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15 September 2022, Volume 17 Issue 9 Previous Issue   

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Astrocytes protect dopaminergic neurons against aminochrome neurotoxicity Juan Segura-Aguilar, Bengt Mannervik, José Inzunza, Mukesh Varshney, Ivan Nalvarte, Patricia Muñoz 2022, 17 (9):  1861-1866.  doi: 10.4103/1673-5374.335690 Abstract ( 347 )   PDF (1589KB) ( 92 )   Save Astrocytes protect neurons by modulating neuronal function and survival. Astrocytes support neurons in several ways. They provide energy through the astrocyte-neuron lactate shuttle, protect neurons from excitotoxicity, and internalize neuronal lipid droplets to degrade fatty acids for neuronal metabolic and synaptic support, as well as by their high capacity for glutamate uptake and the conversion of glutamate to glutamine. A recent reported astrocyte system for protection of dopamine neurons against the neurotoxic products of dopamine, such as aminochrome and other o-quinones, were generated under neuromelanin synthesis by oxidizing dopamine catechol structure. Astrocytes secrete glutathione transferase M2-2 through exosomes that transport this enzyme into dopaminergic neurons to protect these neurons against aminochrome neurotoxicity. The role of this new astrocyte protective mechanism in Parkinson´s disease is discussed. Related Articles | Metrics

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Non-human primate pluripotent stem cells for the preclinical testing of regenerative therapies Ignacio Rodríguez-Polo, Rüdiger Behr 2022, 17 (9):  1867-1874.  doi: 10.4103/1673-5374.335689 Abstract ( 217 )   PDF (1425KB) ( 128 )   Save Non-human primates play a key role in the preclinical validation of pluripotent stem cell-based cell replacement therapies. Pluripotent stem cells used as advanced therapy medical products boost the possibility to regenerate tissues and organs affected by degenerative diseases. Therefore, the methods to derive human induced pluripotent stem cell and embryonic stem cell lines following clinical standards have quickly developed in the last 15 years. For the preclinical validation of cell replacement therapies in non-human primates, it is necessary to generate non-human primate pluripotent stem cell with a homologous quality to their human counterparts. However, pluripotent stem cell technologies have developed at a slower pace in non-human primates in comparison with human cell systems. In recent years, however, relevant progress has also been made with non-human primate pluripotent stem cells. This review provides a systematic overview of the progress and remaining challenges for the generation of non-human primate induced pluripotent stem cells/embryonic stem cells for the preclinical testing and validation of cell replacement therapies. We focus on the critical domains of (1) reprogramming and embryonic stem cell line derivation, (2) cell line maintenance and characterization and, (3) application of non-human primate pluripotent stem cells in the context of selected preclinical studies to treat cardiovascular and neurodegenerative disorders performed in non-human primates. Related Articles | Metrics

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Emerging roles of circular RNAs in retinal diseases Aneliya Hanineva, Karen Sophia Park, Joshua J. Wang, Margaret M. DeAngelis, Michael H. Farkas, Sarah X. Zhang 2022, 17 (9):  1875-1880.  doi: 10.4103/1673-5374.335691 Abstract ( 266 )   PDF (460KB) ( 182 )   Save Retinal disorders are a group of ocular diseases whose onset is associated with a number of aberrant molecular and cellular processes or physical damages that affect retinal structure and function resulting in neural and vascular degeneration in the retina. Current research has primarily focused on delaying retinal disease with minimal success in preventing or reversing neuronal degeneration. In this review, we explore a relatively new field of research involving circular RNAs, whose potential roles as biomarkers and mediators of retinal disease pathogenesis have only just emerged. While knowledge of circular RNAs function is limited given its novelty, current evidence has highlighted their roles as modulators of microRNAs, regulators of gene transcription, and biomarkers of disease development and progression. Here, we summarize how circular RNAs may be implicated in the pathogenesis of common retinal diseases including diabetic retinopathy, glaucoma, proliferative vitreoretinopathy, and age-related macular degeneration. Further, we explore the potential of circular RNAs as novel biomarkers and therapeutic targets for the diagnosis and treatment of retinal diseases. Related Articles | Metrics

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Intranasal neprilysin rapidly eliminates amyloid-beta plaques, but causes plaque compensations: the explanation why the amyloid-beta cascade may fail? Christian Humpel 2022, 17 (9):  1881-1884.  doi: 10.4103/1673-5374.335138 Abstract ( 304 )   PDF (750KB) ( 63 )   Save Neurodegenerative brain disorders are a major burden in our society, such as Alzheimer´s disease. In order to repair or prevent such diseases, drugs are designed which enter the brain, but the blood-brain barrier limits their entry and the search for alternative pathways is important. Recently, we reported that intranasal delivery of the amyloid-beta degrading enzyme neprilysin eliminated amyloid-beta plaques in transgenic Alzheimer´s disease mice. This review describes the anatomical structure of the intranasal pathway, explains the intranasal delivery of pure neprilysin, cell-loaded neprilysin (platelets) and collagen-embedded neprilysin to destruct amyloid-beta plaques in Alzheimer´s disease in transgenic APP_SweDI mice and hypothesizes why this may cause compensation and why the amyloid-beta cascade hypothesis may fail. Related Articles | Metrics

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Neuroprotective agents effective against radiation damage of central nervous system Mária Lalkovičová 2022, 17 (9):  1885-1892.  doi: 10.4103/1673-5374.335137 Abstract ( 168 )   PDF (1090KB) ( 296 )   Save Ionizing radiation caused by medical treatments, nuclear events or even space flights can irreversibly damage structure and function of brain cells. That can result in serious brain damage, with memory and behavior disorders, or even fatal oncologic or neurodegenerative illnesses. Currently used treatments and drugs are mostly targeting biochemical processes of cell apoptosis, radiation toxicity, neuroinflammation, and conditions such as cognitive-behavioral disturbances or others that result from the radiation insult. With most drugs, the side effects and potential toxicity are also to be considered. Therefore, many agents have not been approved for clinical use yet. In this review, we focus on the latest and most effective agents that have been used in animal and also in the human research, and clinical treatments. They could have the potential therapeutical use in cases of radiation damage of central nervous system, and also in prevention considering their radioprotecting effect of nervous tissue. Related Articles | Metrics

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Neuron-fibrous scaffold interfaces in the peripheral nervous system: a perspective on the structural requirements Sanaz Behtaj, James A. St John, Jenny A. K. Ekberg, Maksym Rybachuk 2022, 17 (9):  1893-1897.  doi: 10.4103/1673-5374.329003 Abstract ( 192 )   PDF (527KB) ( 104 )   Save The nerves of the peripheral nervous system are not able to effectively regenerate in cases of severe neural injury. This can result in debilitating consequences, including morbidity and lifelong impairments affecting the quality of the patient’s life. Recent findings in neural tissue engineering have opened promising avenues to apply fibrous tissue-engineered scaffolds to promote tissue regeneration and functional recovery. These scaffolds, known as neural scaffolds, are able to improve neural regeneration by playing two major roles, namely, by being a carrier for transplanted peripheral nervous system cells or biological cues and by providing structural support to direct growing nerve fibers towards the target area. However, successful implementation of scaffold-based therapeutic approaches calls for an appropriate design of the neural scaffold structure that is capable of up- and down-regulation of neuron-scaffold interactions in the extracellular matrix environment. This review discusses the main challenges that need to be addressed to develop and apply fibrous tissue-engineered scaffolds in clinical practice. It describes some promising solutions that, so far, have shown to promote neural cell adhesion and growth and a potential to repair peripheral nervous system injuries. Related Articles | Metrics

