the endolysosomal system to facilitate cargo degradation. However, these MDVs are heterogeneous, with each discrete cargo trafficked via a specific route and destination. Since their initial identification demonstrating the segregation of the outer membrane mitochondrial-anchored protein ligase and its subsequent shuttling to peroxisomes (Neuspiel et al., 2008), MDVs have been shown to incorporate a host of different proteins from the inner and outer membranes or matrix. Indeed, it appears their cargo and potentially their membrane composition defines the trafficking machinery required, the particular route taken and their destination.  Related Articles | Metrics

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Free ubiquitin: a novel therapeutic target for neurodegenerative diseases Chul-Woo Park, Kwon-Yul Ryu 2021, 16 (9):  1781-1782.  doi: 10.4103/1673-5374.306075 Abstract ( 75 )   PDF (586KB) ( 29 )   Save Neurodegenerative diseases are widespread and the increasing number of patients with these diseases can no longer be ignored. Dementia is a symptom of many neurodegenerative diseases, and Alzheimer’s disease (AD), which is associated with memory and learning disabilities, accounts for approximately 60 to 80% of all dementia cases (Wyss-Coray, 2016). In the United States, it is estimated that 13.8 million people over the age of 65 years will be affected by AD in 2050 (Alzheimer’s Association, 2020). Moreover, the onset of AD is closely related to aging, and as such, AD occurs at a frequency of 50% in people over the age of 95 years. Although progress in medical science has contributed to an increase in the average human lifespan, advances in AD treatment strategies have been unable to keep up with the increasing number of elderly individuals. Most drugs targeting AD merely delay the progression of the disease, without providing a bona fide treatment. Moreover, because the life expectancy of AD patients is 3 to 11 years after diagnosis, an effective therapy for AD is urgently required (Alzheimer’s Association, 2020). Related Articles | Metrics

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The therapeutic potential of nerve growth factor combined with blood-brain barrier modulation by focused ultrasound for neurodegenerative disorders  Kristiana Xhima, Isabelle Aubert 2021, 16 (9):  1783-1785.  doi: 10.4103/1673-5374.306076 Abstract ( 66 )   PDF (622KB) ( 35 )   Save Nerve growth factor (NGF) is a neurotrophic factor critical for cholinergic neuronal survival, phenotypic maintenance and plasticity in the mammalian brain. NGF has been implicated in the pathogenesis of neurodegenerative disorders, with direct administration of NGF into the brain capable of facilitating neuroprotection and repair. To date, NGF has been proposed as a potential therapy for Alzheimer’s disease (AD) and Parkinson’s disease due to its regenerative effects on cholinergic neurons located in the basal forebrain and striatum, respectively. In other neurodegenerative diseases, including progressive supranuclear palsy, amyotrophic lateral sclerosis (ALS), vascular dementia, Lewy body dementia and frontotemporal lobar dementia, emerging evidence has revealed the impact of cholinergic dysfunction on clinical outcomes, thereby supporting the therapeutic potential of NGF. In this perspective, we will review the current challenges of NGF-related therapy for clinical use and address the relevance of magnetic resonance imaging (MRI)-guided focused ultrasound (MRIgFUS)-induced blood-brain barrier (BBB) permeability enhancement for the delivery of NGF-related compounds and brain repair. Related Articles | Metrics

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Metabolomic profiling provides new insights into blood-brain barrier regulation Sheng-Fu Huang, Omolara O. Ogunshola 2021, 16 (9):  1786-1787.  doi: 10.4103/1673-5374.306077 Abstract ( 78 )   PDF (216KB) ( 41 )   Save Early blood-brain barrier (BBB) disturbance contributes to many different neurological diseases including Alzheimer’s disease, Parkinson’s disease and stroke, particularly in the etiology and early stages (Abbott et al., 2010). Although supporting barrier function is a potential strategy to radically improve treatment efficacy and disease outcome, ways to achieve this objective remain elusive. Being a sophisticated system consisting of multicellular interactions, better understanding of how individual cell-specific molecular and metabolic changes modulate the unit responses would provide significant insight. In this regard, we have generated severity-related metabolomic databases to reveal fundamental BBB cell-specific processes likely to occur physiologically and during disease (Huang et al., 2020a). This resource provides new opportunities for future clinical applications. Related Articles | Metrics

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Zeb2 directs EMT-like processes that underlies the glial response to injury Ana L. Vivinetto, John W. Cave 2021, 16 (9):  1788-1790.  doi: 10.4103/1673-5374.306078 Abstract ( 68 )   PDF (829KB) ( 36 )   Save In both the peripheral and central nervous systems (PNS and CNS, respectively), glial cells are critical for the wound healing response to injury. However, the glial cell types that orchestrate the response and the extent to which the repair process is successful are different between the PNS and CNS. Nevertheless, there are several cellular features shared by PNS and CNS glia that suggest there are also mutual molecular mechanisms that underlie the injury responses. Establishing these shared molecular mechanisms not only expands our fundamental understanding of how the nervous system responds to injury, but it also facilitates the development of strategies to manipulate the glial responses in order to better protect and restore neurological function. Related Articles | Metrics

