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15 January 2023, Volume 18 Issue 1 Previous Issue    Next Issue

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Neuroaxonal and cellular damage/protection by prostanoid receptor ligands, fatty acid derivatives and associated enzyme inhibitors Najam A. Sharif 2023, 18 (1):  5-17.  doi: 10.4103/1673-5374.343887 Abstract ( 192 )   PDF (3517KB) ( 151 )   Save Cellular and mitochondrial membrane phospholipids provide the substrate for synthesis and release of prostaglandins in response to certain chemical, mechanical, noxious and other stimuli. Prostaglandin D2, prostaglandin E2, prostaglandin F2α, prostaglandin I2 and thromboxane-A2 interact with five major receptors (and their sub-types) to elicit specific downstream cellular and tissue actions. In general, prostaglandins have been associated with pain, inflammation, and edema when they are present at high local concentrations and involved on a chronic basis. However, in acute settings, certain endogenous and exogenous prostaglandins have beneficial effects ranging from mediating muscle contraction/relaxation, providing cellular protection, regulating sleep, and enhancing blood flow, to lowering intraocular pressure to prevent the development of glaucoma, a blinding disease. Several classes of prostaglandins are implicated (or are considered beneficial) in certain central nervous system dysfunctions (e.g., Alzheimer’s, Parkinson’s, and Huntington’s diseases; amyotrophic lateral sclerosis and multiple sclerosis; stroke, traumatic brain injuries and pain) and in ocular disorders (e.g., ocular hypertension and glaucoma; allergy and inflammation; edematous retinal disorders). This review endeavors to address the physiological/pathological roles of prostaglandins in the central nervous system and ocular function in health and disease, and provides insights towards the therapeutic utility of some prostaglandin agonists and antagonists, polyunsaturated fatty acids, and cyclooxygenase inhibitors. Related Articles | Metrics

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Extracellular vesicles in Alzheimer’s disease: from pathology to therapeutic approaches Marta Garcia-Contreras, Avnesh S. Thakor 2023, 18 (1):  18-22.  doi: 10.4103/1673-5374.343882 Abstract ( 200 )   PDF (438KB) ( 131 )   Save Alzheimer’s disease is a progressive and fatal neurodegenerative disorder that starts many years before the onset of cognitive symptoms. Identifying novel biomarkers for Alzheimer’s disease has the potential for patient risk stratification, early diagnosis, and disease monitoring in response to therapy. A novel class of biomarkers is extracellular vesicles given their sensitivity and specificity to specific diseases. In addition, extracellular vesicles can be used as novel biological therapeutics given their ability to efficiently and functionally deliver therapeutic cargo. This is critical given the huge unmet need for novel treatment strategies for Alzheimer’s disease. This review summarizes and discusses the most recent findings in this field. Related Articles | Metrics

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Molecular approaches for spinal cord injury treatment Fernanda Martins de Almeida, Suelen Adriani Marques, Anne Caroline Rodrigues dos Santos, Caio Andrade Prins, Fellipe Soares dos Santos Cardoso, Luiza dos Santos Heringer, Henrique Rocha Mendonça, Ana Maria Blanco Martinez 2023, 18 (1):  23-30.  doi: 10.4103/1673-5374.344830 Abstract ( 172 )   PDF (1457KB) ( 197 )   Save Injuries to the spinal cord result in permanent disabilities that limit daily life activities. The main reasons for these poor outcomes are the limited regenerative capacity of central neurons and the inhibitory milieu that is established upon traumatic injuries. Despite decades of research, there is still no efficient treatment for spinal cord injury. Many strategies are tested in preclinical studies that focus on ameliorating the functional outcomes after spinal cord injury. Among these, molecular compounds are currently being used for neurological recovery, with promising results. These molecules target the axon collapsed growth cone, the inhibitory microenvironment, the survival of neurons and glial cells, and the re-establishment of lost connections. In this review we focused on molecules that are being used, either in preclinical or clinical studies, to treat spinal cord injuries, such as drugs, growth and neurotrophic factors, enzymes, and purines. The mechanisms of action of these molecules are discussed, considering traumatic spinal cord injury in rodents and humans. Related Articles | Metrics

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Sex-biased autophagy as a potential mechanism mediating sex differences in ischemic stroke outcome Brian Noh, Louise D. McCullough, Jose F. Moruno-Manchon 2023, 18 (1):  31-37.  doi: 10.4103/1673-5374.340406 Abstract ( 173 )   PDF (852KB) ( 176 )   Save Stroke is the second leading cause of death and a major cause of disability worldwide, and biological sex is an important determining factor in stroke incidence and pathology. From childhood through adulthood, men have a higher incidence of stroke compared with women. Abundant research has confirmed the beneficial effects of estrogen in experimental ischemic stroke but genetic factors such as the X-chromosome complement can also play an important role in determining sex differences in stroke. Autophagy is a self-degrading cellular process orchestrated by multiple core proteins, which leads to the engulfment of cytoplasmic material and degradation of cargo after autophagy vesicles fuse with lysosomes or endosomes. The levels and the activity of components of these signaling pathways and of autophagy-related proteins can be altered during ischemic insults. Ischemic stroke activates autophagy, however, whether inhibiting autophagy after stroke is beneficial in the brain is still under a debate. Autophagy is a potential mechanism that may contribute to differences in stroke progression between the sexes. Furthermore, the effects of manipulating autophagy may also differ between the sexes. Mechanisms that regulate autophagy in a sex-dependent manner in ischemic stroke remain unexplored. In this review, we summarize clinical and pre-clinical evidence for sex differences in stroke. We briefly introduce the autophagy process and summarize the effects of gonadal hormones in autophagy in the brain and discuss X-linked genes that could potentially regulate brain autophagy. Finally, we review pre-clinical studies that address the mechanisms that could mediate sex differences in brain autophagy after stroke. Related Articles | Metrics

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Adipose tissue, systematic inflammation, and neurodegenerative diseases Ana Paula de A. Boleti, Pedro Henrique de O. Cardoso, Breno Emanuel F. Frihling, Patrícia Souza e Silva, Luiz Filipe R.N. de Moraes, Ludovico Migliolo 2023, 18 (1):  38-46.  doi: 10.4103/1673-5374.343891 Abstract ( 224 )   PDF (2540KB) ( 369 )   Save Obesity is associated with several diseases, including mental health. Adipose tissue is distributed around the internal organs, acting in the regulation of metabolism by storing and releasing fatty acids and adipokine in the tissues. Excessive nutritional intake results in hypertrophy and proliferation of adipocytes, leading to local hypoxia in adipose tissue and changes in these adipokine releases. This leads to the recruitment of immune cells to adipose tissue and the release of pro-inflammatory cytokines. The presence of high levels of free fatty acids and inflammatory molecules interfere with intracellular insulin signaling, which can generate a neuroinflammatory process. In this review, we provide an up-to-date discussion of how excessive obesity can lead to possible cognitive dysfunction. We also address the idea that obesity-associated systemic inflammation leads to neuroinflammation in the brain, particularly the hypothalamus and hippocampus, and that this is partially responsible for these negative cognitive outcomes. In addition, we discuss some clinical models and animal studies for obesity and clarify the mechanism of action of anti-obesity drugs in the central nervous system. Related Articles | Metrics

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Interleukin-1: an important target for perinatal neuroprotection? Sharmony B. Kelly, Elys Green, Rod W. Hunt, Claudia A. Nold-Petry, Alistair J. Gunn, Marcel F. Nold, Robert Galinsky 2023, 18 (1):  47-50.  doi: 10.4103/1673-5374.341044 Abstract ( 190 )   PDF (1016KB) ( 133 )   Save Perinatal inflammation is a significant risk factor for lifelong neurodevelopmental impairments such as cerebral palsy. Extensive clinical and preclinical evidence links the severity and pattern of perinatal inflammation to impaired maturation of white and grey matters and reduced brain growth. Multiple pathways are involved in the pathogenesis of perinatal inflammation. However, studies of human and experimental perinatal encephalopathy have demonstrated a strong causative link between perinatal encephalopathy and excessive production of the pro-inflammatory effector cytokine interleukin-1. In this review, we summarize clinical and preclinical evidence that underpins interleukin-1 as a critical factor in initiating and perpatuating systemic and central nervous system inflammation and subsequent perinatal brain injury. We also highlight the important role of endogenous interleukin-1 receptor antagonist in mitigating interleukin-1-driven neuroinflammation and tissue damage, and summarize outcomes from clinical and mechanistic animal studies that establish the commercially available interleukin-1 receptor antagonist, anakinra, as a safe and effective therapeutic intervention. We reflect on the evidence supporting clinical translation of interleukin-1 receptor antagonist for infants at the greatest risk of perinatal inflammation and impaired neurodevelopment, and suggest a path to advance interleukin-1 receptor antagonist along the translational path for perinatal neuroprotection. Related Articles | Metrics