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Role of exosomes in the pathogenesis of inflammation in Parkinson’s disease Ke-Lu Li, Hong-Yan Huang, Hui Ren, Xing-Long Yang 2022, 17 (9):  1898-1906.  doi: 10.4103/1673-5374.335143 Abstract ( 278 )   PDF (1737KB) ( 141 )   Save Inflammatory responses, including glial cell activation and peripheral immune cell infiltration, are involved in the pathogenesis of Parkinson’s disease (PD). These inflammatory responses appear to be closely related to the release of extracellular vesicles, such as exosomes. However, the relationships among different forms of glial cell activation, synuclein dysregulation, mitochondrial dysfunction, and exosomes are complicated. This review discusses the multiple roles played by exosomes in PD-associated inflammation and concludes that exosomes can transport toxic α-synuclein oligomers to immature neurons and into the extracellular environment, inducing the oligomerization of α-synuclein in normal neurons. Misfolded α-synuclein causes microglia and astrocytes to activate and secrete exosomes. Glial cell-derived exosomes participate in communications between glial cells and neurons, triggering anti-stress and anti-inflammatory responses, in addition to axon growth. The production and release of mitochondrial vesicles and exosomes establish a new mechanism for linking mitochondrial dysfunction to systemic inflammation associated with PD. Given the relevance of exosomes as mediators of neuron-glia communication in neuroinflammation and neuropathogenesis, new targeted treatment strategies are currently being developed that use these types of extracellular vesicles as drug carriers. Exosome-mediated inflammation may be a promising target for intervention in PD patients. Related Articles | Metrics

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Neuroprotective effects of naturally sourced bioactive polysaccharides: an update Xiao-Lan Xu, Song Li, Rong Zhang, Wei-Dong Le 2022, 17 (9):  1907-1912.  doi: 10.4103/1673-5374.335142 Abstract ( 576 )   PDF (3793KB) ( 277 )   Save Polysaccharides are macromolecular complexes that have various biological activities. In vivo and in vitro studies have shown that polysaccharides play neuroprotective roles through multiple mechanisms; consequently, they have potential in the prevention and treatment of neurodegenerative diseases. This paper summarizes related research published during 2015–2020 and reviews advances in the understanding of the neuroprotective effects of bioactive polysaccharides. This review focuses on 15 bioactive polysaccharides from plants and fungi that have neuroprotective properties against oxidative stress, apoptosis, neuroinflammation, and excitatory amino acid toxicity mainly through the regulation of nuclear factor kappa-B, phosphatidylinositol-3-kinase/protein kinase B, mitogen-activated protein kinase, nuclear factor-E2-related factor 2/ hemeoxygenase-1, c-jun N-terminal kinase, protein kinase B-mammalian target of rapamycin, and reactive oxygen species-nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 signaling pathways. Natural bioactive polysaccharides have potential in the prevention and treatment of neurodegenerative diseases because of their advantageous characteristics, including multi-targeting, low toxicity, and synergistic effects. However, most of the recent related research has focused on cell and animal models. Future randomized clinical trials involving large sample sizes are needed to validate the therapeutic benefits of these neuroprotective polysaccharides in patients having neurodegenerative diseases. Related Articles | Metrics

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Repurposed anti-cancer epidermal growth factor receptor inhibitors: mechanisms of neuroprotective effects in Alzheimer’s disease Heba M. Mansour, Hala M. Fawzy, Aiman S. El-Khatib, Mahmoud M. Khattab 2022, 17 (9):  1913-1918.  doi: 10.4103/1673-5374.332132 Abstract ( 359 )   PDF (822KB) ( 133 )   Save Numerous molecular mechanisms are being examined in an attempt to discover disease-modifying drugs to slow down the underlying neurodegeneration in Alzheimer’s disease. Recent studies have shown the beneficial effects of epidermal growth factor receptor inhibitors on the enhancement of behavioral and pathological sequelae in Alzheimer’s disease. Despite the promising effects of epidermal growth factor receptor inhibitors in Alzheimer’s disease, there is no irrefutable neuroprotective evidence in well-established animal models using epidermal growth factor receptor inhibitors due to many un-explored downstream signaling pathways. This caused controversy about the potential involvement of epidermal growth factor receptor inhibitors in any prospective clinical trial. In this review, the mystery beyond the under-investigation of epidermal growth factor receptor in Alzheimer’s disease will be discussed. Furthermore, their molecular mechanisms in neurodegeneration will be explained. Also, we will shed light on SARS-COVID-19 induced neurological manifestations mediated by epidermal growth factor modulation. Finally, we will discuss future perspectives and under-examined epidermal growth factor receptor downstream signaling pathways that warrant more exploration. We conclude that epidermal growth factor receptor inhibitors are novel effective therapeutic approaches that require further research in attempts to be repositioned in the delay of Alzheimer’s disease progression.  Related Articles | Metrics

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Recent developments of neuroprotective agents for degenerative retinal disorders Kepeng Ou, Youjian Li, Ling Liu, Hua Li, Katherine Cox, Jiahui Wu, Jian Liu, Andrew D. Dick 2022, 17 (9):  1919-1928.  doi: 10.4103/1673-5374.335140 Abstract ( 358 )   PDF (1725KB) ( 115 )   Save Retinal degeneration is a debilitating ocular complication characterized by the progressive loss of photoreceptors and other retinal neurons, which are caused by a group of retinal diseases affecting various age groups, and increasingly prevalent in the elderly. Age-related macular degeneration, diabetic retinopathy and glaucoma are among the most common complex degenerative retinal disorders, posing significant public health problems worldwide largely due to the aging society and the lack of effective therapeutics. Whilst pathoetiologies vary, if left untreated, loss of retinal neurons can result in an acquired degeneration and ultimately severe visual impairment. Irrespective of underlined etiology, loss of neurons and supporting cells including retinal pigment epithelium, microvascular endothelium, and glia, converges as the common endpoint of retinal degeneration and therefore discovery or repurposing of therapies to protect retinal neurons directly or indirectly are under intensive investigation. This review overviews recent developments of potential neuroprotectants including neuropeptides, exosomes, mitochondrial-derived peptides, complement inhibitors, senolytics, autophagy enhancers and antioxidants either still experimentally or in clinical trials. Effective treatments that possess direct or indirect neuroprotective properties would significantly lift the burden of visual handicap. Related Articles | Metrics