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Neuroimmune actions in the brain and interactions with the effects of alcohol Donna L. Gruol 2021, 16 (9):  1791-1792.  doi: 10.4103/1673-5374.306079 Abstract ( 74 )   PDF (542KB) ( 31 )   Save Early studies (1990’s) on the neurological consequences of human immunodeficiency virus-1 (HIV-1) infection in the brain were instrumental in establishing that specific brain cell types can function as an innate immune system within the brain and in that role influence cognitive function (Kaul et al., 2005). It is now known that this system, referred to as the neuroimmune system, is an important signaling system that plays a key role in brain function under both physiological and pathophysiological conditions. The principal cellular components of the neuroimmune system are the glial cells, primarily astrocytes and microglia. Astrocytes are the most populous cell type in the brain, whereas microglia comprise about 10% of the brain cells. These cell types produce many of the same chemical signaling factors commonly associated with the peripheral immune system, including small proteins such as the cytokine interleukin-6 (IL-6) and the chemokines C-C motif chemokine 2 (CCL2) and C-X-C Motif Chemokine Ligand 10 (CXCl10), the focus of our studies and the neuroimmune factors that are used as examples in this short perspective.  Related Articles | Metrics

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Asymmetric dimethylarginine-induced oxidative damage leads to cerebrovascular dysfunction Mushfiquddin Khan, Inderjit Singh, Jeseong Won 2021, 16 (9):  1793-1794.  doi: 10.4103/1673-5374.306080 Abstract ( 80 )   PDF (596KB) ( 25 )   Save Asymmetric dimethylarginine (ADMA) and its enantiomer, symmetric dimethylarginine (SDMA), are naturally-occurring methylated metabolites of the L-arginine amino acid moiety of proteins followed by proteolysis (Grosse et al., 2020). These metabolites were first identified in human urine in 1970. At present, several other L-arginine metabolic products are known to occur naturally and invoke their distinct biological effects in health and disease. It is well established that both these metabolites, ADMA and SDMA, compete with L-arginine as a substrate of nitric oxide synthases (NOS). ADMA and SDMA inhibit and uncouple NOS, leading to the formation of superoxide (O2–) rather than nitric oxide (NO). Thus, these metabolites are linked to a dysregulated NO metabolome in neuronal/inflammatory cells, and this dysregulation is implicated in the neurodegeneration that follows brain trauma. Under pathological conditions, ADMA/SDMA is secreted and therefore found in excess in circulation and picked up by endothelial cells. In endothelial cells, ADMA uncouples endothelial NOS (eNOS). Uncoupled NOS enzymes produce superoxide, and normal NOS form NO in the same compartment, resulting in the formation of increasing amounts of peroxynitrite (ONOO–). As a consequence, the bioavailability of NO is decreased. This reduced level of NO and excessive accumulation of ONOO– causes a reduction in cerebral blood flow (CBF) and thus hypoxia/hypoperfusion. This “ADMA-induced uncoupling” of eNOS is maintained by sustained and prolonged production of ONOO– in a vicious cycle (Figure 1). This cycle leads to secondary injury to the neurovascular unit and, thus, cerebrovascular dysfunction and functional deficits (Choi et al., 2020). Because the role of high levels of ADMA has been established in cerebrovascular pathologies, including Alzheimer’s disease and stroke (Choi et al., 2020; Grosse et al., 2020; Selley, 2003), the discussion in this perspective is limited to ADMA/SDMA-induced aberrant activity of eNOS and its consequences on cellular functions and functional deficits. Related Articles | Metrics

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Retrograde nerve growth factor signaling abnormalities and the pathogenesis of familial dysautonomia Soumitra Ghosh, Lin Li, Warren G. Tourtellotte 2021, 16 (9):  1795-1796.  doi: 10.4103/1673-5374.306081 Abstract ( 64 )   PDF (607KB) ( 39 )   Save Familial dysautonomia (FD, OMIM 223900; also known as HSAN III or Riley-Day syndrome) is the most prevalent form of hereditary sensory and autonomic neuropathy (HSAN; Axelrod et al., 1974). Patients suffering from autonomic and sensory nervous system impairment have no available effective treatment and the average age of death is approximately 24 years. FD is a congenital and progressive disease almost exclusively caused by inheritance of a single nucleotide mutation in the splice acceptor site in intron 20 of the ELP1 (IKBKAP) gene. The germline mutation leads to particularly poor transcript splicing in sympathetic and some sensory neurons which in turn leads to a translational frame shift, introduction of a non-sense codon, and premature truncation and degradation of the encoded Elp1 protein (Anderson et al., 2001; Slaugenhaupt et al., 2001). The resulting low level of Elp1 protein in sympathetic and some sensory neurons leads to their death and results in physiologic sympathetic and sensory nervous system dysfunction (Tourtellotte, 2016). Several laboratories have developed transgenic mice to recapitulate major features of the disease to provide experimental tools to better study disease pathophysiology and potential therapy (Hims et al., 2007; Chen et al., 2009; Jackson et al., 2014; Morini et al., 2016), but how Elp1 functions in disease relevant neurons has not been precisely defined until recently. Related Articles | Metrics