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Neurotrophic fragments as therapeutic alternatives to ameliorate brain aging Itzel Ortiz Flores, Samuel Treviño, Alfonso Díaz 2023, 18 (1):  51-56.  doi: 10.4103/1673-5374.331867 Abstract ( 185 )   PDF (635KB) ( 137 )   Save Aging is a global phenomenon and a complex biological process of all living beings that introduces various changes. During this physiological process, the brain is the most affected organ due to changes in its structural and chemical functions, such as changes in plasticity and decrease in the number, diameter, length, and branching of dendrites and dendritic spines. Likewise, it presents a great reduction in volume resulting from the contraction of the gray matter. Consequently, aging can affect not only cognitive functions, including learning and memory, but also the quality of life of older people. As a result of the phenomena, various molecules with notable neuroprotective capacity have been proposed, which provide a therapeutic alternative for people under conditions of aging or some neurodegenerative diseases. It is important to indicate that in recent years the use of molecules with neurotrophic activity has shown interesting results when evaluated in in vivo models. This review aims to describe the neurotrophic potential of molecules such as resveratrol (3,5,4′-trihydroxystilbene), neurotrophins (brain-derived neurotrophic factor), and neurotrophic-type compounds such as the terminal carboxyl domain of the heavy chain of tetanus toxin, cerebrolysin, neuropeptide-12, and rapamycin. Most of these molecules have been evaluated by our research group. Studies suggest that these molecules exert an important therapeutic potential, restoring brain function in aging conditions or models of neurodegenerative diseases. Hence, our interest is in describing the current scientific evidence that supports the therapeutic potential of these molecules with active neurotrophic. Related Articles | Metrics

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The neuroprotective effects of oxygen therapy in Alzheimer’s disease: a narrative review Cui Yang, Qiu Yang, Yang Xiang, Xian-Rong Zeng, Jun Xiao, Wei-Dong Le 2023, 18 (1):  57-63.  doi: 10.4103/1673-5374.343897 Abstract ( 197 )   PDF (849KB) ( 127 )   Save Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD. Related Articles | Metrics

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Security breach: peripheral nerves provide unrestricted access for toxin delivery into the central nervous system Igor Lupinski, Allison S. Liang, Randall D. McKinnon 2023, 18 (1):  64-67.  doi: 10.4103/1673-5374.345472 Abstract ( 113 )   PDF (921KB) ( 63 )   Save We explore the hypothesis that a potential explanation for the initiation of motor neuron disease is an unappreciated vulnerability in central nervous system defense, the direct delivery of neurotoxins into motor neurons via peripheral nerve retrograde transport.  This further suggests a mechanism for focal initiation of neuro-degenerative diseases in general, with subsequent spread by network degeneration as suggested by the Frost-Diamond hypothesis.  We propose this vulnerability may be a byproduct of vertebrate evolution in a benign aquatic environment, where external surfaces were not exposed to concentrated neurotoxins. Related Articles | Metrics

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Protocadherin gamma C3: a new player in regulating vascular barrier function Victoria Kaupp, Kinga G. Blecharz-Lang, Christina Dilling, Patrick Meybohm, Malgorzata Burek 2023, 18 (1):  68-73.  doi: 10.4103/1673-5374.343896 Abstract ( 311 )   PDF (826KB) ( 99 )   Save Defects in the endothelial cell barrier accompany diverse malfunctions of the central nervous system such as neurodegenerative diseases, stroke, traumatic brain injury, and systemic diseases such as sepsis, viral and bacterial infections, and cancer. Compromised endothelial sealing leads to leaking blood vessels, followed by vasogenic edema. Brain edema as the most common complication caused by stroke and traumatic brain injury is the leading cause of death. Brain microvascular endothelial cells, together with astrocytes, pericytes, microglia, and neurons form a selective barrier, the so-called blood-brain barrier, which regulates the movement of molecules inside and outside of the brain. Mechanisms that regulate blood-brain barrier permeability in health and disease are complex and not fully understood. Several newly discovered molecules that are involved in the regulation of cellular processes in brain microvascular endothelial cells have been described in the literature in recent years. One of these molecules that are highly expressed in brain microvascular endothelial cells is protocadherin gamma C3. In this review, we discuss recent evidence that protocadherin gamma C3 is a newly identified key player involved in the regulation of vascular barrier function. Related Articles | Metrics

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The regulatory role of Pin1 in neuronal death Shu-Chao Wang, Xi-Min Hu, Kun Xiong 2023, 18 (1):  74-80.  doi: 10.4103/1673-5374.341043 Abstract ( 210 )   PDF (2286KB) ( 107 )   Save Regulated cell death predominantly involves apoptosis, autophagy, and regulated necrosis. It is vital that we understand how key regulatory signals can control the process of cell death. Pin1 is a cis-trans isomerase that catalyzes the isomerization of phosphorylated serine or threonine-proline motifs of a protein, thereby acting as a crucial molecular switch and regulating the protein functionality and the signaling pathways involved. However, we know very little about how Pin1-associated pathways might play a role in regulated cell death. In this paper, we review the role of Pin1 in regulated cell death and related research progress and summarize Pin1-related pathways in regulated cell death. Aside from the involvement of Pin1 in the apoptosis that accompanies neurodegenerative diseases, accumulating evidence suggests that Pin1 also plays a role in regulated necrosis and autophagy, thereby exhibiting distinct effects, including both neurotoxic and neuroprotective effects. Gaining an enhanced understanding of Pin1 in neuronal death may provide us with new options for the development of therapeutic target for neurodegenerative disorders.  Related Articles | Metrics

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Gangliosides in nervous system development, regeneration, and pathologies Juliana F. Vasques, Renata Guedes de Jesus Gonçalves, Almir Jordão da Silva-Junior, Robertta Silva Martins, Fernanda Gubert, Rosalia Mendez-Otero 2023, 18 (1):  81-86.  doi: 10.4103/1673-5374.343890 Abstract ( 178 )   PDF (887KB) ( 104 )   Save Gangliosides, sialic acid-containing sphingolipids, are major constituents of neuronal membranes. According to the number of sialic acids and the structure of the oligosaccharide chain, gangliosides can be classified as simple or complex and grouped in different ganglio-series. Hundreds of gangliosides have been identified in vertebrate cells, with different expression patterns during development and related to several physiological processes, especially in the nervous system. While GD3 and its O-acetylated form, 9acGD3, are highly expressed in early developmental stages, GM1, GD1a, GD1b, and GT1b are the most abundant ganglioside species in the mature nervous system. Mutations in enzymes involved in ganglioside metabolism can lead to the accumulation of specific species, a condition termed gangliosidosis and usually marked by severe neurological impairment. Changes in ganglioside levels have also been described in several neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. In this review, we summarized recent information about the roles of GD3, 9acGD3, GM1, GD1a, GD1b, GT1b, and other ganglioside species in nervous system development and regeneration, as well as clinical trials evaluating possible therapeutic applications of these molecules. Related Articles | Metrics

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Regulatory mechanisms of retinal ganglion cell death in normal tension glaucoma and potential therapies Wen-Cui Shen, Bing-Qing Huang, Jin Yang 2023, 18 (1):  87-93.  doi: 10.4103/1673-5374.344831 Abstract ( 229 )   PDF (4266KB) ( 138 )   Save Normal tension glaucoma (NTG) is a multifactorial optic neuropathy characterized by normal intraocular pressure, progressive retinal ganglion cell (RGC) death, and glaucomatous visual field loss. Recent studies have described the mechanisms underlying the pathogenesis of NTG. In addition to controlling intraocular pressure, neuroprotection and reduction of RGC degeneration may be beneficial therapies for NTG. In this review, we summarized the main regulatory mechanisms of RGC death in NTG, including autophagy, glutamate neurotoxicity, oxidative stress, neuroinflammation, immunity, and vasoconstriction. Autophagy can be induced by retinal hypoxia and axonal damage. In this process, ischemia can cause mutations of optineurin and activate the nuclear factor-kappa B pathway. Glutamate neurotoxicity is induced by the over-stimulation of N-methyl-D-aspartate membrane receptors by glutamate, which occurs in RGCs and induces progressive glaucomatous optic neuropathy. Oxidative stress also participates in NTG-related glaucomatous optic neuropathy. It impairs the mitochondrial and DNA function of RGCs through the apoptosis signal-regulating kinase-JUN N-terminal kinase pathway. Moreover, it increases inflammation and the immune response of RGCs. Endothelin 1 causes endothelial dysfunction and impairment of ocular blood flow, promoting vasospasm and glaucomatous optic neuropathy, as a result of NTG. In conclusion, we discussed research progress on potential options for the protection of RGCs, including TANK binding kinase 1 inhibitors regulating autophagy, N-methyl-D-aspartate receptor antagonists inhibiting glutamate toxicity, ASK1 inhibitors regulating mitochondrial function, and antioxidants inhibiting oxidative stress. In NTG, RGC death is regulated by a network of mechanisms, while various potential targets protect RGCs. Collectively, these findings provide insight into the pathogenesis of NTG and potential therapeutic strategies. Related Articles | Metrics