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Alerting effects of light in healthy individuals: a systematic review and meta-analysis#br# Yi-Man Mu, Xiao-Dan Huang, Sui Zhu, Zheng-Fang Hu, Kwok-Fai So, Chao-Ran Ren, Qian Tao 2022, 17 (9):  1929-1936.  doi: 10.4103/1673-5374.335141 Abstract ( 176 )   PDF (604KB) ( 123 )   Save Light plays an essential role in psychobiological and psychophysiological processes, such as alertness. The alerting effect is influenced by light characteristics and the timing of interventions. This meta-analysis is the first to systematically review the effect of light intervention on alertness and to discuss the optimal protocol for light intervention. In this meta-analysis, registered at PROSPERO (Registration ID: CRD42020181485), we conducted a systematic search of the Web of Science, PubMed, and PsycINFO databases for studies published in English prior to August 2021. The outcomes included both subjective and objective alertness. Subgroup analyses considered a variety of factors, such as wavelength, correlated color temperature (CCT), light illuminance, and timing of interventions (daytime, night-time, or all day). Twenty-seven crossover studies and two parallel-group studies were included in this meta-analysis, with a total of 1210 healthy participants (636 (52%) male, mean age 25.62 years). The results revealed that light intervention had a positive effect on both subjective alertness (standardized mean difference (SMD) = –0.28, 95% confidence interval (CI): –0.49 to  –0.06, P = 0.01) and objective alertness in healthy subjects (SMD = –0.34, 95% CI: –0.68 to –0.01, P = 0.04). The subgroup analysis revealed that cold light was better than warm light in improving subjective alertness (SMD = –0.37, 95% CI: –0.65 to –0.10, P = 0.007, I2 = 26%) and objective alertness (SMD = –0.36, 95% CI: –0.66 to  –0.07, P = 0.02, I2 = 0). Both daytime (SMD = –0.22, 95% CI: –0.37 to  –0.07, P = 0.005, I2 = 74%) and night-time (SMD = –0.32, 95% CI: –0.61 to –0.02, P = 0.04, I2 = 0) light exposure improved subjective alertness. The results of this meta-analysis and systematic review indicate that light exposure is associated with significant improvement in subjective and objective alertness. In addition, light exposure with a higher CCT was more effective in improving alertness than light exposure with a lower CCT. Our results also suggest that both daytime and night-time light exposure can improve subjective alertness. Related Articles | Metrics

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Bone marrow-derived mononuclear stem cells in the treatment of retinal degenerations Diego García-Ayuso, Johnny Di Pierdomenico, David García-Bernal, Manuel Vidal-Sanz , María P. Villegas-Pérez 2022, 17 (9):  1937-1944.  doi: 10.4103/1673-5374.335692 Abstract ( 163 )   PDF (8737KB) ( 26 )   Save Retinal degenerative diseases affecting the outer retina in its many forms (inherited, acquired or induced) are characterized by photoreceptor loss, and represent currently a leading cause of irreversible vision loss in the world. At present, there are very few treatments capable of preventing, recovering or reversing photoreceptor degeneration or the secondary retinal remodeling, which follows photoreceptor loss and can also cause the death of other retinal cells. Thus, these diseases are nowadays one of the greatest challenges in the field of ophthalmological research. Bone marrow derived-mononuclear stem cell transplantation has shown promising results for the treatment of photoreceptor degenerations. These cells may have the potential to slow down photoreceptor loss, and therefore should be applied in the early stages of photoreceptor degenerations. Furthermore, because of their possible paracrine effects, they may have a wide range of clinical applications, since they can potentially impact on several retinal cell types at once and photoreceptor degenerations can involve different cells and/or begin in one cell type and then affect adjacent cells. The intraocular injection of bone marrow derived-mononuclear stem cells also enhances the outcomes of other treatments aimed to protect photoreceptors. Therefore, it is likely that future investigations may combine bone marrow derived-mononuclear stem cell therapy with other systemic or intraocular treatments to obtain greater therapeutic effects in degenerative retinal diseases. Related Articles | Metrics

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Is there a window of opportunity for the therapeutic use of vitamin D in multiple sclerosis? Sofia Fernanda Gonçalves Zorzella-Pezavento, Luiza Ayumi Nishiyama Mimura, Marina Bonifácio Denadai, William Danilo Fernandes de Souza, Thais Fernanda de Campos Fraga-Silva, Alexandrina Sartori 2022, 17 (9):  1945-1954.  doi: 10.4103/1673-5374.335139 Abstract ( 350 )   PDF (1837KB) ( 451 )   Save Multiple sclerosis is an autoimmune treatable but not curable disease. There are a multiplicity of medications for multiple sclerosis therapy, including a class entitled disease-modifying drugs that are mainly indicated to reduce the number and severity of disease relapses. Not all patients respond well to these therapies, and minor to severe adverse effects have been reported. Vitamin D, called sunshine vitamin, is being studied as a possible light at the end of the tunnel. In this review, we recapitulated the similar immunopathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis, the immunomodulatory and neuroprotective potential of vitamin D and the state-of-art concerning its supplementation to multiple sclerosis patients. Finally, based on our and other groups’ experimental findings, we analyzed the need to consider the relevance of the route and the different time-point administration aspects for a more rational indication of this vitamin to multiple sclerosis patients. Related Articles | Metrics

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Inhibition of central axon regeneration: perspective from chondroitin sulfate proteoglycans in lamprey spinal cord injury Jianli Hu, Li-Qing Jin, Michael E. Selzer 2022, 17 (9):  1955-1956.  doi: 10.4103/1673-5374.335144 Abstract ( 177 )   PDF (623KB) ( 101 )   Save Background: Failure of axon regeneration after spinal cord injury (SCI) underlies the paralysis that so profoundly affects patients’ quality of life.  Many factors are involved in the regeneration failure. Chondroitin sulfate proteoglycans (CSPGs), normal constituents of the perineuronal nets in central nervous system (CNS), are secreted at the injury site and initially were thought to act as a purely physical barrier. In the past decade, the receptor-like protein tyrosine phosphatases, protein tyrosine phosphatase sigma (PTPσ), and leukocyte common antigen-related phosphatase (LAR), have been identified as transmembrane receptors for CSPGs. The two receptors for myelin-associated growth inhibitors, Nogo receptors 1 and 3 (NgR1 and NgR3) also have been found to bind with CSPGs (Sharma et al., 2012). These findings suggest that CSPGs inhibit regeneration by interacting with these receptors, initiating downstream inhibitory signaling (Figure 1).  Related Articles | Metrics

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N-acetyl-L-leucine: a promising treatment option for traumatic brain injury Chinmoy Sarkar, Marta M. Lipinski 2022, 17 (9):  1957-1958.  doi: 10.4103/1673-5374.335146 Abstract ( 211 )   PDF (361KB) ( 81 )   Save Traumatic brain injury (TBI) is a mechanical injury to the brain, which can be sustained due to falls, accidents, contact sports or in combat situation. It is a serious health problem-affecting people of all ages worldwide. As per the recent epidemiological study, more than 55 million people suffer from TBI annually (GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators, 2019), and its prevalence has increased by almost 8.4% between 1990 and 2016 (GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators, 2019). Depending on severity, TBI can lead to premature death and disability. In long-term survivors, it is also a major risk factor for development of neurodegenerative diseases like Alzheimer’s disease or Parkinson’s disease (Smith et al., 2013). All together TBI causes immense emotional distress and brings huge financial burden not only to the patients and family members but also to the society (GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators, 2019). Unfortunately, there is no effective pharmacological treatment available for TBI. Current therapeutic approaches are primarily focused on minimizing or alleviating injury-inflicted symptoms but do not restrict injury-induced brain damage. Thus, there is an urgent need to identify and develop pharmacological agents that can improve TBI outcomes and prevent neurodegeneration.  Related Articles | Metrics