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State and perspectives on flavonoid neuroprotection against aminochrome-induced neurotoxicity Victor Silva, Juan Segura-Aguilar 2021, 16 (9):  1797-1798.  doi: 10.4103/1673-5374.306082 Abstract ( 62 )   PDF (398KB) ( 374 )   Save Parkinson’s disease (PD) motor symptoms are induced by the loss of dopaminergic neurons containing neuromelanin in the nigrostriatal system. The exact mechanism that triggers the degeneration of the nigrostriatal neurons is still unknown but there is general consensus in the scientific community that mitochondrial dysfunction, alpha-synuclein aggregation to neurotoxic oligomers, protein degradation dysfunction of both lysosomal and proteasomal systems, endoplasmic reticulum stress, neuroinflammation and oxidative stress are involved in the degeneration of dopaminergic neurons containing neuromelanin. The pigmentation of dopaminergic neurons in the substantia nigra results from dopamine oxidation to neuromelanin. The hydroxyl groups of the dopamine catechol structure oxidize to carbonyl groups generating quinones. Dopamine oxidizes to dopamine ortho-quinone that is completely unstable at physiological pH and cyclizes spontaneously to aminochrome. Aminochrome is the most stable quinone formed during dopamine oxidation to neuromelanin; it can be one- or two-electron reduced by flavoenzymes or form adducts with proteins such as alpha synuclein, parkin, dopamine transporter, and other proteins. Interestingly, aminochrome has been reported to induce mitochondrial dysfunction, alpha-synuclein aggregation to neurotoxic oligomers, protein degradation dysfunction, endoplasmic reticulum stress, neuroinflammation and oxidative stress (Figure 1; for a review, see Segura-Aguilar, 2019). Therefore, we have proposed that aminochrome is the endogenous neurotoxin formed in neurons containing neuromelanin that triggers the degeneration of the nigrostriatal neurons in PD. Related Articles | Metrics

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Generation of patient-specific motor neurons in modeling movement diseases Baojin Ding 2021, 16 (9):  1799-1800.  doi: 10.4103/1673-5374.306083 Abstract ( 66 )   PDF (1095KB) ( 74 )   Save Generating neurons from human induced pluripotent stem cells (hiPSCs) overcomes the limited access to human brain tissues and greatly facilitates the research in neuroscience (Karagiannis et al., 2019). However, it is still a big challenge to obtain a particular neuronal subtype with high purity and yield to conduct certain studies, such as determining the pathogenesis of diseased neurons using biochemical approaches. Motor neurons (MNs) are a specialized neuronal subtype responsible for innervating musculature in the periphery and governing both autonomic and volitional movements. Dysfunctions in MNs are implicated in a variety of movement diseases, such as amyotrophic lateral sclerosis (ALS), progressive muscular atrophy, and dystonia (Sances et al., 2016; Ding et al., 2020b). ALS belongs to MN diseases, which are caused by gradual degeneration and death of MNs in the brain (upper MNs) and/or in the spinal cord (lower MNs). Several pathogenic mechanisms are involved in ALS, including glutamate excitotoxicity, dysregulated interactions between neurons and glial cells, intracytoplasmic and intranuclear aggregation of certain proteins and RNAs, impaired nucleocytoplasmic transport, and changes in the axon terminals and neuromuscular junctions (NMJs) (Sances et al., 2016). So far, there are no specific treatments available to cure these diseases due to unclear pathophysiological mechanisms. Generation of patient-specific MNs will provide valuable in vitro model systems in deciphering the pathogenesis of these diseases. Recently, we have developed an approach by which functional MNs could be generated from hiPSCs via lentiviral delivery of three transcription factors (Figure 1). These MNs robustly expressed generic neuronal markers, MN-specific markers, and showed electrical maturation and firing of action potentials within 3 weeks (Sepehrimanesh and Ding, 2020). Compared to previous methods (Tang et al., 2017), this approach significantly improved the neuronal survival, purity, and yield, making it feasible to obtain abundant patient-specific MNs for biochemical studies in modeling movement diseases. Related Articles | Metrics

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Microglial exosomes in retinal neuroinflammation: focus in glaucoma Inês Dinis Aires, Ana Raquel Santiago 2021, 16 (9):  1801-1802.  doi: 10.4103/1673-5374.306084 Abstract ( 70 )   PDF (388KB) ( 39 )   Save Glaucoma is a leading cause of irreversible blindness, expected to affect 140 million people worldwide by the year 2040. The pathophysiology of glaucoma involves retinal ganglion cell loss, optic nerve atrophy and cupping of the optic disk, culminating in visual field loss (Boia et al., 2020). Glaucoma is a multifactorial disease in which increased intraocular pressure is the main risk factor. Therefore, the majority of experimental models are based on ocular hypertension that mimics in some extend the features of clinical glaucoma (Aires et al., 2017). Elevated hydrostatic pressure is also suitable to disentangle the cellular mechanisms involved in disease progression, using cultured cells or tissues (Aires et al., 2017).  Related Articles | Metrics

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Is neurotrophic factor a second language that neuron and tooth speak? Nan Xiao 2021, 16 (9):  1803-1804.  doi: 10.4103/1673-5374.306068 Abstract ( 71 )   PDF (214KB) ( 38 )   Save Neurotrophic factors are growth factors that can nourish neurons and promote neuron survival and regeneration. Dental origin mesenchymal stem cells express various neurotrophic factors during tooth development and the expression level changes during cell differentiation. Dental origin stem cells are reported to mediate neuronal tissue repair by increasing the secretion of neurotrophic factors. On the other hand, neurotrophic factors promote survival, proliferation, angiogenesis, migration and neuron - like differentiation in dental origin stem cells, which can be applied to the dental clinic. The prospective emphasizes the connection of the dental pulp stem cells and nervous system through neurotrophic factors. Related Articles | Metrics