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Crosslink between mutations in mitochondrial genes and brain disorders: implications for mitochondrial-targeted therapeutic interventions Jaspreet Kalra 2023, 18 (1):  94-101.  doi: 10.4103/1673-5374.343884 Abstract ( 164 )   PDF (753KB) ( 175 )   Save At the present, association of mitochondrial dysfunction and progression of neurological disorders has gained significant attention. Defects in mitochondrial network dynamics, point mutations, deletions, and interaction of pathogenomic proteins with mitochondria are some of the possible underlying mechanisms involved in these neurological disorders. Mitochondrial genetics, defects in mitochondrial oxidative phosphorylation machinery, and reactive oxygen species production might share common crosstalk in the progression of these neurological disorders. It is of significant interests to explore and develop therapeutic strategies aimed at correcting mitochondrial abnormalities. This review provided insights on mitochondrial dysfunction/mutations involved in the progression of Alzheimer’s disease, Huntington’s disease, and epilepsy with a special focus on Parkinson’s disease pathology. Along with the deleterious effects of mitochondrial mutations in aforesaid neurological disorders, this paper unraveled the available therapeutic strategy, specifically aiming to improve mitochondrial dysfunction, drugs targeting mitochondrial proteins, gene therapies aimed at correcting mutant mtDNA, peptide-based approaches, and lipophilic cations.  Related Articles | Metrics

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Brain-derived neurotrophic factor rs6265 (Val66Met) single nucleotide polymorphism as a master modifier of human pathophysiology Van Thuan Nguyen, Braxton Hill, Naiya Sims, Aaron Heck, Marcus Negron, Claire Lusk, Cristi L. Galindo 2023, 18 (1):  102-106.  doi: 10.4103/1673-5374.343894 Abstract ( 183 )   PDF (629KB) ( 131 )   Save Brain-derived neurotrophic factor is the most prevalent member of the nerve growth factor family. Since its discovery in 1978, this enigmatic molecule has spawned more than 27,000 publications, most of which are focused on neurological disorders. Brain-derived neurotrophic factor is indispensable during embryogenesis and postnatally for the normal development and function of both the central and peripheral nervous systems. It is becoming increasingly clear, however, that brain-derived neurotrophic factor likewise plays crucial roles in a variety of other biological functions independently of sympathetic or parasympathetic involvement. Brain-derived neurotrophic factor is also increasingly recognized as a sophisticated environmental sensor and master coordinator of whole organismal physiology. To that point, we recently found that a common nonsynonymous (Val66→Met) single nucleotide polymorphism in the brain-derived neurotrophic factor gene (rs6265) not only substantially alters basal cardiac transcriptomics in mice but subtly influences heart gene expression and function differentially in males and females. In addition to a short description of recent results from associative neuropsychiatric studies, this review provides an eclectic assortment of research reports that support a modulatory role for rs6265 including and beyond the central nervous system.  Related Articles | Metrics

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A potential new tool to enhance translational success rate in stroke research by backcrossing techniques in transgenic mice Takayuki Nakagomi, Hideaki Nishie, Toshinori Sawano, Akiko Nakano-Doi 2023, 18 (1):  107-108.  doi: 10.4103/1673-5374.343899 Abstract ( 147 )   PDF (346KB) ( 73 )   Save Ischemic stroke is a leading disease of the central nervous system, frequently coupled to severe damage and dysfunction in patients. Animal models mimicking human stroke provide useful tools for studying the pathomechanisms (e.g., inflammation, neuroprotection, and neural regeneration), the treatment efficiency of various materials (e.g., bioactive molecules or drugs), and transplantation usefulness by various cell types [e.g., neural stem/progenitor cells (NSPCs), and mesenchymal or hematopoietic stem cells] under ischemic stroke. Related Articles | Metrics

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Glial regenerative response in the imaginal discs of Drosophila melanogaster Sergio B. Velarde, Antonio Baonza 2023, 18 (1):  109-110.  doi: 10.4103/1673-5374.339479 Abstract ( 143 )   PDF (1570KB) ( 89 )   Save Glial cells play a key role during nervous system development and actively participate in all the cellular processes involved in maintaining its structural robustness and functional plasticity. In response to neuronal damage, glial cells proliferate, migrate to the injured region and change their morphology, function, and behavior (Gallo and Deneen, 2014; Kato et al., 2018). This glial regenerative response is associated with the repairing function of these cells and is found across species, suggesting that it may reflect a common underlying genetic mechanism (Kato et al., 2018). In mammals, while the central nervous system has very limited capacity to regenerate after traumatic injury or disease, the peripheral nervous system (PNS) exhibits a far greater capacity for regeneration and damaged peripheral nerves can be totally restored (Brosius Lutz and Barres, 2014; Gallo and Deneen, 2014). The PNS largely owes its regenerative potential to the ability of the main glial cells present in the PNS, myelin, and non-myelin (Remak) Schwann cells, to convert to cells devoted to repairing after injury (Nocera and Jacob, 2020). During the regeneration of peripheral nerves in vertebrates, Schwann cells function as a central hub, collecting signals from neurons and other cell types and undergoing a complex process of reprogramming which converts them into a specialized cell for repair. Even though many aspects of regeneration in peripheral nerves have been studied, there is still a lack of understanding regarding the genetic network that controls the flexible differentiation state of PNS neurons and Schwann. The identification of those signals is essential for getting new insight to develop innovative regenerative therapies. In this scenario, the use of relatively simple model organisms, amenable to genetic, cellular, and molecular analysis is fundamental to study the behavior of glial cells in response to damage in their natural context. Related Articles | Metrics

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Translation stalling and ribosome collision leading to proteostasis failure: implications for neurodegenerative diseases Bingwei Lu 2023, 18 (1):  111-112.  doi: 10.4103/1673-5374.340404 Abstract ( 213 )   PDF (353KB) ( 173 )   Save Proteostasis denotes a cellular state in which protein synthesis, folding, and degradation are maintained at a homeostatic state such that an intact yet dynamic proteome is preserved. Cellular capacity to preserve proteostasis declines with age, which is assumed to contribute to the pathogenesis of age-related diseases. Proteostasis failure manifested as the formation of aberrant protein aggregates, including the amyloid plaques in Alzheimer’s disease (AD), Lewy bodies in Parkinson’s disease, and TAR DNA binging protein 43 inclusions in amyotrophic lateral sclerosis (ALS), is a defining feature of neurodegenerative diseases. The root cause of the proteostasis failure and protein aggregation is still enigmatic. Studies in various systems suggest that cellular co-factors play important roles in “seeding” the aforementioned pathogenic protein aggregation. But the molecular nature of the initial seeding activities remains poorly defined. The pathogenic role of the disease-characterizing, macroscopically visible protein aggregates is also uncertain. Several high-profile clinical trials targeting specific protein aggregates are inconclusive and there is no evidence for a clinically relevant therapeutic effect as of now (Mullane and Williams, 2018), suggesting that the key proteostasis-disruptive, disease-causing events remain to be identified. In this perspective, I will discuss recent evidence supporting that faulty translation products resulting from inadequate quality control of translational stalling and ribosome collision during the translation of certain problematic mRNAs can be the root cause of proteostasis failure and may represent novel therapeutic targets for neurodegenerative diseases. Related Articles | Metrics

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Globodera pallida, a non-transgenic invertebrate as a new model for investigating Alzheimer’s disease (and other proteinopathies)? Norah A. Althobaiti, Farid Menaa, Johnathan J. Dalzell, Brian D. Green 2023, 18 (1):  113-114.  doi: 10.4103/1673-5374.341042 Abstract ( 150 )   PDF (1167KB) ( 75 )   Save Biological models of Alzheimer’s disease (AD): Non-human models have contributed tremendously to the understanding of AD and its underlying pathological processes. These models have aided the investigation of the genetic and environmental risk factors. They also have enabled the progression of candidate therapies into human clinical trials. Because of similarities with human brain anatomy and genetics, rodent models have been used extensively to recapitulate some aspects of AD pathology, measure AD-associated behavioral parameters and related nervous system dysfunctions (Eriksen and Janus, 2007). For instance, transgenic mice overexpressing human amyloid precursor protein have furthered the development of the amyloid cascade hypothesis as a central pillar of familial AD. Although considered as advantageous, mammalian models have practical and ethical problems when it comes to high-throughput screening (HTS) of drugs. Therefore, alternative models, including the use of invertebrates with very short lifecycles, represent rapid, simple, and highly cost-effective platforms for HTS or drug target identification (Artal‐Sanz et al., 2006). Indeed, the use of such organisms, as opposed to individual cell models, provides advantages for understanding the wider complexity of human pathology. Thereby, prominent invertebrate model organisms, such as Drosophila melanogaster (fruit fly), and the nematode Caenorhabditis elegans (roundworm), were insightful into the aging process, AD and Parkinson’s disease (Newman et al., 2011). The genome of D. melanogaster is ~70% homologous to that of humans and shows relatively complex brain and neuronal structures. Its eye is an accessible organ for phenotypic characterization, measuring of behavioral deficits, and determining responses to drug compounds. This fruit fly has unique learning and memory behaviors and can induce the gene expression of proteins considered to be the major hallmarks of AD, such as amyloid-beta (Aβ) or tau, both leading to AD pathological features and phenotypes. Furthermore, compounds such as GSK3-β inhibitors can rescue axonal transport and locomotion defects in these models. C. elegans is another invertebrate model organism employed in AD research. Several attempts have been made to use this free-living nematode (natively occurring in temperate soil environments) to generate transgenic AD models. One transgenic C. elegans model expressing Aβ peptides in muscle has a paralysis transgene-induced phenotype (Dostal and Link, 2010). Other models that neuronally express human Aβ exhibit phenotypes such as impaired chemotaxis and deficits in associated learning. Reported defects include impaired odor associative learning behavior, impaired serotonin-stimulated egg-laying, and decreased lifespan evidently resulting from Aβ toxicity. Related Articles | Metrics