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Neuronal circuitry reconstruction after stem cell therapy in damaged brain Daniel Tornero 2022, 17 (9):  1959-1960.  doi: 10.4103/1673-5374.335145 Abstract ( 448 )   PDF (642KB) ( 105 )   Save Transplantation of neuronal precursors derived from human pluripotent stem cells is a promising therapy for the treatment of neurological disorders associated with neuronal loss, such us neurodegenerative diseases, brain trauma and stroke. The functional integration of grafted neurons differentiated from stem cells into the host injured neuronal circuitry has been a major challenge in cell therapy strategies for brain repair (Palma-Tortosa et al., 2021). Even though other cell types or mechanisms may provide modest clinical improvements, neuronal replacement and reconstruction of the damaged area are crucial for an optimal and long-term recovery. This process entails three important aspects (Figure 1): (1) the generation of specific neuronal subtypes representative of the damaged brain area, (2) the formation of functional afferent synaptic connections from the host brain to the grafted neurons, and (3) the establishment of functional efferent synaptic contacts from grafted cells to specific areas of the host brain. We previously showed that human skin-derived neural precursors, transplanted into the somatosensory cortex of rats after ischemic stroke, develop a pattern of afferent synaptic connections similar to endogenous neurons located in this area of the brain (Tornero et al., 2017), and form efferent connections with neurons of proper host brain structures (Palma-Tortosa et al., 2020). The ability of grafted cells to functionally integrate in the damaged host brain circuitry has been further demonstrated by other recent studies using animal models (Palma-Tortosa et al., 2021). Interestingly, also transplantation of human cortical neurons onto ex vivo organotypic cultures of adult human cortex proved the establishment of afferent and efferent synapses between host and grafted cells (Grønning Hansen et al., 2020). However, the mechanisms behind functional recovery and integration of new neurons into the brain network still present some unknown aspects that will be discussed in this article (Figure 1). Related Articles | Metrics

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Heme as an inducer of cerebral damage in hemorrhagic stroke: potential therapeutic implications Luiz Ricardo da Costa Vasconcellos, Pedro Moreno Pimentel-Coelho 2022, 17 (9):  1961-1962.  doi: 10.4103/1673-5374.335148 Abstract ( 198 )   PDF (960KB) ( 133 )   Save Intracerebral hemorrhage (ICH) consists of the rupture of a cerebral artery leading to bleeding into the surrounding parenchyma. This event has a primary phase of brain injury consisting of mechanical tissue damage due to the mass effect, followed by a secondary phase of brain injury triggered by the presence of blood components released at the site of bleeding (Bulters et al., 2018). Despite the high rates of mortality and morbidity from ICH, no effective treatment is available so far. Related Articles | Metrics

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Chronic traumatic encephalopathy: genes load the gun and repeated concussion pulls the trigger Robert Vink, Frances Corrigan 2022, 17 (9):  1963-1964.  doi: 10.4103/1673-5374.335147 Abstract ( 196 )   PDF (702KB) ( 56 )   Save The association between traumatic brain injury (TBI) and an increased risk of neurodegeneration has been recognized for some decades now (Faden and Loane, 2015), with recent evidence suggesting that a history of TBI, either as repeated concussive/mild TBI insults typically experienced by some athletes or less commonly as a single moderate/severe injury, may be linked with an increased risk of developing a specific form of neurodegeneration known as chronic traumatic encephalopathy (CTE) (McKee et al., 2016). The pathognomonic lesions of CTE are hyperphosphorylated tau aggregates, initially in neurons and astrocytes close to blood vessels at the base of the sulci, but later spreading throughout the brain (McKee et al., 2016). Recent work has focused on developing diagnostic criteria for traumatic encephalopathy syndrome, the clinical disorder associated with CTE, which is thought to encompass cognitive impairment and/or neurobehavioral impairment characterized by explosiveness, impulsivity and emotional lability (Katz et al., 2021). However, this work has yet to be validated with CTE currently only being definitively diagnosed post-mortem using well defined pathological criteria (McKee et al., 2016).  Related Articles | Metrics

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Can we promote neural regeneration through microbiota-targeted strategies? Introducing the new concept of neurobiotics Celia Herrera-Rincon, Julia Murciano-Brea, Stefano Geuna 2022, 17 (9):  1965-1966.  doi: 10.4103/1673-5374.335149 Abstract ( 134 )   PDF (581KB) ( 125 )   Save The human body is populated by a large number of microbial colonies, with an estimated 10–100 trillion microbes. The total genome size of human microbial colonies by far overwhelms the size of the host’s genome. This heterogenous group of microbial colonies (primarily bacteria, but also archaea, eukaryotes and viruses) is referred to with the term microbiota, and although most of them populate the gut, microbes are also detectable in many other organs of the body, especially in the distal tracts of the genitourinary system and the skin. Over the last years, an increasing amount of evidence has been accumulated on how the microbiota exerts a significant influence on the development and physiology of the human body. The nervous system interacts extensively with the microbiota. To refer to communication between gut microbes and neurons, we have recently suggested that the traditionally established term microbiota-gut-brain axis be replaced with a more specific brain-bacteria axis, which emphasizes the direct interrelationship between these two entities (Herrera-Rincon et al., 2020; Murciano-Brea et al., 2021). Related Articles | Metrics

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Gut microbiome: a balancing act between degeneration and regeneration Nitin Saksena, Matt Keon 2022, 17 (9):  1967-1968.  doi: 10.4103/1673-5374.335151 Abstract ( 128 )   PDF (292KB) ( 59 )   Save In a symbiotic and mutualistic manner, the gut microbiota strongly influences many vital aspects of host physiology, biology, repair, and regeneration. The role of microbiota in many areas of regenerative medicine is just beginning to emerge, but it is under-recognized because of its complexity. As we remove the barriers that impede our understanding of this complex entity, we will uncover some of the most vital facets of our microbiome that make us who we are, its intrinsic connection with not only our wellbeing, but also with regeneration within. This will subsequently define its utility in regenerative medicine. Related Articles | Metrics

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Perspective on the relationship between microbiota dysbiosis and neuroinflammation: probiotics as a treatment option Chiao W. Ng, Zahoor A. Shah 2022, 17 (9):  1969-1970.  doi: 10.4103/1673-5374.335150 Abstract ( 178 )   PDF (350KB) ( 66 )   Save Introduction: In the 1680s, Antonie van Leewenhoek was the first to observe the differences in the human gut microbiome versus the oral cavity diversity, and it led to the birth of a new term, “microbiota”. Later, the link between the brain and the gut was observed to be facilitated by the vagus nerve, allowing for neurotransmitters secreted in the gastrointestinal tract to travel to the brain, directing signals that influence brain function. The gut microbiome is linked to various diseases ranging from autism spectrum disorder to Parkinson’s disease (PD) and is projected to be the new “disease-causing mechanism,” calling for interventions that can modulate gut microbiota and mitigate brain disorders. Gut dysbiosis is observed before and after the onset of various neurodegenerative diseases and often manifests itself into gut-related diseases such as; gut inflammation, chronic constipation, and colitis. Dysbiosis of the gut can be the outcome of neuroinflammatory signaling, and the phenomenon could possibly become a marker for neurodegenerative diseases. Based on the microbiota and its role in disease conditions, new and emerging therapeutic alternatives such as probiotics (Figure 1) and prebiotics are recommended, including the fiber and the gut bacterial products such as short-chain fatty acids. Related Articles | Metrics