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Recent advancements toward gapless neural-electrode interface post-cochlear implantation Crystal Y. Li, Rahul Mittal, Jenna Bergman, Jeenu Mittal, Adrien A. Eshraghi 2021, 16 (9):  1805-1806.  doi: 10.4103/1673-5374.306085 Abstract ( 111 )   Save Cochlear implants (CI) are widely used to provide auditory rehabilitation to individuals with moderate to severe sensorineural hearing loss (Eshraghi et al., 2012). The scala tympani (ST) of the cochlea is the site of implantation of the intracochlear electrode array. In a healthy, normal ear, the cell bodies of the spiral ganglion neurons (SGNs) reside in Rosenthal’s canal, a small cavity adjacent to the ST. SGNs have a peripheral neurite that projects to the hair cells on the basilar membrane of the organ of corti, and a central axon that projects to the brainstem via the auditory nerve (Landry et al., 2013). From SGN cell bodies, the dendrites extend through the modiolus and the osseous spiral lamina to make synaptic contact with hair cells in the organ of corti (Rusznák et al., 2009). In severe to profound deafness, the cochlea has few to no hair cells (Shibata et al., 2010). A CI helps overcome the problem of functional hair cells by directly stimulating the SGNs in the inner ear via short biphasic electric pulses (Li et al., 2017). Related Articles | Metrics

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Do statins reduce the mortality rate in stroke patients treated with systemic thrombolysis in a 5-year single-center study? Toralf Brüning, Mohamed Al-Khaled 2021, 16 (9):  1807-1812.  doi: 10.4103/1673-5374.306088 Abstract ( 88 )   PDF (366KB) ( 72 )   Save The present study investigated the association between pre-treatment with a cholesterol-lowering drug (statin) or new setting hereon and the effect on the mortality rate in patients with acute ischemic stroke who received intravenous systemic thrombolysis. During a 5-year period (starting in October 2008), 542 consecutive stroke patients who received intravenous systemic thrombolysis with recombinant tissue plasminogen activator (rt-PA) at the Department of Neurology, University Hospital Schleswig-Holstein, Campus Lübeck, Germany, were included. Patients were characterized according to statins. The primary endpoint was mortality; it was assessed twice: in hospital and 3 months after discharge. The secondary outcome was the rate of symptomatic intracerebral hemorrhage. Of the 542 stroke patients examined (mean age 72 ± 13 years; 51% women, mean National Institutes of Health Stroke Scale (NIHSS) score 11), 138 patients (25.5%) had been pre-treated with statin, while in 190 patients (35.1%) statin therapy was initiated during their stay in hospital, whereas 193 (35.6%) never received statins. Patients pre-treated with statin were older and more frequently had previous illnesses (arterial hypertension, diabetes mellitus and previous cerebral infarctions), but were comparably similarly affected by the stroke (NIHSS 11 vs. 11; P = 0.76) compared to patients who were not on statin treatment at the time of cerebral infarction. Patients pretreated with statin did not differ in 3-month mortality from those newly treated to a statin (7.6% vs. 8%; P = 0.9).  Interestingly, the group of patients pretreated with statin showed a lower rate of in hospital mortality (6.6% vs. 17.0; P = 0.005) and 3-month mortality (10.7% vs. 23.7%; P = 0.005) than the group of patients who had no statin treatment at all. The same effect was seen for patients newly adjusted to a statin during the hospital stay compared to patients who did not receive statins (3-month mortality: 7.1% vs. 23.7%; P < 0.001). With a good functional outcome (mRS ≤ 2), 60% of patients were discharged, the majority (69.6%; P < 0.001) of whom received a statin at discharge.  The rate of symptomatic intracerebral hemorrhages in the course of cranial computed tomography was independent of whether the patients were pretreated with a statin or not (8.8% vs. 8.7%,  P = 0.96).  Pre-treatment with statin as well as new adjustment could reveal positive effect on prognosis of intravenous thrombolyzed stroke patients. Further investigations are required. The study was approved by the Ethic Committee of the University of Lübeck (approval No. 4-147). Related Articles | Metrics

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Mitochonic acid 5 regulates mitofusin 2 to protect microglia Jian Tan, Shuang-Xi Chen, Qing-Yun Lei, Shan-Qing Yi, Na Wu, Yi-Lin Wang, Zi-Jian Xiao, Heng Wu 2021, 16 (9):  1813-1820.  doi: 10.4103/1673-5374.306094 Abstract ( 116 )   PDF (3570KB) ( 136 )   Save Microglial apoptosis is associated with neuroinflammation and no effective strategies are currently available to protect microglia against inflammation-induced apoptosis. Mouse microglial BV-2 cells (5 × 106) were incubated with 10 μg/mL lipopolysaccharides for 12 hours to mimic an inflammatory environment. Then the cells were co-cultured with mitochonic acid 5 (MA-5) for another 12 hours. MA-5 improved the survival of lipopolysaccharide-exposed cells. MA-5 decreased the activity of caspase-3, which is associated with apoptosis. MA-5 reduced the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells, and increased adenosine triphosphate levels in cells. MA-5 decreased the open state of the mitochondrial permeability transition pore and reduced calcium overload and diffusion of second mitochondria-derived activator of caspase (Smac). MA-5 decreased the expression of apoptosis-related proteins (mitochondrial Smac, cytoplasmic Smac, pro-caspase-3, cleaved-caspase-3, and caspase-9), and increased the levels of anti-apoptotic proteins (Bcl2 and X-linked inhibitor of apoptosis protein), mitochondria-related proteins (mitochondrial fusion protein 2, mitochondrial microtubule-associated proteins 1A/1B light chain 3B II), and autophagy-related proteins (Beclin1, p62 and autophagy related 5). However, MA-5 did not promote mitochondrial homeostasis or decrease microglial apoptosis when Mitofusin 2 expression was silenced. This shows that MA-5 increased Mitofusin 2-related mitophagy, reversed cellular energy production and maintained energy metabolism in BV-2 cells in response to lipopolysaccharide-induced inflammation. These findings indicate that MA-5 may promote the survival of microglial cells via Mitofusin 2-related mitophagy in response to lipopolysaccharide-induced inflammation. Related Articles | Metrics