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Brain network modulation in Alzheimer’s disease: clinical phenotypes and windows of opportunity Lorenzo Pini 2023, 18 (1):  115-116.  doi: 10.4103/1673-5374.340410 Abstract ( 139 )   PDF (4726KB) ( 105 )   Save Dementia, for which there is no cure or effective treatment, is the leading cause of disability and death worldwide. Due to the high global prevalence and economic impact on families, caregivers, and communities, this condition represents one of the most significant public health challenges of our time. Dementia is an umbrella term describing a range of progressive neurodegenerative diseases, including Alzheimer’s disease (AD), which is the most common cause of cognitive and functional impairment among older adults. The presence of misfolded protein aggregates characterizes neurodegenerative disorders (e.g., amyloid-beta (Aβ) and tau in AD). Stemming from this, advancements in the molecular imaging field paved the way to new experimental AD treatments targeting Aβ. However, the results have been disappointing so far, and there is an ongoing debate about the emerging role and efficacy of anti-Aβ monoclonal antibodies (Musiek and Bennett, 2021), stressing the need for alternative biomarkers to guide new, effective preventive, and therapeutic interventions. Here, we report recent advancements in the field of functional connectivity in AD, underscoring the link with the underlying molecular pathology. We then discuss the meaning of the interplay between AD phenotypes, disease stage, and brain stimulation interventions. Related Articles | Metrics

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Initial failures of anti-tau antibodies in Alzheimer’s disease are reminiscent of the amyloid-β story Bruno P. Imbimbo, Claudia Balducci, Stefania Ippati, Mark Watling 2023, 18 (1):  117-118.  doi: 10.4103/1673-5374.340409 Abstract ( 181 )   PDF (1103KB) ( 127 )   Save Tau is an important protein of the central nervous system formed by 352–441 amino acids and encoded by the MAPT (microtubule-associated protein tau) gene on chromosome 17 which generates 6 isoforms. Tau is located in axons, dendrites, nucleus, cell membrane, and synapses of neurons. The protein is also expressed to a lesser extent in astrocytes and oligodendrocytes, although its role in these cells has been little investigated. The protein is also present in the interstitial fluid and can cross into the cerebrospinal fluid (CSF) and reach the systemic circulation. The main function of tau is promoting the assembly and stabilization of microtubules in neuronal axons. Tau plays also a role in a range of other biological processes including myelination, neurogenesis, motor function, learning, and memory (Kent et al., 2020). The binding of tau to microtubules is regulated by its phosphorylation/dephosphorylation equilibrium. In physiological conditions, tau is unfolded and phosphorylated, while the pathological form is characterized by an excess of hyperphosphorylation leading to disengagement from the microtubules, and conformational changes that lead to the formation of paired helical and straight filaments of abnormally phosphorylated tau and subsequently to tau aggregates. These aggregates can cause degeneration of neurons and glial cells that ultimately lead to various clinical cognitive, behavioral, and motor manifestations, which are classified into different types of neurodegenerative disorders called ‘tauopathies’. Tauopathies are classified into primary and secondary tauopathies. In primary tauopathies, the abnormal tau accounts for the primary underlying neurodegenerative process. Primary tauopathies include progressive supranuclear palsy (PSP), corticobasal degeneration, corticobasal syndrome tauopathy, Pick’s disease, frontotemporal dementia, frontotemporal lobar degeneration, primary progressive aphasia, MAPT mutation, argyrophilic grain disease, and primary age-related tauopathy. In secondary tauopathies, tau neuronal inclusions occur in association with the extracellular deposition of a second aggregated protein. Secondary tauopathies include Alzheimer’s disease (AD) and Down syndrome (in which amyloid-beta [Aβ] accumulates), Lewy body dementia (in which α-synuclein accumulates), and chronic traumatic encephalopathy (in which TAR DNA-binding protein 43) accumulates. Related Articles | Metrics

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Misfolded amyloid-β strains and their potential roles in the clinical and pathological variability of Alzheimer’s disease Sara Kelley, Nelson Perez-Urrutia, Rodrigo Morales 2023, 18 (1):  119-120.  doi: 10.4103/1673-5374.340403 Abstract ( 138 )   PDF (944KB) ( 50 )   Save Potential causes for the clinical and pathological variability observed in Alzheimer’s disease (AD): AD is an age-related neurodegenerative disorder characterized by the impairment of cognitive functions such as memory, learning, and reasoning. These commonly described clinical symptoms are due to particular pathological changes in the brain, including inflammation, synaptic loss, and neuronal death. These changes are a consequence of the accumulation of abnormally folded amyloid-β (Aβ) and tau proteins in specific areas of the central nervous system. Considering the progressive aging of the world’s population, the number of people affected by AD is expected to substantially and consistently increase in the coming years. This positions AD as one of the main public health challenges in the near future. Related Articles | Metrics

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Myelin lipid deficiency: a new key driver of Alzheimer’s disease Shulan Qiu, Juan Pablo Palavicini, Xianlin Han 2023, 18 (1):  121-122.  doi: 10.4103/1673-5374.343893 Abstract ( 193 )   PDF (1442KB) ( 132 )   Save Lipids play essential biological functions that include acting as components of biological membranes, energy storage, signaling, nutrients, transporters, enzyme activators, among others. Compared with the multiple research methods to assess DNA, RNA, and protein content, location, and function in cells, there are relatively fewer methods to study lipids. Therefore, lipid-oriented mechanistic studies remain rare and challenging. Lipidomics which allows large-scale analysis of cellular lipids, is a critical strategy for achieving this. One revolutionary advance in lipidomics pioneered by our group is the development of multidimensional mass spectrometry-based shotgun lipidomics, which has become a foundational analytical technology platform among current lipidomics practices due to its high efficiency, sensitivity, and reproducibility, as well as its broad coverage and minimal batch effects. Related Articles | Metrics

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Hebbian plasticity: the elusive missing link at the heart of Alzheimer’s disease pathogenesis? Alexander F. Jeans 2023, 18 (1):  123-124.  doi: 10.4103/1673-5374.340402 Abstract ( 234 )   PDF (1128KB) ( 85 )   Save The amyloid cascade hypothesis of Alzheimer’s pathogenesis: The amyloid cascade hypothesis of Alzheimer’s disease (AD) pathogenesis will shortly celebrate its thirtieth birthday (Hardy and Higgins, 1992). Based on abundant genetic and biochemical evidence, it proposes that deposition of the amyloid-β (Aβ) peptide in brain parenchyma is an essential upstream trigger in AD pathogenesis that drives a cascade of events, specifically including the recruitment and pathological hyper-phosphorylation of the micro-tubule-associated protein tau, that culminate in derangement of synaptic function and, eventually, neuronal death. Although the hypothesis has been challenged many times over the last three decades, principally based on a number of observations of AD pathology and clinical progression that it appears not to readily explain (Makin, 2018), its fundamental assertions that Aβ deposition is a critical early event, and that this somehow leads to the later recruitment of hyperphosphorylated tau, still appear to hold true (Selkoe and Hardy, 2016). Therefore, and in spite of its difficulties, the amyloid cascade hypothesis, albeit slightly refined and qualified over the years, is still the dominant model of AD pathogenesis. The central importance of tau to the disease process has been confirmed by a number of more recent studies that demonstrate convincingly that tau is essential for many of the canonical AD-associated synaptic and behavioral phenotypes, which can be rescued in animal models of AD by tau knockout (Mucke and Selkoe, 2012). However, despite its clear significance in AD pathogenesis, the cellular mechanism by which Aβ recruits tau to bring about synaptic and cognitive decline has remained obscure. Related Articles | Metrics