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Early life stress-induced neuroinflammation and neurological disorders: a novel perspective for research Clarissa Catale, Valeria Carola, Maria Teresa Viscomi 2022, 17 (9):  1971-1972.  doi: 10.4103/1673-5374.335152 Abstract ( 143 )   PDF (296KB) ( 116 )   Save Childhood maltreatment (CM) has been consistently linked with numerous detrimental outcomes concerning physical and psychological health. However, few studies have explored vulnerability to neurological disorders after CM. Early life adversity, in the form of poverty, stress and abuse, has been associated with decline in cognitive function and dementia later in life (Short and Baram, 2019). Robust preclinical data suggest that early life stress (ELS) may increase the risk and worsen the course of neurological disorders such as Alzheimer’s (AD) and Parkinson’s (PD) diseases, and traumatic brain injury (TBI) (Lesuis et al., 2018; Short and Baram, 2019; He et al., 2020; Catale et al., 2021; Sanchez et al., 2021). Related Articles | Metrics

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The blood-brain barrier models to study apolipoprotein E genotypes in Alzheimer’s disease Irundika HK Dias, Rachelle Taiwo, Dan Ma 2022, 17 (9):  1973-1974.  doi: 10.4103/1673-5374.331538 Abstract ( 173 )   PDF (412KB) ( 86 )   Save Alzheimer’s disease (AD) is a neurodegenerative disease that is characterized by an age-dependent progressive decline of memory, impairment of cognitive functions and changes in personality and behavior. Despite the improvement in understanding of the mechanisms underlying the disease, AD remains an incurable complex disorder with multifaceted pathophysiology to date. Apolipoprotein E (ApoE) is the main cholesterol carrier in the brain that supports lipid transport between brain cells. The individuals carrying the APOE4 allele are known to be at increased risk of developing AD compared with those carrying the more common APOE3 allele. Many researches have been undertaken to understand the role of APOE4 on brain cells and in AD (Shi et al., 2017). Despite the APOE allele being identified as an important genetic risk factor for cardiovascular disease and formation of blood vessels, there is comparatively less research focused on the blood-brain barrier functions in AD. The complex nature of the blood-brain barrier (BBB) and species differences hindered the development in this field. Recent advancement to induced pluripotent stem cell (iPSC) technologies provides an ideal platform to fine-tune BBB models and the possibilities to develop isogeneic models now allow us to improve our knowledge of the BBB and to model more disease relevant models. Related Articles | Metrics

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Glucose metabolism in amyotrophic lateral sclerosis: it is bitter-sweet Titaya Lerskiatiphanich, Jianina Marallag, John D. Lee 2022, 17 (9):  1975-1977.  doi: 10.4103/1673-5374.335154 Abstract ( 224 )   PDF (575KB) ( 89 )   Save A recent study by McDonald et al. (2021) focused on how peripheral glucose metabolism and handling are compromised in amyotrophic lateral sclerosis (ALS). Dysfunctions in glucose and energy metabolism have been identified in transgenic mouse models and patients with ALS. However, how these processes are altered and contribute to disease progression are not fully understood. The aforementioned study has identified several changes to glucose homeostasis in the transgenic SOD1G93A mouse model of ALS at the later stages of the disease. Specifically, the authors found that despite insulin resistance being present, there was increased glucose uptake in ALS mice, and increased glycogen accumulation in the liver. Additionally, there was evidence of glucagon resistance developing in these mice, which supports clinical observations. This perspective outlines the key aspects of glucose metabolism and demonstrates how multiple pathways relating to these processes are compromised in ALS.  Related Articles | Metrics

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Opportunities for agent based modeling of retinal stem cell transplantation Larissa M. DePamphilis, Troy Shinbrot, Maribel Vazquez 2022, 17 (9):  1978-1980.  doi: 10.4103/1673-5374.331868 Abstract ( 122 )   PDF (638KB) ( 72 )   Save Late stage blindness and visual impairment (BVI) affects over 400 million adults worldwide. These disabilities severely impact the ability of adults to function independently, reduce their quality of life, and worsen socio-economic burdens on health care systems. Importantly, the World Health Organization projects worldwide BVI from degenerated retina to more than double by the year 2050 (Bourne et al., 2021). To understand the clinical problem, consider Figure 1A depicting the retina’s seven neuronal cell types that interconnect across three nuclear layers. Retinal photoreceptors of the outer nuclear layer (ONL) are light sensitive neurons that absorb and convert photons into bioelectrical signals. Photoreceptors synapse with neurons in the inner nuclear layer, which in turn synapse with neurons of the retinal ganglion layer to transduce photonic signals through the optic nerve to the brain. Degeneration or dysfunction in any of these neuronal components can disrupt the visual circuity and result in BVI.  Related Articles | Metrics

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Cryogel scaffolds: soft and easy to use tools for neural tissue culture Ben Newland, Katherine R. Long 2022, 17 (9):  1981-1983.  doi: 10.4103/1673-5374.335156 Abstract ( 179 )   PDF (1026KB) ( 72 )   Save The mammalian central nervous system (CNS) is highly complex, with a vast array of processes and interactions occurring in a dynamic and often transient manner. How these processes are combined to regulate our behavior remains poorly understood. This has in turn led to a lack of understanding of how these processes have gone awry in the many disorders of the nervous system. In order to address this, researchers need a controlled way to manipulate the nervous system in in vitro and ex vivo cultures, in both a specific area and for a specific period of time to start to pick apart these interactions. To date, this has been technically challenging, especially when modeling focal injury to the CNS or when working with human brain tissue.   Related Articles | Metrics

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K+/Cl− co-transporter-2  upmodulation: a multi-modal therapy to treat spinal cord injury Shane V. Hegarty, Joanna Stanicka 2022, 17 (9):  1984-1986.  doi: 10.4103/1673-5374.335155 Abstract ( 185 )   PDF (429KB) ( 71 )   Save Herein, the rationale and supporting evidence for the promise of developing K+/Cl− co-transporter-2 (KCC2) neuromodulatory therapies for spinal cord injury (SCI) is discussed. SCI is commonly a life-changing, unforeseen neurotrauma that has devastating consequences for the injured person, their families and society as a whole. Because less than 1% of patients have a complete recovery, the vast majority of people after SCI have significant disabilities and can be entirely dependent upon others for assistance in their activities of daily living. The socioeconomic costs are a significant global burden, with SCI often occurring in adults during their peak earning years. Currently, there are no approved drugs that improve functional outcomes for people with SCI. Therefore, SCI commonly leads to a lifetime of disability, and new therapeutic approaches are urgently needed.  Related Articles | Metrics

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Endocannabinoid metabolism and Alzheimer’s disease Chu Chen 2022, 17 (9):  1987-1988.  doi: 10.4103/1673-5374.335153 Abstract ( 251 )   PDF (343KB) ( 70 )   Save Alzheimer’s disease (AD) is the most common cause of dementia in the elderly.  Unfortunately, there are no effective therapies currently available for prevention and treatment of AD. As it is clear now, the etiology of AD is multifactorial and complex. This means that development of AD is linked to multiple mechanisms or signaling pathways and that a single-target therapy for AD is likely insufficient to achieve therapeutic goals. Therefore, an ideal therapy for AD should be able to modify the disease through multiple signaling pathways.  2-Arachidonoylglycerol (2-AG) is an endogenous cannabinoid (endocannabinoid) displaying anti-inflammatory and neuroprotective properties, while its metabolites are arachidonic acid (AA) and AA-derived prostaglandins and leukotrienes, which are proinflammatory and neurotoxic (Figure 1). The results from recent studies show that restraining 2-AG degradation reduces neuroinflammation, Aβ formation and tau phosphorylation, maintains the synaptic integrity, and improves long-term synaptic plasticity and cognitive function in mouse models of AD (Chen et al., 2012; Piro et al., 2012; Zhang et al., 2014; Zhang and Chen, 2018; Hashem et al., 2021). These beneficial effects produced by inhibition of 2-AG metabolism result likely from enhanced 2-AG signaling and concurrently decreased eicosanoid levels as 2-AG and eicosanoids mediate multiple signaling pathways (Figure 1), suggesting that limiting 2-AG metabolism in the brain would be an ideal therapy for AD.  Related Articles | Metrics