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Dental pulp stem cells stimulate neuronal differentiation of PC12 cells Nessma Sultan, Laila E. Amin, Ahmed R. Zaher, Mohammed E. Grawish, Ben A. Scheven 2021, 16 (9):  1821-1828.  doi: 10.4103/1673-5374.306089 Abstract ( 139 )   PDF (1841KB) ( 104 )   Save Dental pulp stem cells (DPSCs) secrete neurotrophic factors which may play an important therapeutic role in neural development, maintenance and repair. To test this hypothesis, DPSCs-conditioned medium (DPSCs-CM) was collected from 72 hours serum-free DPSCs cultures. The impact of DPSCs-derived factors on PC12 survival, growth, migration and differentiation was investigated. PC12 cells were treated with nerve growth factor (NGF), DPSCs-CM or co-cultured with DPSCs using Transwell inserts for 8 days. The number of surviving cells with neurite outgrowths and the length of neurites were measured by image analysis. Immunocytochemical staining was used to evaluate the expression of neuronal markers NeuN, microtubule associated protein 2 (MAP-2) and cytoskeletal marker βIII-tubulin. Gene expression levels of axonal growth-associated protein 43 and synaptic protein Synapsin-I, NeuN, MAP-2 and βIII-tubulin were analysed by quantitative polymerase chain reaction (qRT-PCR). DPSCs-CM was analysed for the neurotrophic factors (NGF, brain-derived neurotrophic factor [BDNF], neurotrophin-3, and glial cell-derived neurotrophic factor [GDNF]) by specific ELISAs. Specific neutralizing antibodies against the detected neurotrophic factors were used to study their exact role on PC12 neuronal survival and neurite outgrowth extension. DPSCs-CM significantly promoted cell survival and induced the neurite outgrowth confirmed by NeuN, MAP-2 and βIII-tubulin immunostaining. Furthermore, DPSCs-CM was significantly more effective in stimulating PC12 neurite outgrowths than live DPSCs/PC12 co-cultures over the time studied. The morphology of induced PC12 cells in DPSCs-CM was similar to NGF positive controls; however, DPSCs-CM stimulation of cell survival was significantly higher than what was seen in NGF-treated cultures. The number of surviving PC12 cells treated with DPSCs-CM was markedly reduced by the addition of anti-GDNF, whilst PC12 neurite outgrowth was significantly attenuated by anti-NGF, anti-GDNF and anti-BDNF antibodies. These findings demonstrated that DPSCs were able to promote PC12 survival and differentiation. DPSCs-derived NGF, BDNF and GDNF were involved in the stimulatory action on neurite outgrowth, whereas GDNF also had a significant role in promoting PC12 survival. DPSCs-derived factors may be harnessed as a cell-free therapy for peripheral nerve repair. All experiments were conducted on dead animals that were not sacrificed for the purpose of the study. All the methods were carried out in accordance with Birmingham University guidelines and regulations and the ethical approval is not needed. Related Articles | Metrics

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Graphene oxide-composited chitosan scaffold contributes to functional recovery of injured spinal cord in rats Bing Yang, Pang-Bo Wang, Ning Mu, Kang Ma, Shi Wang, Chuan-Yan Yang, Zhong-Bing Huang, Ying Lai, Hua Feng, Guang-Fu Yin, Tu-Nan Chen, Chen-Shi Hu 2021, 16 (9):  1829-1835.  doi: 10.4103/1673-5374.306095 Abstract ( 103 )   PDF (3561KB) ( 103 )   Save The study illustrates that graphene oxide nanosheets can endow materials with continuous electrical conductivity for up to 4 weeks. Conductive nerve scaffolds can bridge a sciatic nerve injury and guide the growth of neurons; however, whether the scaffolds can be used for the repair of spinal cord nerve injuries remains to be explored. In this study, a conductive graphene oxide composited chitosan scaffold was fabricated by genipin crosslinking and lyophilization. The prepared chitosan-graphene oxide scaffold presented a porous structure with an inner diameter of 18–87 μm, and a conductivity that reached 2.83 mS/cm because of good distribution of the graphene oxide nanosheets, which could be degraded by peroxidase. The chitosan-graphene oxide scaffold was transplanted into a T9 total resected rat spinal cord. The results show that the chitosan-graphene oxide scaffold induces nerve cells to grow into the pores between chitosan molecular chains, inducing angiogenesis in regenerated tissue, and promote neuron migration and neural tissue regeneration in the pores of the scaffold, thereby promoting the repair of damaged nerve tissue. The behavioral and electrophysiological results suggest that the chitosan-graphene oxide scaffold could significantly restore the neurological function of rats. Moreover, the functional recovery of rats treated with chitosan-graphene oxide scaffold was better than that treated with chitosan scaffold. The results show that graphene oxide could have a positive role in the recovery of neurological function after spinal cord injury by promoting the degradation of the scaffold, adhesion, and migration of nerve cells to the scaffold. This study was approved by the Ethics Committee of Animal Research at the First Affiliated Hospital of Third Military Medical University (Army Medical University) (approval No. AMUWEC20191327) on August 30, 2019.  Related Articles | Metrics