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The intricate debate on neurodegeneration and neuroinflammation in Parkinson’s disease: which came first? Antonella Cardinale, Valeria Calabrese 2023, 18 (1):  125-126.  doi: 10.4103/1673-5374.343895 Abstract ( 142 )   PDF (934KB) ( 62 )   Save Parkinson’s disease (PD) is a heterogeneous multifactorial disorder and, during the last years, new scientific evidence has supported this concept. The principal hallmarks of PD are the loss of dopaminergic neurons in the substantia nigra pars compacta and the aggregation of misfolded alpha-synuclein (α-syn). In particular, α-syn is receiving great attention for its key role in PD neuropathology. Both genetic mutations and post-translational modifications (i.e., α-syn phosphorylation) can induce protein misfolding. An abnormal accumulation of this misfolded α-syn crushes both the ubiquitin-proteosome and autophagy systems, which are involved in protein clearance. As a result, α-syn aggregation leads to neuronal dysfunction and neurodegeneration. Along with this pathological condition, dysregulated mitochondrial activity, reactive oxygen species production, oxidative stress, and blood-brain barrier alteration, are typical features of neurological disorders such as PD. In addition, neuroinflammatory processes are critical for PD pathogenesis and strictly interconnected to α-syn pathology. According to this, neuroinflammation could be considered as a potential early drug target. Related Articles | Metrics

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Synaptic pathology in multiple sclerosis: a role for Nogo-A signaling in astrocytes? Sheila Espírito-Santo, Vinícius Gabriel Coutinho, Flávia Carvalho Alcantara Gomes 2023, 18 (1):  127-128.  doi: 10.4103/1673-5374.340407 Abstract ( 142 )   PDF (3183KB) ( 137 )   Save Multiple sclerosis (MS) is characterized as an inflammatory demyelinating disease that affects the central nervous system (CNS), leading to sensory, motor and cognitive impairments. Ultimately, axonal denudation culminates in axonal lesions and neurodegeneration. Inflammatory demyelinating lesions in MS are associated with infiltration of immune cells combined with activation of the resident CNS inflammatory cells, astro- and microglia. Recently, synaptopathy has been associated with MS pathophysiology, though, intriguingly, it can occur independently of demyelination (Jürgens et al., 2016). Although inflammation also seems to corroborate with synaptic abnormalities, associated or not with demyelinating lesions, the underlying mechanisms are not fully understood (Mandolesi et al., 2015). In the last decades, the myelin inhibitory protein neurite outgrowth inhibitor-A (Nogo-A) has emerged as a potential mediator of axonal and synaptic dysfunctions in MS and a promising target to be neutralized  (Ineichen et al., 2017). Based on our recent findings demonstrating that Nogo-A signaling regulates astrocyte-driven synaptogenesis (Espírito-Santo et al., 2021),  and considering the critical role of astrocytes in regulating synaptic plasticity and function (Allen and Eroglu, 2017), we propose that modulation of Nogo-A pathway in these cells is a new mechanism driving circuitry alterations of MS. Related Articles | Metrics

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Exploring magneto-electric nanoparticles (MENPs): a platform for implanted deep brain stimulation Małgorzata Kujawska, Ajeet Kaushik 2023, 18 (1):  129-130.  doi: 10.4103/1673-5374.340411 Abstract ( 202 )   PDF (1589KB) ( 138 )   Save Towards implanted deep brain stimulation (DBS): The human brain is a complex network of 86 billion neurons and 85 billion nonneuronal cells and they are coordinated in a well-defined ratio (1:1) which is required for desired body functions. The connectivity among neuronal cells secretes neurotransmitters (e.g., dopamine) to establish a perfect connection between the brain and a peripheral system i.e., motor coordination. The secretion of neurotransmitters was found to be affected by aspects of lifestyle, age, and deteriorated health can damage the neurons’ connectivity, which can cause neurodegeneration leading to neurological disorders (Wang and Guo, 2016; Kumar et al., 2021). Circuit disturbances resulting from changes within the synapses, cells’ intrinsic excitability, and impaired connectivity within local networks and between projection areas mediate neurodegenerative disease and are associated symptomatic features (Werner et al., 2019; McTeague et al., 2020; Vissani et al., 2020). Disruptions in neural circuitry have also been demonstrated to underly emotional processing across various psychiatric conditions (Werner et al., 2019). In this context, techniques for adequate circuit reconstruction offer therapeutic potential. The lack of effective treatment made this situation very complicated to manage and in need of alternative treatment strategies, which are always in high demand. As a result of this, introducing external stimulation to modulate electrical communication among neurons’ circuitry is getting attention for understanding the neurobiology needed for diagnostics and treatment (Kozielski et al., 2021). Related Articles | Metrics

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Astrocyte evolution and human specificity Carmen Falcone, Verónica Martínez-Cerdeño 2023, 18 (1):  131-132.  doi: 10.4103/1673-5374.340405 Abstract ( 178 )   PDF (735KB) ( 79 )   Save The cerebral cortex is one of the most complex structures of the mammalian central nervous system and accounts for the extraordinary cognitive abilities in primates and humans. Since the 19th century, neur ons have been believed to be the main players in the building of the brain, yet astrocytes also play a crucial role as fundamental building blocks of the cerebral cortex complexity. Currently, astrocytes are recognized as pivotal players in the central nervous system exerting a myriad of functions, such as water homeostasis and exchange of nutrients with the blood-brain barrier. Astrocytes also play a crucial role in the development and regulation of connectivity including synapse formation and elimination, and synaptic function and plasticity (Verkhratsky and Nedergaard, 2018). Furthermore, injury or stress induces reactive astrogliosis that provides antioxidant defense and scar formation. While astrocytes have been mostly studied in mice, we are becoming aware of astrocyte heterogeneity and increased complexity in mammals and primates (Oberheim et al., 2009; Falcone et al., 2019, 2020). Astrocytes likely co-evolved with neurons, becoming more specialized in mammals versus other vertebrates. Only recently attention has been put towards specific types of astrocytes in the primate brain. Understanding how astrocytes develop, evolve across mammalian species, and regulate neuronal development and function is crucial to understand the cerebral cortex complexity characteristic of human and nonhuman primates. Related Articles | Metrics

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Emerging role of neuregulin-1beta1 in pathogenesis and progression of multiple sclerosis Seyyed Mohyeddin Ziaee, Soheila Karimi-Abdolrezaee 2023, 18 (1):  133-134.  doi: 10.4103/1673-5374.343900 Abstract ( 137 )   PDF (676KB) ( 58 )   Save Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system (CNS) that causes focal demyelinating lesions, followed by axonal and neuronal degeneration. Several genetic and environmental factors are found to be associated with MS incidence. While MS etiology seems to be multifactorial and needs further elucidation, it is understood that the response of an immune system to specific myelin antigens triggers the onset of MS (Dendrou et al., 2015). However, how the autoimmune response initiates against myelin, and the cellular and molecular mechanisms underpinning the development and progression of MS are not fully understood. Thus, deconstructing MS pathogenesis is of paramount importance for identifying novel diagnostic and therapeutic targets for this complex disease. Related Articles | Metrics

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Characterization of retinal ganglion cell damage at single axon bundle level in mice by visible-light optical coherence tomography fibergraphy Xiaorong Liu, Hao F. Zhang 2023, 18 (1):  135-136.  doi: 10.4103/1673-5374.343906 Abstract ( 144 )   PDF (377KB) ( 70 )   Save Retinal ganglion cells (RGCs) receive synaptic inputs through their dendritic trees in the inner plexiform layer (IPL) and convey the visual information via their axons which form the optic nerve to the brain (Sanes and Masland, 2015). In glaucoma, RGCs and their axons degenerate and die, leading to irreversible vision loss and eventually blindness if left untreated (Quigley, 2016). The self-destructive programs in RGCs induced by glaucomatous insults are often spatially compartmentalized (Syc-Mazurek and Libby, 2019), which results in changes in the IPL, the ganglion cell layer, and the retinal nerve fiber layer (RNFL) before cell death in humans and rodents (Wollstein et al., 2012; Chen et al., 2015; Grannonico et al., 2021). Characterizing RGC morphological changes is thus potentially pertinent for timely intervention to preserve RGCs and vision, but much remains unknown to establish a sensitive and specific marker of RGC damage for better diagnosis and management of glaucoma. Related Articles | Metrics