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DNAzyme as a rising gene-silencing agent in theranostic settings Nan Zhang 2022, 17 (9):  1989-1990.  doi: 10.4103/1673-5374.335157 Abstract ( 278 )   PDF (1480KB) ( 97 )   Save Decades of biochemical studies have advanced DNA beyond its primary role as genetic blueprint. DNAzymes are single-stranded enzymatic DNA molecules that do not exist in nature. They are ideal candidates for gene silencing owing to their scalability by solid-phase synthesis (without batch variations), reprogrammability by directed evolution and local sequence alterations, compatibility with diverse delivery methods, and capability of achieving high catalytic turnover independent of any auxiliary proteins. With these unique features, various artificially evolved DNAzymes have been employed as theranostic tools in designing biosensors and logic gates, RNA/DNA cleavage and ligation, phosphorylation and dephosphorylation, DNA photorepair, and peptide side-chain modifications, to name but a few (Ponce-Salvatierra et al., 2021). This perspective will focus on the functional aspects and therapeutic potentials of RNA-cleaving DNAzymes.  Related Articles | Metrics

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Stellate ganglion block reduces inflammation and improves neurological function in diabetic rats during ischemic stroke Ting-Ting Li, Qiang Wan, Xin Zhang, Yuan Xiao, Li-Ying Sun, Yu-Rong Zhang, Xiang-Nan Liu, Wan-Chao Yang 2022, 17 (9):  1991-1997.  doi: 10.4103/1673-5374.335162 Abstract ( 313 )   PDF (2839KB) ( 101 )   Save Diabetes mellitus is an independent risk factor for ischemic stroke. Both diabetes mellitus and stroke are linked to systemic inflammation that aggravates patient outcomes. Stellate ganglion block can effectively regulate the inflammatory response. Therefore, it is hypothesized that stellate ganglion block could be a potential therapy for ischemic stroke in diabetic subjects. In this study, we induced diabetes mellitus in rats by feeding them a high-fat diet for 4 successive weeks. The left middle cerebral artery was occluded to establish models of ischemic stroke in diabetic rats. Subsequently, we performed left stellate ganglion block with 1% lidocaine using the percutaneous posterior approach 15 minutes before reperfusion and again 20 and 44 hours after reperfusion. Our results showed that stellate ganglion block did not decrease the blood glucose level in diabetic rats with diabetes mellitus but did reduce the cerebral infarct volume and the cerebral water content. It also improved the recovery of neurological function, increased 28-day survival rate, inhibited Toll like receptor 4/nuclear factor kappa B signaling pathway and reduced inflammatory response in the plasma of rats. However, injection of Toll like receptor 4 agonist lipopolysaccharide 5 minutes before stellate ganglion block inhibited the effect of stellate ganglion block, whereas injection of Toll like receptor 4 inhibitor TAK242 had no such effect. We also found that stellate ganglion block performed at night had no positive effect on diabetic ischemic stroke. These findings suggest that stellate ganglion block is a potential therapy for diabetic ischemic stroke and that it may be mediated through the Toll like receptor 4/nuclear factor kappa B signaling pathway. We also found that the therapeutic effect of stellate ganglion block is affected by circadian rhythm.  Related Articles | Metrics

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The proteome of distal nerves: implication in delayed repair and poor functional recovery Song Guo, Raymond M. Moore, M. Cristine Charlesworth, Kenneth L. Johnson, Robert J. Spinner, Anthony J. Windebank, Huan Wang 2022, 17 (9):  1998-2006.  doi: 10.4103/1673-5374.335159 Abstract ( 134 )   PDF (3509KB) ( 76 )   Save Chronic denervation is one of the key factors that affect nerve regeneration. Chronic axotomy deteriorates the distal nerve stump, causes protein changes, and renders the microenvironment less permissive for regeneration. Some of these factors/proteins have been individually studied. To better delineate the comprehensive protein expression profiles and identify proteins that contribute to or are associated with this detrimental effect, we carried out a proteomic analysis of the distal nerve using an established delayed rat sciatic nerve repair model. Four rats that received immediate repair after sciatic nerve transection served as control, whereas four rats in the experimental group (chronic denervation) had their sciatic nerve repaired after a 12-week delay. All the rats were sacrificed after 16 weeks to harvest the distal nerves for extracting proteins. Twenty-five micrograms of protein from each sample were fractionated in SDS-PAGE gels. NanoLC-MS/MS analysis was applied to the gels. Protein expression levels of nerves on the surgery side were compared to those on the contralateral side. Any protein with a P value of less than 0.05 and a fold change of 4 or higher was deemed differentially expressed. All the differentially expressed proteins in both groups were further stratified according to the biological processes. A PubMed search was also conducted to identify the differentially expressed proteins that have been reported to be either beneficial or detrimental to nerve regeneration. Ingenuity Pathway Analysis (IPA) software was used for pathway analysis. The results showed that 709 differentially expressed proteins were identified in the delayed repair group, with a bigger proportion of immune and inflammatory process-related proteins and a smaller proportion of proteins related to axon regeneration and lipid metabolism in comparison to the control group where 478 differentially expressed proteins were identified. The experimental group also had more beneficial proteins that were downregulated and more detrimental proteins that were upregulated. IPA revealed that protective pathways such as LXR/RXR, acute phase response, RAC, ERK/MAPK, CNTF, IL-6, and FGF signaling were inhibited in the delayed repair group, whereas three detrimental pathways, including the complement system, PTEN, and apoptosis signaling, were activated. An available database of the adult rodent sciatic nerve was used to assign protein changes to specific cell types.  The poor regeneration seen in the delayed repair group could be associated with the down-regulation of beneficial proteins and up-regulation of detrimental proteins. The proteins and pathways identified in this study may offer clues for future studies to identify therapeutic targets. Related Articles | Metrics

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Urolithin A alleviates blood-brain barrier disruption and attenuates neuronal apoptosis following traumatic brain injury in mice Qiu-Yuan Gong, Lin Cai, Yao Jing, Wei Wang, Dian-Xu Yang, Shi-Wen Chen, Heng-Li Tian 2022, 17 (9):  2007-2013.  doi: 10.4103/1673-5374.335163 Abstract ( 308 )   PDF (2816KB) ( 131 )   Save Urolithin A (UA) is a natural metabolite produced from polyphenolics in foods such as pomegranates, berries, and nuts. UA is neuroprotective against Parkinson’s disease, Alzheimer’s disease, and cerebral hemorrhage. However, its effect against traumatic brain injury remains unknown. In this study, we established adult C57BL/6J mouse models of traumatic brain injury by controlled cortical impact and then intraperitoneally administered UA. We found that UA greatly reduced brain edema; increased the expression of tight junction proteins in injured cortex; increased the immunopositivity of two neuronal autophagy markers, microtubule-associated protein 1A/B light chain 3A/B (LC3) and p62; downregulated protein kinase B (Akt) and mammalian target of rapamycin (mTOR), two regulators of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signaling pathway; decreased the phosphorylation levels of inhibitor of NFκB (IκB) kinase alpha (IKKα) and nuclear factor kappa B (NFκB), two regulators of the neuroinflammation-related Akt/IKK/NFκB signaling pathway; reduced blood-brain barrier permeability and neuronal apoptosis in injured cortex; and improved mouse neurological function. These findings suggest that UA may be a candidate drug for the treatment of traumatic brain injury, and its neuroprotective effects may be mediated by inhibition of the PI3K/Akt/mTOR and Akt/IKK/NFκB signaling pathways, thus reducing neuroinflammation and enhancing autophagy.  Related Articles | Metrics