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VX-765 reduces neuroinflammation after spinal cord injury in mice Jing Chen, Yu-Qing Chen, Yu-Jiao Shi, Shu-Qin Ding, Lin Shen, Rui Wang, Qi-Yi Wang, Cheng Zha, Hai Ding, Jian-Guo Hu, He-Zuo Lü 2021, 16 (9):  1836-1847.  doi: 10.4103/1673-5374.306096 Abstract ( 102 )   PDF (7475KB) ( 50 )   Save Inflammation is a major cause of neuronal injury after spinal cord injury. We hypothesized that inhibiting caspase-1 activation may reduce neuroinflammation after spinal cord injury, thus producing a protective effect in the injured spinal cord. A mouse model of T9 contusive spinal cord injury was established using an Infinite Horizon Impactor, and VX-765, a selective inhibitor of caspase-1, was administered for 7 successive days after spinal cord injury. The results showed that: (1) VX-765 inhibited spinal cord injury-induced caspase-1 activation and interleukin-1β and interleukin-18 secretion. (2) After spinal cord injury, an increase in M1 cells mainly came from local microglia rather than infiltrating macrophages. (3) Pro-inflammatory Th1Th17 cells were predominant in the Th subsets. VX-765 suppressed total macrophage infiltration, M1 macrophages/microglia, Th1 and Th1Th17 subset differentiation, and cytotoxic T cells activation; increased M2 microglia; and promoted Th2 and Treg differentiation. (4) VX-765 reduced the fibrotic area, promoted white matter myelination, alleviated motor neuron injury, and improved functional recovery. These findings suggest that VX-765 can reduce neuroinflammation and improve nerve function recovery after spinal cord injury by inhibiting caspase-1/interleukin-1β/interleukin-18. This may be a potential strategy for treating spinal cord injury. This study was approved by the Animal Care Ethics Committee of Bengbu Medical College (approval No. 2017-037) on February 23, 2017.  Related Articles | Metrics

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High mobility group box 1 mediates inflammatory response of astrocytes via cyclooxygenase 2/prostaglandin E2 signaling following spinal cord injury Hong-Hua Song, Tian-Cheng Song, Ting Yang, Chun-Shuai Sun, Bing-Qiang He, Hui Li, Ying-Jie Wang, Yu Li, Hao Wu, Yu-Ming Hu, Yong-Jun Wang 2021, 16 (9):  1848-1855.  doi: 10.4103/1673-5374.303039 Abstract ( 89 )   PDF (3371KB) ( 79 )   Save High mobility group box 1 (HMGB1) interacts with pattern-recognition receptors of immune cells to activate the inflammatory response. Astrocytes play a positive role in the inflammatory response of the central nervous system by expressing a broad range of pattern-recognition receptors. However, the underlying relationship between HMGB1 and the inflammatory reaction of astrocytes remains unclear. In this study, we established rat models of spinal cord injury via laminectomy at the T8–10 level, and the injured spinal cord was subjected to transcriptome sequencing. Our results showed that the HMGB1/Toll-like receptor 4 (TLR4) axis was involved in the activation of astrocyte inflammatory response through regulation of cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2) signaling. Both TLR4 and COX2 were distributed in astrocytes and showed elevated protein levels following spinal cord injury. Stimulation of primary astrocytes with recombinant HMGB1 showed that COX2 and microsomal PGE synthase (mPGES)-1, rather than COX1, mPGES-2, or cytosolic PGE synthase, were significantly upregulated. Accordingly, PGE2 production in astrocytes was remarkably increased in response to recombinant HMGB1 challenges. Pharmacologic blockade of TLR2/4 attenuated HMGB1-mediated activation of the COX2/PGE2 pathway. Interestingly, HMGB1 did not impact the production of tumor necrosis factor-α or interleukin-1β in astrocytes. Our results suggest that HMGB1 mediates the astrocyte inflammatory response through regulating the COX2/PGE2 signaling pathway. The study was approved by the Laboratory Animal Ethics Committee of Nantong University, China (approval No. 20181204-001) on December 4, 2018. Related Articles | Metrics

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Characteristics of neural growth and cryopreservation of the dorsal root ganglion using three-dimensional collagen hydrogel culture versus conventional culture Ze-Kai Cui, Shen-Yang Li, Kai Liao, Zhi-Jie Wang, Yong-Long Guo, Luo-Sheng Tang, Shi-Bo Tang, Jacey Hongjie Ma, Jian-Su Chen 2021, 16 (9):  1856-1864.  doi: 10.4103/1673-5374.306097 Abstract ( 132 )   PDF (7537KB) ( 51 )   Save In vertebrates, most somatosensory pathways begin with the activation of dorsal root ganglion (DRG) neurons. The development of an appropriate DRG culture method is a prerequisite for establishing in vitro peripheral nerve disease models and for screening therapeutic drugs. In this study, we compared the changes in morphology, molecular biology, and transcriptomics of chicken embryo DRG cultured on tissue culture plates (T-DRG) versus three-dimensional collagen hydrogels (C-DRG). Our results showed that after 7 days of culture, the transcriptomics of T-DRG and C-DRG were quite different. The upregulated genes in C-DRG were mainly related to neurogenesis, axon guidance, and synaptic plasticity, whereas the downregulated genes in C-DRG were mainly related to cell proliferation and cell division. In addition, the genes related to cycles/pathways such as the synaptic vesicle cycle, cyclic adenosine monophosphate signaling pathway, and calcium signaling pathway were activated, while those related to cell-cycle pathways were downregulated. Furthermore, neurogenesis- and myelination-related genes were highly expressed in C-DRG, while epithelial–mesenchymal transition-, apoptosis-, and cell division-related genes were suppressed. Morphological results indicated that the numbers of branches, junctions, and end-point voxels per C-DRG were significantly greater than those per T-DRG. Furthermore, cells were scattered in T-DRG and more concentrated in C-DRG, with a higher ratio of 5-ethynyl-2′-deoxyuridine (EdU)-positive cells in T-DRG compared with C-DRG. C-DRG also had higher S100 calcium-binding protein B (S100B) and lower α-smooth muscle actin (α-SMA) expression than T-DRG, and contained fewer terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells after 48 hours of serum starvation. After cryopreservation, C-DRG maintained more intact morphological characteristics, and had higher viability and less TUNEL-positive cells than T-DRG. Furthermore, newly formed nerve bundles were able to grow along the existing Schwann cells in C-DRG. These results suggest that C-DRG may be a promising in vitro culture model, with better nerve growth and anti-apoptotic ability, quiescent Schwann cells, and higher viability. Results from this study provide a reference for the construction, storage, and transportation of tissue-engineered nerves. The study was approved by the Ethics Committee of Aier School of Ophthalmology, Central South University, China (approval No. 2020-IRB16), on March 15, 2020. Related Articles | Metrics