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Pointing fingers at blood contact: mechanisms of subventricular zone neural stem cell differentiation Subash C. Malik, Yu-Hsuan Chu, Christian Schachtrup 2023, 18 (1):  137-138.  doi: 10.4103/1673-5374.338998 Abstract ( 163 )   PDF (1034KB) ( 114 )   Save The limited ability of the central nervous system (CNS) to regenerate in adult mammals after injury or disease is a significant problem. Intriguingly, neural stem/progenitor cells (NSPCs) offer great promise for regenerating the CNS. Endogenous or transplanted NSPCs contribute to repair processes, but their differentiation and function are abnormal in CNS injury and disease. The main reasons for these abnormalities are changes in the extracellular environment in the injured CNS that affect signaling pathways and transcriptional regulation in NSPCs. In CNS disease with vascular permeability or blood-brain barrier disruption, blood-derived fibrinogen enters the parenchyma and drastically changes the extracellular environment of brain cells, including NSPCs. Fibrinogen is present in the brain in a wide range of CNS pathologies, such as multiple sclerosis, Alzheimer’s disease, stroke, and traumatic brain injury. Here, within this perspective, we focus on how the blood-derived coagulation factor fibrinogen alters the subventricular zone (SVZ) stem cell niche environment to activate the bone morphogenetic protein (BMP) receptor (BMPR) signaling pathway in NSPCs. The activated BMPR signaling increases p75 neurotrophin receptor (p75NTR) and inhibitor of DNA binding 3 (Id3) abundance in NSPCs, and thus, regulates NSPC migration and differentiation in a mouse model of cortical ischemic stroke (photothrombotic ischemia) and cortical brain trauma (stab wound injury) (Pous et al., 2020; Deshpande et al., 2021). NSPCs located in the adult mammalian SVZ are an endogenous source for cell replacement and brain repair. The fine-tuned cellular and molecular niche environment controls the cardinal features of the SVZ NSPCs: an unlimited capacity for self-renewal, indefinite ability to proliferate, and multipotency for the different neuroectodermal lineages of the CNS. Pathological states induce dynamic changes in this niche and trigger a regenerative response, but the regulatory mechanisms that control NSPC differentiation in CNS disease are largely unknown. In contrast to the human brain SVZ, where production of new neurons is highly reduced by 2 years of age and little to no neurogenesis is observed after childhood, the adult rodent brain SVZ continuously produces new neurons throughout life and reacts to CNS injury and disease. Therefore, the adult rodent SVZ is ideally suited for studying cellular signaling cascades and transcriptional programs in adult NSPCs and for identifying potential pharmacological and regenerative cell-based therapies for neuronal regeneration. Improved control of the endogenous or transplanted NSPC fate and functions will provide optimized therapeutic effects by replacement of lost neurons and severed axons and creation of a permissive microenvironment to promote CNS tissue repair. Related Articles | Metrics

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Regenerative capacity of Müller cells and their modulation as a tool to treat retinal degenerations Federica M. Conedera, Volker Enzmann 2023, 18 (1):  139-140.  doi: 10.4103/1673-5374.340408 Abstract ( 188 )   PDF (675KB) ( 64 )   Save Vision is one of our most precious senses, and its impairment has a high socio-economic impact. In the industrialized world, degenerative diseases of the retina lead to vision loss, particularly among the elderly. These degenerations include, for instance, retinitis pigmentosa, age-related macular degeneration, and diabetic retinopathy. Although treatments are evolving to manage late-stage symptoms of retinal degenerations, no effective therapies to recover vision loss exist. Retinal degeneration often involves loss or damage to specialized neural cells, such as photoreceptors, and their death stimulates the activation and proliferation of Müller cells (Salman et al., 2021). Related Articles | Metrics

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Maraviroc promotes recovery from traumatic brain injury in mice by suppression of neuroinflammation and activation of neurotoxic reactive astrocytes Xi-Lei Liu, Dong-Dong Sun, Mu-Tian Zheng, Xiao-Tian Li, Han-Hong Niu, Lan Zhang, Zi-Wei Zhou, Hong-Tao Rong, Yi Wang, Ji-Wei Wang, Gui-Li Yang, Xiao Liu, Fang-Lian Chen, Yuan Zhou, Shu Zhang, Jian-Ning Zhang 2023, 18 (1):  141-149.  doi: 10.4103/1673-5374.344829 Abstract ( 235 )   PDF (19180KB) ( 91 )   Save Neuroinflammation and the NACHT, LRR, and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury (TBI). Maraviroc, a C-C chemokine receptor type 5 antagonist, has been viewed as a new therapeutic strategy for many neuroinflammatory diseases. We studied the effect of maraviroc on TBI-induced neuroinflammation. A moderate-TBI mouse model was subjected to a controlled cortical impact device. Maraviroc or vehicle was injected intraperitoneally 1 hour after TBI and then once per day for 3 consecutive days. Western blot, immunohistochemistry, and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) analyses were performed to evaluate the molecular mechanisms of maraviroc at 3 days post-TBI. Our results suggest that maraviroc administration reduced NACHT, LRR, and PYD domains-containing protein 3 inflammasome activation, modulated microglial polarization from M1 to M2, decreased neutrophil and macrophage infiltration, and inhibited the release of inflammatory factors after TBI. Moreover, maraviroc treatment decreased the activation of neurotoxic reactive astrocytes, which, in turn, exacerbated neuronal cell death. Additionally, we confirmed the neuroprotective effect of maraviroc using the modified neurological severity score, rotarod test, Morris water maze test, and lesion volume measurements. In summary, our findings indicate that maraviroc might be a desirable pharmacotherapeutic strategy for TBI, and C-C chemokine receptor type 5 might be a promising pharmacotherapeutic target to improve recovery after TBI. Related Articles | Metrics

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Dysregulated expression and distribution of Kif5α in neurites of wobbler motor neurons Kilian Kürten, Anne-Christin Gude, Aimo Samuel Christian Epplen, Jan Stein, Carsten Theiss, Veronika Matschke 2023, 18 (1):  150-154.  doi: 10.4103/1673-5374.343883 Abstract ( 173 )   PDF (3302KB) ( 99 )   Save Impaired axonal transport has been observed in patients with amyotrophic lateral sclerosis (ALS) and in animal models, suggesting that transport proteins likely play a critical role in the pathological mechanism of ALS. Dysregulation of Kinesin-family-member 5α (Kif5α), a neuron-specific isoform of heavy chain kinesin family, has been described in several neurological disorders, in humans and animal models, including ALS. In this study, we determined Kif5α expression by gene sequencing, quantitative reverse transcription-polymerase chain reaction, and western blot assay in the cervical spinal cord of wobbler mice and immunofluorescence staining in dissociated cultures of the ventral horn. Further, we observed the distribution of Kif5α and mitochondria along motor neuronal branches by confocal imaging. Our results showed that Kif5α expression was greatly dysregulated in wobbler mice, which resulted in altered distribution of Kif5α along motor neuronal branches with an abnormal mitochondrial distribution. Thus, our results indicate that dysregulation of Kif5 and therefore abnormal transport in motor neuronal branches in this ALS model could be causative for several pathological findings at the cellular level, like misallocation of cytoskeletal proteins or organelles like mitochondria. Related Articles | Metrics

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Tandem Mass Tag-based proteomics analysis reveals the vital role of inflammation in traumatic brain injury in a mouse model Jin-Qian Dong, Qian-Qian Ge, Sheng-Hua Lu, Meng-Shi Yang, Yuan Zhuang, Bin Zhang, Fei Niu, Xiao-Jian Xu, Bai-Yun Liu 2023, 18 (1):  155-161.  doi: 10.4103/1673-5374.343886 Abstract ( 193 )   PDF (3449KB) ( 134 )   Save Proteomics is a powerful tool that can be used to elucidate the underlying mechanisms of diseases and identify new biomarkers. Therefore, it may also be helpful for understanding the detailed pathological mechanism of traumatic brain injury (TBI). In this study, we performed Tandem Mass Tag-based quantitative analysis of cortical proteome profiles in a mouse model of TBI. Our results showed that there were 302 differentially expressed proteins in TBI mice compared with normal mice 7 days after injury. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that these differentially expressed proteins were predominantly involved in inflammatory responses, including complement and coagulation cascades, as well as chemokine signaling pathways. Subsequent transcription factor analysis revealed that the inflammation-related transcription factors NF-κB1, RelA, IRF1, STAT1, and Spi1 play pivotal roles in the secondary injury that occurs after TBI, which further corroborates the functional enrichment for inflammatory factors. Our results suggest that inflammation-related proteins and inflammatory responses are promising targets for the treatment of TBI.  Related Articles | Metrics

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Nerve growth factor-basic fibroblast growth factor poly-lactide co-glycolid sustained-release microspheres and the small gap sleeve bridging technique to repair peripheral nerve injury Ming Li, Ting-Min Xu, Dian-Ying Zhang, Xiao-Meng Zhang, Feng Rao, Si-Zheng Zhan, Man Ma, Chen Xiong, Xiao-Feng Chen, Yan-Hua Wang 2023, 18 (1):  162-169.  doi: 10.4103/1673-5374.344842 Abstract ( 190 )   PDF (3294KB) ( 94 )   Save We previously prepared nerve growth factor poly-lactide co-glycolid sustained-release microspheres to treat rat sciatic nerve injury using the small gap sleeve technique. Multiple growth factors play a synergistic role in promoting the repair of peripheral nerve injury; as a result, in this study, we added basic fibroblast growth factors to the microspheres to further promote nerve regeneration. First, in an in vitro biomimetic microenvironment, we developed and used a drug screening biomimetic microfluidic chip to screen the optimal combination of nerve growth factor/basic fibroblast growth factor to promote the regeneration of Schwann cells. We found that 22.56 ng/mL nerve growth factor combined with 4.29 ng/mL basic fibroblast growth factor exhibited optimal effects on the proliferation of primary rat Schwann cells. The successfully prepared nerve growth factor-basic fibroblast growth factor-poly-lactide-co-glycolid sustained-release microspheres were used to treat rat sciatic nerve transection injury using the small gap sleeve bridge technique. Compared with epithelium sutures and small gap sleeve bridging alone, the small gap sleeve bridging technique combined with drug-free sustained-release microspheres has a stronger effect on rat sciatic nerve transfection injury repair at the structural and functional level.  Related Articles | Metrics