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Abnormal characterization of dynamic functional connectivity in Alzheimer’s disease Cui Zhao, Wei-Jie Huang, Feng Feng, Bo Zhou, Hong-Xiang Yao, Yan-E Guo, Pan Wang, Lu-Ning Wang, Ni Shu, Xi Zhang 2022, 17 (9):  2014-2021.  doi: 10.4103/1673-5374.332161 Abstract ( 244 )   PDF (11067KB) ( 241 )   Save Numerous studies have shown abnormal brain functional connectivity in individuals with Alzheimer’s disease (AD) or amnestic mild cognitive impairment (aMCI). However, most studies examined traditional resting state functional connections, ignoring the instantaneous connection mode of the whole brain. In this case-control study, we used a new method called dynamic functional connectivity (DFC) to look for abnormalities in patients with AD and aMCI. We calculated dynamic functional connectivity strength from functional magnetic resonance imaging data for each participant, and then used a support vector machine to classify AD patients and normal controls. Finally, we highlighted brain regions and brain networks that made the largest contributions to the classification. We found differences in dynamic function connectivity strength in the left precuneus, default mode network, and dorsal attention network among normal controls, aMCI patients, and AD patients. These abnormalities are potential imaging markers for the early diagnosis of AD.  Related Articles | Metrics

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MicroRNA-101a-3p mimic ameliorates spinal cord ischemia/reperfusion injury Zai-Li Zhang, Dan Wang, Feng-Shou Chen 2022, 17 (9):  2022-2028.  doi: 10.4103/1673-5374.335164 Abstract ( 160 )   PDF (3104KB) ( 91 )   Save miR-101a-3p is expressed in a variety of organs and tissues and plays a regulatory role in many diseases, but its role in spinal cord ischemia/reperfusion injury remains unclear. In this study, we established a rat model of spinal cord ischemia/reperfusion injury by clamping the aortic arch for 14 minutes followed by reperfusion for 24 hours. Results showed that miR-101a-3p expression in L4–L6 spinal cord was greatly decreased, whereas MYCN expression was greatly increased. Dual-luciferase reporter assay results showed that miR-101a-3p targeted MYCN. MYCN immunoreactivity, which was primarily colocalized with neurons in L4–L6 spinal tissue, greatly increased after spinal cord ischemia/reperfusion injury. However, intrathecal injection of an miR-101a-3p mimic within 24 hours before injury decreased MYCN, p53, caspase-9 and interleukin-1β expression, reduced p53 immunoreactivity, reduced the number of MYCN/NeuN-positive cells and the number of necrotic cells in L4–L6 spinal tissue, and increased Tarlov scores. These findings suggest that the miR-101a-3p mimic improved spinal ischemia/reperfusion injury-induced nerve cell apoptosis and inflammation by inhibiting MYCN and the p53 signaling pathway. Therefore, miR-101a-3p mimic therapy may be a potential treatment option for spinal ischemia/reperfusion injury.  Related Articles | Metrics

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Ruxolitinib attenuates secondary injury after traumatic spinal cord injury Zhan-Yang Qian, Ren-Yi Kong, Sheng Zhang, Bin-Yu Wang, Jie Chang, Jiang Cao, Chao-Qin Wu, Zi-Yan Huang, Ao Duan, Hai-Jun Li, Lei Yang, Xiao-Jian Cao 2022, 17 (9):  2029-2035.  doi: 10.4103/1673-5374.335165 Abstract ( 183 )   PDF (4132KB) ( 115 )   Save Excessive inflammation post-traumatic spinal cord injury (SCI) induces microglial activation, which leads to prolonged neurological dysfunction. However, the mechanism underlying microglial activation-induced neuroinflammation remains poorly understood. Ruxolitinib (RUX), a selective inhibitor of JAK1/2, was recently reported to inhibit inflammatory storms caused by SARS-CoV-2 in the lung. However, its role in disrupting inflammation post-SCI has not been confirmed. In this study, microglia were treated with RUX for 24 hours and then activated with interferon-γ for 6 hours. The results showed that interferon-γ-induced phosphorylation of JAK and STAT in microglia was inhibited, and the mRNA expression levels of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-1β, interleukin-6, and cell proliferation marker Ki67 were reduced. In further in vivo experiments, a mouse model of spinal cord injury was treated intragastrically with RUX for 3 successive days, and the findings suggest that RUX can inhibit microglial proliferation by inhibiting the interferon-γ/JAK/STAT pathway. Moreover, microglia treated with RUX centripetally migrated toward injured foci, remaining limited and compacted within the glial scar, which resulted in axon preservation and less demyelination. Moreover, the protein expression levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 were reduced. The neuromotor function of SCI mice also recovered. These findings suggest that RUX can inhibit neuroinflammation through inhibiting the interferon-γ/JAK/STAT pathway, thereby reducing secondary injury after SCI and producing neuroprotective effects.  Related Articles | Metrics

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Nerve root magnetic stimulation improves locomotor function following spinal cord injury with electrophysiological improvements and cortical synaptic reconstruction Ya Zheng, Dan Zhao, Dong-Dong Xue, Ye-Ran Mao, Ling-Yun Cao, Ye Zhang, Guang-Yue Zhu, Qi Yang, Dong-Sheng Xu 2022, 17 (9):  2036-2042.  doi: 10.4103/1673-5374.335161 Abstract ( 233 )   PDF (3086KB) ( 164 )   Save Following a spinal cord injury, there are usually a number of neural pathways that remain intact in the spinal cord. These residual nerve fibers are important, as they could be used to reconstruct the neural circuits that enable motor function. Our group previously designed a novel magnetic stimulation protocol, targeting the motor cortex and the spinal nerve roots, that led to significant improvements in locomotor function in patients with a chronic incomplete spinal cord injury. Here, we investigated how nerve root magnetic stimulation contributes to improved locomotor function using a rat model of spinal cord injury. Rats underwent surgery to clamp the spinal cord at T10; three days later, the rats were treated with repetitive magnetic stimulation (5 Hz, 25 pulses/train, 20 pulse trains) targeting the nerve roots at the L5–L6 vertebrae. The treatment was repeated five times a week over a period of three weeks. We found that the nerve root magnetic stimulation improved the locomotor function and enhanced nerve conduction in the injured spinal cord. In addition, the nerve root magnetic stimulation promoted the recovery of synaptic ultrastructure in the sensorimotor cortex. Overall, the results suggest that nerve root magnetic stimulation may be an effective, noninvasive method for mobilizing the residual spinal cord pathways to promote the recovery of locomotor function.  Related Articles | Metrics