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Transcriptomic analysis reveals essential microRNAs after peripheral nerve injury Yu Wang, Shu Wang, Jiang-Hong He 2021, 16 (9):  1865-1870.  doi: 10.4103/1673-5374.306092 Abstract ( 123 )   PDF (1749KB) ( 121 )   Save Studies have shown that microRNAs (miRNAs) mediate posttranscriptional regulation of target genes and participate in various physiological and pathological processes, including peripheral nerve injury. However, it is hard to select key miRNAs with essential biological functions among a large number of differentially expressed miRNAs. Previously, we collected injured sciatic nerve stumps at multiple time points after nerve crush injury, examined gene changes at different stages (acute, sub-acute, and post-acute), and obtained mRNA expression profiles. Here, we jointly analyzed mRNAs and miRNAs, and investigated upstream miRNAs of differentially expressed mRNAs using Ingenuity Pathway Analysis bioinformatic software. A total of 31, 42, 30, and 23 upstream miRNAs were identified at 1, 4, 7, and 14 days after rat sciatic nerve injury, respectively. Temporal expression patterns and biological involvement of commonly involved upstream miRNAs (miR-21, let-7, miR-223, miR-10b, miR-132, miR-15b, miR-127, miR-29a, miR-29b, and miR-9) were then determined at multiple time points. Expression levels of miR-21, miR-132, miR-29a, and miR-29b were robustly increased after sciatic nerve injury. Biological processes involving these miRNAs include multicellular organismal response to stress, positive regulation of the epidermal growth factor receptor signaling pathway, negative regulation of epithelial cell differentiation, and regulation of myocardial tissue growth. Moreover, we constructed mechanistic networks of let-7, miR-21, and miR-223, the most significantly involved upstream miRNAs. Our findings reveal that multiple upstream miRNAs (i.e., let-7, miR-21, and miR-223) were associated with gene expression changes in rat sciatic nerve stumps after nerve injury, and these miRNAs play an important role in peripheral nerve regeneration. This study was approved by the Experimental Animal Ethics Committee of Jiangsu Province of China (approval No. 20190303-18) on March 3, 2019. Related Articles | Metrics

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Visual response characteristics of neurons in the second visual area of marmosets Yin Yang, Ke Chen, Marcello G. P. Rosa, Hsin-Hao Yu, Li-Rong Kuang, Jie Yang 2021, 16 (9):  1871-1876.  doi: 10.4103/1673-5374.303043 Abstract ( 84 )   PDF (1025KB) ( 45 )   Save The physiological characteristics of the marmoset second visual area (V2) are poorly understood compared with those of the primary visual area (V1). In this study, we observed the physiological response characteristics of V2 neurons in four healthy adult marmosets using intracortical tungsten microelectrodes. We recorded 110 neurons in area V2, with receptive fields located between 8° and 15° eccentricity. Most (88.2%) of these neurons were orientation selective, with half-bandwidths typically ranging between 10° and 30°. A significant proportion of neurons (28.2%) with direction selectivity had a direction index greater than 0.5. The vast majority of V2 neurons had separable spatial frequency and temporal frequency curves and, according to this criterion, they were not speed selective. The basic functional response characteristics of neurons in area V2 resemble those found in area V1. Our findings show that area V2 together with V1 are important in primate visual processing, especially in locating objects in space and in detecting an object’s direction of motion. The methods used in this study were approved by the Monash University Animal Ethics Committee, Australia (MARP 2009-2011) in 2009.  Related Articles | Metrics