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Early brainstem hemorrhage progression: multi-sequence magnetic resonance imaging and histopathology Xi Guo, Jia-Ke Xu, Xin Qi, Yang Wei, Cheng-Wei Wang, Hao Li, Lu Ma, Chao You, Meng Tian 2023, 18 (1):  170-175.  doi: 10.4103/1673-5374.344838 Abstract ( 201 )   PDF (6979KB) ( 38 )   Save According to clinical statistics, the mortality of patients with early brainstem hemorrhage is high. In this study, we established rat models of brainstem hemorrhage by injecting type VII collagenase into the right basotegmental pontine and investigated the pathological changes of early brainstem hemorrhage using multi-sequence magnetic resonance imaging and histopathological methods. We found that brainstem hematoma gradually formed in the injured rats over the first 3 days and then reduced after 7 days. The edema that occurred was mainly of the vasogenic type. No complete myelin sheath structure was found around the focus of the brainstem hemorrhage. The integrity and continuity of nerve fibers gradually deteriorated over the first 7 days. Neuronal degeneration was mild in the first 3 days and then obviously aggravated on the 7th day. Inflammatory cytokines, interleukin-1β, and tumor necrosis factor α appeared on the 1st day after intracerebral hemorrhage, reached peak levels on the 3rd day, and decreased from the 7th day. Our findings show the characteristics of the progression of early brainstem hemorrhage. Related Articles | Metrics

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Diffusion tensor imaging reveals brain structure changes in dogs after spinal cord injury Chang-Bin Liu, De-Gang Yang, Jun Li, Chuan Qin, Xin Zhang, Jun Liu, Da-Peng Li, Jian-Jun Li 2023, 18 (1):  176-182.  doi: 10.4103/1673-5374.344839 Abstract ( 176 )   PDF (9740KB) ( 37 )   Save Based on the Wallerian degeneration in the spinal cord pathways, the changes in synaptic connections, and the spinal cord-related cellular responses that alter the cellular structure of the brain, we presumed that brain diffusion tensor imaging (DTI) parameters may change after spinal cord injury. However, the dynamic changes in DTI parameters remain unclear. We established a Beagle dog model of T10 spinal cord contusion and performed DTI of the injured spinal cord. We found dynamic changes in DTI parameters in the cerebral peduncle, posterior limb of the internal capsule, pre- and postcentral gyri of the brain within 12 weeks after spinal cord injury. We then performed immunohistochemistry to detect the expression of neurofilament heavy polypeptide (axonal marker), glial fibrillary acidic protein (glial cell marker), and NeuN (neuronal marker). We found that these pathological changes were consistent with DTI parameter changes. These findings suggest that DTI can display brain structure changes after spinal cord injury. Related Articles | Metrics

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Icariin ameliorates memory deficits through regulating brain insulin signaling and glucose transporters in 3×Tg-AD mice Fei Yan, Ju Liu, Mei-Xiang Chen, Ying Zhang, Sheng-Jiao Wei, Hai Jin, Jing Nie, Xiao-Long Fu, Jing-Shan Shi, Shao-Yu Zhou, Feng Jin 2023, 18 (1):  183-188.  doi: 10.4103/1673-5374.344840 Abstract ( 148 )   PDF (3814KB) ( 112 )   Save Icariin, a major prenylated flavonoid found in Epimedium spp., is a bioactive constituent of Herba Epimedii and has been shown to exert neuroprotective effects in experimental models of Alzheimer’s disease. In this study, we investigated the neuroprotective mechanism of icariin in an APP/PS1/Tau triple-transgenic mouse model of Alzheimer’s disease. We performed behavioral tests, pathological examination, and western blot assay, and found that memory deficits of the model mice were obviously improved, neuronal and synaptic damage in the cerebral cortex was substantially mitigated, and amyloid-β accumulation and tau hyperphosphorylation were considerably reduced after 5 months of intragastric administration of icariin at a dose of 60 mg/kg body weight per day. Furthermore, deficits of proteins in the insulin signaling pathway and their phosphorylation levels were significantly reversed, including the insulin receptor, insulin receptor substrate 1, phosphatidylinositol-3-kinase, protein kinase B, and glycogen synthase kinase 3β, and the levels of glucose transporter 1 and 3 were markedly increased. These findings suggest that icariin can improve learning and memory impairments in the mouse model of Alzheimer’s disease by regulating brain insulin signaling and glucose transporters, which lays the foundation for potential clinical application of icariin in the prevention and treatment of Alzheimer’s disease. Related Articles | Metrics

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Lamotrigine protects against cognitive deficits, synapse and nerve cell damage, and hallmark neuropathologies in a mouse model of Alzheimer’s disease Xin-Xin Fu, Rui Duan, Si-Yu Wang, Qiao-Quan Zhang, Bin Wei, Ting Huang, Peng-Yu Gong, Yan E, Teng Jiang, Ying-Dong Zhang 2023, 18 (1):  189-193.  doi: 10.4103/1673-5374.343888 Abstract ( 179 )   PDF (2665KB) ( 131 )   Save Lamotrigine (LTG) is a widely used drug for the treatment of epilepsy. Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease. However, the underlying molecular mechanisms remain unclear. In this study, amyloid precursor protein/presenilin 1 (APP/PS1) double transgenic mice were used as a model of Alzheimer’s disease. Five-month-old APP/PS1 mice were intragastrically administered 30 mg/kg LTG or vehicle once per day for 3 successive months. The cognitive functions of animals were assessed using Morris water maze. Hyperphosphorylated tau and markers of synapse and glial cells were detected by western blot assay. The cell damage in the brain was investigated using hematoxylin and eosin staining. The levels of amyloid-β and the concentrations of interleukin-1β, interleukin-6 and tumor necrosis factor-α in the brain were measured using enzyme-linked immunosorbent assay. Differentially expressed genes in the brain after LTG treatment were analyzed by high-throughput RNA sequencing and real-time polymerase chain reaction. We found that LTG substantially improved spatial cognitive deficits of APP/PS1 mice; alleviated damage to synapses and nerve cells in the brain; and reduced amyloid-β levels, tau protein hyperphosphorylation, and inflammatory responses. High-throughput RNA sequencing revealed that the beneficial effects of LTG on Alzheimer’s disease-related neuropathologies may have been mediated by the regulation of Ptgds, Cd74, Map3k1, Fosb, and Spp1 expression in the brain. These findings revealed potential molecular mechanisms by which LTG treatment improved Alzheimer’s disease. Furthermore, these data indicate that LTG may be a promising therapeutic drug for Alzheimer’s disease. Related Articles | Metrics

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DL-3-n-butylphthalide alleviates motor disturbance by suppressing ferroptosis in a rat model of Parkinson’s disease Chun-Bo Hu, Hui Jiang, Yin Yang, Guo-Hua Wang, Qiu-Hong Ji, Zhong-Zheng Jia, Li-Hua Shen, Qian-Qian Luo 2023, 18 (1):  194-199.  doi: 10.4103/1673-5374.343892 Abstract ( 207 )   PDF (4012KB) ( 69 )   Save DL-3-n-butylphthalide (NBP)—a compound isolated from Apium graveolens seeds—is protective against brain ischemia via various mechanisms in humans and has been approved for treatment of acute ischemic stroke. NBP has shown recent potential as a treatment for Parkinson’s disease. However, the underlying mechanism of action of NBP remains poorly understood. In this study, we established a rat model of Parkinson’s disease by intraperitoneal injection of rotenone for 28 successive days, followed by intragastric injection of NBP for 14–28 days. We found that NBP greatly alleviated rotenone-induced motor disturbance in the rat model of Parkinson’s disease, inhibited loss of dopaminergic neurons and aggregation of α-synuclein, and reduced iron deposition in the substantia nigra and iron content in serum. These changes were achieved by alterations in the expression of the iron metabolism-related proteins transferrin receptor, ferritin light chain, and transferrin 1. NBP also inhibited oxidative stress in the substantia nigra and protected mitochondria in the rat model of Parkinson’s disease. Our findings suggest that NBP alleviates motor disturbance by inhibition of iron deposition, oxidative stress, and ferroptosis in the substantia nigra. Related Articles | Metrics

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Reduced graphene oxide-embedded nerve conduits loaded with bone marrow mesenchymal stem cell-derived extracellular vesicles promote peripheral nerve regeneration Wei Zhang, Xing-Xing Fang, Qi-Cheng Li, Wei Pi, Na Han 2023, 18 (1):  200-206.  doi: 10.4103/1673-5374.343889 Abstract ( 194 )   PDF (5959KB) ( 150 )   Save We previously combined reduced graphene oxide (rGO) with gelatin-methacryloyl (GelMA) and polycaprolactone (PCL) to create an rGO-GelMA-PCL nerve conduit and found that the conductivity and biocompatibility were improved. However, the rGO-GelMA-PCL nerve conduits differed greatly from autologous nerve transplants in their ability to promote the regeneration of injured peripheral nerves and axonal sprouting. Extracellular vesicles derived from bone marrow mesenchymal stem cells (BMSCs) can be loaded into rGO-GelMA-PCL nerve conduits for repair of rat sciatic nerve injury because they can promote angiogenesis at the injured site. In this study, 12 weeks after surgery, sciatic nerve function was measured by electrophysiology and sciatic nerve function index, and myelin sheath and axon regeneration were observed by electron microscopy, immunohistochemistry, and immunofluorescence. The regeneration of microvessel was observed by immunofluorescence. Our results showed that rGO-GelMA-PCL nerve conduits loaded with BMSC-derived extracellular vesicles were superior to rGO-GelMA-PCL conduits alone in their ability to increase the number of newly formed vessels and axonal sprouts at the injury site as well as the recovery of neurological function. These findings indicate that rGO-GelMA-PCL nerve conduits loaded with BMSC-derived extracellular vesicles can promote peripheral nerve regeneration and neurological function recovery, and provide a new direction for the curation of peripheral nerve defect in the clinic. Related Articles | Metrics

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Electrodeposition of chitosan/graphene oxide conduit to enhance peripheral nerve regeneration Ya-Nan Zhao, Ping Wu, Zi-Yuan Zhao, Fei-Xiang Chen, Ao Xiao, Zhi-Yi Yue, Xin-Wei Han, Yong Zheng, Yun Chen 2023, 18 (1):  207-212.  doi: 10.4103/1673-5374.344836 Abstract ( 174 )   PDF (5920KB) ( 271 )   Save Currently available commercial nerve guidance conduits have been applied in the repair of peripheral nerve defects. However, a conduit exhibiting good biocompatibility remains to be developed. In this work, a series of chitosan/graphene oxide (GO) films with concentrations of GO varying from 0–1 wt% (collectively referred to as CHGF-n) were prepared by an electrodeposition technique. The effects of CHGF-n on proliferation and adhesion abilities of Schwann cells were evaluated. The results showed that Schwann cells exhibited elongated spindle shapes and upregulated expression of nerve regeneration-related factors such as Krox20 (a key myelination factor), Zeb2 (essential for Schwann cell differentiation, myelination, and nerve repair), and transforming growth factor β (a cytokine with regenerative functions). In addition, a nerve guidance conduit with a GO content of 0.25% (CHGFC-0.25) was implanted to repair a 10-mm sciatic nerve defect in rats. The results indicated improvements in sciatic functional index, electrophysiology, and sciatic nerve and gastrocnemius muscle histology compared with the CHGFC-0 group, and similar outcomes to the autograft group. In conclusion, we provide a candidate method for the repair of peripheral nerve defects using free-standing chitosan/GO nerve conduits produced by electrodeposition. Related Articles | Metrics

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Muse cells decrease the neuroinflammatory response by modulating the proportion of M1 and M2 microglia in vitro Xin-Yao Yin, Chen-Chun Wang, Pan Du, Xue-Song Wang, Yi-Chi Lu, Yun-Wei Sun, Yue-Hui Sun, Yi-Man Hu, Xue Chen 2023, 18 (1):  213-218.  doi: 10.4103/1673-5374.343885 Abstract ( 193 )   PDF (2272KB) ( 105 )   Save Neuroinflammation hinders repair of the central nervous system (CNS). Stem cell transplantation is a very promising approach for treatment of CNS injuries. However, it is difficult to select seed cells that can both facilitate nerve regeneration and improve the microenvironment in the CNS. In this study, we isolated multilineage-differentiating stress-enduring (Muse) cells from bone marrow mesenchymal stem cells. We explored the anti-inflammatory effect and mechanism of Muse cells in vitro by coculture of Muse cells with lipopolysaccharide-stimulated microglia. Our results showed that Muse cells effectively reduced the transcription and secretion of tumor necrosis factor α and interleukin-1β and increased the expression of transforming growth factor-β and interleukin-10 in microglia. In addition, Muse cells decreased the number of M1 microglia and increased the proportion of M2 microglia in an inflammatory environment more effectively than bone marrow mesenchymal stem cells. We also show that Muse cells inhibited the protein expression of toll-like receptor 4 (TLR4) and myeloid differentiation primary response protein (MyD88) and inhibited the expression of the phosphorylated forms of transcription factor p65, nuclear factor (NF)-κB inhibitor alpha, and p38 mitogen-activated protein kinase (MAPK) in microglia. Therefore, we suggest Muse cells cause antineuroinflammatory effects by inhibition of the TLR4/MyD88/NF-κB and p38 MAPK signaling pathways in microglia. Our results shed light on the function of Muse cells in relation to CNS diseases and provide insight into the selection of seed cells. Related Articles | Metrics

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Optic nerve injury-induced regeneration in the adult zebrafish is accompanied by spatiotemporal changes in mitochondrial dynamics An Beckers, Luca Masin, Annelies Van Dyck, Steven Bergmans, Sophie Vanhunsel, Anyi Zhang, Tine Verreet, Fabienne E. Poulain, Karl Farrow, Lieve Moons 2023, 18 (1):  219-225.  doi: 10.4103/1673-5374.344837 Abstract ( 181 )   PDF (7859KB) ( 48 )   Save Axonal regeneration in the central nervous system is an energy-intensive process. In contrast to mammals, adult zebrafish can functionally recover from neuronal injury. This raises the question of how zebrafish can cope with this high energy demand. We previously showed that in adult zebrafish, subjected to an optic nerve crush, an antagonistic axon-dendrite interplay exists wherein the retraction of retinal ganglion cell dendrites is a prerequisite for effective axonal repair. We postulate a ‘dendrites for regeneration’ paradigm that might be linked to intraneuronal mitochondrial reshuffling, as ganglion cells likely have insufficient resources to maintain dendrites and restore axons simultaneously. Here, we characterized both mitochondrial distribution and mitochondrial dynamics within the different ganglion cell compartments (dendrites, somas, and axons) during the regenerative process. Optic nerve crush resulted in a reduction of mitochondria in the dendrites during dendritic retraction, whereafter enlarged mitochondria appeared in the optic nerve/tract during axonal regrowth. Upon dendritic regrowth in the retina, mitochondrial density inside the retinal dendrites returned to baseline levels. Moreover, a transient increase in mitochondrial fission and biogenesis was observed in retinal ganglion cell somas after optic nerve damage. Taken together, these findings suggest that during optic nerve injury-induced regeneration, mitochondria shift from the dendrites to the axons and back again and that temporary changes in mitochondrial dynamics support axonal and dendritic regrowth after optic nerve crush.  Related Articles | Metrics

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Lactoferrin modification of berberine nanoliposomes enhances the neuroprotective effects in a mouse model of Alzheimer’s disease Lin Wang, Bi-Qiang Zhou, Ying-Hong Li, Qian-Qian Jiang, Wei-Hong Cong, Ke-Ji Chen, Xiao-Min Wen, Zheng-Zhi Wu 2023, 18 (1):  226-232.  doi: 10.4103/1673-5374.344841 Abstract ( 176 )   PDF (2953KB) ( 162 )   Save Previous studies have shown that berberine has neuroprotective effects against Alzheimer’s disease, including antagonizing tau phosphorylation, and inhibiting acetylcholinesterase activity and neural cell apoptosis. However, its low bioavailability and adverse reactions with conventional administration limit its clinical application. In this study, we prepared berberine nanoliposomes using liposomes characterized by low toxicity, high entrapment efficiency, and biodegradability, and modified them with lactoferrin. Lactoferrin-modified berberine nanoliposomes had uniform particle size and high entrapment efficiency. We used the lactoferrin-modified berberine nanoliposomes to treat a mouse model of Alzheimer’s disease established by injection of amyloid-beta 1–42 into the lateral ventricle. Lactoferrin-modified berberine nanoliposomes inhibited acetylcholinesterase activity and apoptosis in the hippocampus, reduced tau over-phosphorylation in the cerebral cortex, and improved mouse behavior. These findings suggest that modification with lactoferrin can enhance the neuroprotective effects of berberine nanoliposomes in Alzheimer’s disease. Related Articles | Metrics