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Effects of long non-coding RNA myocardial infarction-associated transcript on retinal neovascularization in a newborn mouse model of oxygen-induced retinopathy Yu Di, Yue Wang, Xue Wang, Qing-Zhu Nie 2021, 16 (9):  1877-1881.  doi: 10.4103/1673-5374.306098 Abstract ( 76 )   PDF (1690KB) ( 67 )   Save Whether long non-coding RNA myocardial infarction-associated transcript is involved in oxygen-induced retinopathy remains poorly understood. To validate this hypothesis, we established a newborn mouse model of oxygen-induced retinopathy by feeding in an oxygen concentration of 75 ± 2% from postnatal day 8 to postnatal day 12, followed by in normal air. On postnatal day 11, the mice were injected with the myocardial infarction-associated transcript siRNA plasmid via the vitreous cavity to knockdown long non-coding RNA myocardial infarction-associated transcript. Myocardial infarction-associated transcript siRNA transcription significantly inhibited myocardial infarction-associated transcript mRNA expression, reduced the phosphatidylinosital-3-kinase, phosphorylated Akt and vascular endothelial growth factor immunopositivities, protein and mRNA expression, and alleviated the pathological damage to the retina of oxygen-induced retinopathy mouse models. These findings suggest that myocardial infarction-associated transcript is likely involved in the retinal neovascularization in retinopathy of prematurity and that inhibition of myocardial infarction-associated transcript can downregulate phosphatidylinosital-3-kinase, phosphorylated Akt and vascular endothelial growth factor expression levels and inhibit neovascularization. This study was approved by the Animal Ethics Committee of Shengjing Hospital of China Medical University, China (approval No. 2016PS074K) on February 25, 2016.  Related Articles | Metrics

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Angiogenesis and nerve regeneration induced by local administration of plasmid pBud-coVEGF165-coFGF2 into the intact rat sciatic nerve Ruslan Masgutov, Alina Zeinalova, Alexey Bogov, Galina Masgutova, Ilnur Salafutdinov, Ekaterina Garanina, Valeriia Syromiatnikova, Kamilla Idrisova, Adelya Mullakhmetova, Dina Andreeva, Liliya Mukhametova, Adilet Kadyrov, Igor Pankov, Albert Rizvanov 2021, 16 (9):  1882-1889.  doi: 10.4103/1673-5374.306090 Abstract ( 69 )   PDF (2698KB) ( 45 )   Save Vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) are well-known growth factors involved in the regeneration of various tissues and organs, including peripheral nerve system. In the present study, we elucidated the local and systemic effects of plasmid construct рBud-coVEGF165-coFGF2 injected into the epineurium of intact rat sciatic nerve. Results of histological examination of sciatic nerve and multiplex immunoassays of serum showed the absence of immunogenicity and biosafety of plasmid рBud-coVEGF165-coFGF2. Moreover, local administration of plasmid DNA construct resulted in significantly decreased levels of pro-inflammatory cytokines in the peripheral blood, including tumor necrosis factor α (TNFα) and interleukin-12, and significantly increased levels of cytokines and chemokines including Regulated upon Activation, Normal T Cell Expressed and Presumably Secrete (RANTES), epidermal growth factor, interleukin-2, and monocyte chemoattractant protein 1. These changes in the peripheral blood on day 7 after injection of plasmid construct рBud-coVEGF165-coFGF2 show that the plasmid construct has systemic effects and may modulate immune response. At the same time, reverse transcription-polymerase chain reaction revealed transient expression of coFGF2, coVEGF165, ratFGF2 and ratVEGFA with direct transport of transcripts from distal part to proximal part of the sciatic nerve.  Immunohistochemical staining revealed prolonged presence of VEGFA in sciatic nerve till 14 days post-injection. These findings suggest that local administration of plasmid construct рBud-coVEGF165-coFGF2 at a concentration of 30 ng/µL results in the formation of pro-angiogenic stimuli and, and the plasmid construct, used as a drug for gene therapy, might potentially facilitate regeneration of the sciatic nerve. The study was approved by the Animal Ethics Committee of Kazan Federal University, procedures were approved by the Local Ethics Committee (approval No. 5) on May 27, 2014. Related Articles | Metrics

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Preparation of human decellularized peripheral nerve allograft using amphoteric detergent and nuclease Joo-Yul Bae, Suk Young Park, Young Ho Shin, Shin Woo Choi, Jae Kwang Kim 2021, 16 (9):  1890-1896.  doi: 10.4103/1673-5374.306091 Abstract ( 80 )   PDF (6710KB) ( 109 )   Save Animal studies have shown that amphoteric detergent and nuclease (DNase I and ribonuclease A) is the most reliable decellularization method of the peripheral nerve. However, the optimal combination of chemical reagents for decellularization of human nerve allograft needs further investigation. To find the optimal protocol to remove the immunogenic cellular components of the nerve tissue and preserve the basal lamina and extracellular matrix and whether the optimal protocol can be applied to larger-diameter human peripheral nerves, in this study, we decellularized the median and sural nerves from the cadavers with two different methods: nonionic and anionic detergents (Triton X-100 and sodium deoxycholate) and amphoteric detergent and nuclease (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), deoxyribonuclease I, and ribonuclease A). All cellular components were successfully removed from the median and sural nerves by amphoteric detergent and nuclease. Not all cellular components were removed from the median nerve by nonionic and anionic detergent. Both median and sural nerves treated with amphoteric detergent and nuclease maintained a completely intact extracellular matrix. Treatment with nonionic and anionic detergent decreased collagen content in both median and sural nerves, while the amphoteric detergent and nuclease treatment did not reduce collagen content. In addition, a contact cytotoxicity assay revealed that the nerves decellularized by amphoteric detergent and nuclease was biocompatible. Strength failure testing demonstrated that the biomechanical properties of nerves decellularized with amphoteric detergent and nuclease were comparable to those of fresh controls. Decellularization with amphoteric detergent and nuclease better remove cellular components and better preserve extracellular matrix than decellularization with nonionic and anionic detergents, even in large-diameter human peripheral nerves. In Korea, cadaveric studies are not yet legally subject to Institutional Review Board review. Related Articles | Metrics