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Delivery of nitric oxide-releasing silica nanoparticles for in vivo revascularization and functional recovery after acute peripheral nerve crush injury Jung Il Lee, Ji Hun Park, Yeong-Rim Kim, Kihak Gwon, Hae Won Hwang, Gayoung Jung, Joo-Yup Lee, Jeong-Yun Sun, Jong Woong Park, Jae Ho Shin, Myoung-Ryul Ok 2022, 17 (9):  2043-2049.  doi: 10.4103/1673-5374.335160 Abstract ( 197 )   PDF (8571KB) ( 56 )   Save Nitric oxide (NO) has been shown to promote revascularization and nerve regeneration after peripheral nerve injury. However, in vivo application of NO remains challenging due to the lack of stable carrier materials capable of storing large amounts of NO molecules and releasing them on a clinically meaningful time scale. Recently, a silica nanoparticle system capable of reversible NO storage and release at a controlled and sustained rate was introduced. In this study, NO-releasing silica nanoparticles (NO-SNs) were delivered to the peripheral nerves in rats after acute crush injury, mixed with natural hydrogel, to ensure the effective application of NO to the lesion. Microangiography using a polymer dye and immunohistochemical staining for the detection of CD34 (a marker for revascularization) results showed that NO-releasing silica nanoparticles increased revascularization at the crush site of the sciatic nerve. The sciatic functional index revealed that there was a significant improvement in sciatic nerve function in NO-treated animals. Histological and anatomical analyses showed that the number of myelinated axons in the crushed sciatic nerve and wet muscle weight excised from NO-treated rats were increased. Moreover, muscle function recovery was improved in rats treated with NO-SNs. Taken together, our results suggest that NO delivered to the injured sciatic nerve triggers enhanced revascularization at the lesion in the early phase after crushing injury, thereby promoting axonal regeneration and improving functional recovery.  Related Articles | Metrics

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Sustained release of exosomes loaded into polydopamine-modified chitin conduits promotes peripheral nerve regeneration in rats Ci Li, Song-Yang Liu, Meng Zhang, Wei Pi, Bo Wang, Qi-Cheng Li, Chang-Feng Lu, Pei-Xun Zhang 2022, 17 (9):  2050-2057.  doi: 10.4103/1673-5374.335167 Abstract ( 202 )   PDF (4705KB) ( 118 )   Save Exosomes derived from mesenchymal stem cells are of therapeutic interest because of their important role in intracellular communication and biological regulation. On the basis of previously studied nerve conduits, we designed a polydopamine-modified chitin conduit loaded with mesenchymal stem cell-derived exosomes that release the exosomes in a sustained and stable manner. In vitro experiments revealed that rat mesenchymal stem cell-derived exosomes enhanced Schwann cell proliferation and secretion of neurotrophic and growth factors, increased the expression of Jun and Sox2 genes, decreased the expression of Mbp and Krox20 genes in Schwann cells, and reprogrammed Schwann cells to a repair phenotype. Furthermore, mesenchymal stem cell-derived exosomes promoted neurite growth of dorsal root ganglia. The polydopamine-modified chitin conduits loaded with mesenchymal stem cell-derived exosomes were used to bridge 2 mm rat sciatic nerve defects. Sustained release of exosomes greatly accelerated nerve healing and improved nerve function. These findings confirm that sustained release of mesenchymal stem cell-derived exosomes loaded into polydopamine-modified chitin conduits promotes the functional recovery of injured peripheral nerves. Related Articles | Metrics

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Transcranial focused ultrasound stimulation reduces vasogenic edema after middle cerebral artery occlusion in mice Li-Dong Deng, Lin Qi, Qian Suo, Sheng-Ju Wu, Muyassar Mamtilahun, Ru-Bing Shi, Ze Liu, Jun-Feng Sun, Yao-Hui Tang, Zhi-Jun Zhang, Guo-Yuan Yang, Ji-Xian Wang 2022, 17 (9):  2058-2063.  doi: 10.4103/1673-5374.335158 Abstract ( 339 )   PDF (2710KB) ( 213 )   Save Blood-brain barrier (BBB) disruption underlies the vasogenic edema and neuronal cell death induced by acute ischemic stroke. Reducing this disruption has therapeutic potential. Transcranial focused ultrasound stimulation has shown neuromodulatory and neuroprotective effects in various brain diseases including ischemic stroke. Ultrasound stimulation can reduce inflammation and promote angiogenesis and neural circuit remodeling. However, its effect on the BBB in the acute phase of ischemic stroke is unknown. In this study of mice subjected to middle cerebral artery occlusion for 90 minutes, low-intensity low-frequency (0.5 MHz) transcranial focused ultrasound stimulation was applied 2, 4, and 8 hours after occlusion. Ultrasound stimulation reduced edema volume, improved neurobehavioral outcomes, improved BBB integrity (enhanced tight junction protein ZO-1 expression and reduced IgG leakage), and reduced secretion of the inflammatory factors tumor necrosis factor-α and activation of matrix metalloproteinase-9 in the ischemic brain. Our results show that low-intensity ultrasound stimulation attenuated BBB disruption and edema formation, which suggests it may have therapeutic use in ischemic brain disease as a protector of BBB integrity.  Related Articles | Metrics

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Sustained delivery of vascular endothelial growth factor mediated by bioactive methacrylic anhydride hydrogel accelerates peripheral nerve regeneration after crush injury Wanlin Xu, Yifan Wu, Hao Lu, Yun Zhu, Jinhai Ye, Wenjun Yang 2022, 17 (9):  2064-2071.  doi: 10.4103/1673-5374.335166 Abstract ( 169 )   PDF (8083KB) ( 53 )   Save Neurotrophic factors, currently administered orally or by intravenous drip or intramuscular injection, are the main method for the treatment of peripheral nerve crush injury. However, the low effective drug concentration arriving at the injury site results in unsatisfactory outcomes. Therefore, there is an urgent need for a treatment method that can increase the effective drug concentration in the injured area. In this study, we first fabricated a gelatin modified by methacrylic anhydride hydrogel and loaded it with vascular endothelial growth factor that allowed the controlled release of the neurotrophic factor. This modified gelatin exhibited good physical and chemical properties, biocompatibility and supported the adhesion and proliferation of RSC96 cells and human umbilical vein endothelial cells. When injected into the epineurium of crushed nerves, the composite hydrogel in the rat sciatic nerve crush injury model promoted nerve regeneration, functional recovery and vascularization. The results showed that the modified gelatin gave sustained delivery of vascular endothelial growth factors and accelerated the repair of crushed peripheral nerves.  Related Articles | Metrics

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(D-Ser2) oxyntomodulin recovers hippocampal synaptic structure and theta rhythm in Alzheimer’s disease transgenic mice Guang-Zhao Yang, Qi-Chao Gao, Wei-Ran Li, Hong-Yan Cai, Hui-Min Zhao, Jian-Ji Wang, Xin-Rui Zhao, Jia-Xin Wang, Mei-Na Wu, Jun Zhang, Christian Hölscher, Jin-Shun Qi, Zhao-Jun Wang 2022, 17 (9):  2072-2078.  doi: 10.4103/1673-5374.335168 Abstract ( 170 )   PDF (2764KB) ( 75 )   Save In our previous studies, we have shown that (D-Ser2) oxyntomodulin (Oxm), a glucagon-like peptide 1 (GLP-1) receptor (GLP1R)/glucagon receptor (GCGR) dual agonist peptide, protects hippocampal neurons against Aβ1–42-induced cytotoxicity, and stabilizes the calcium homeostasis and mitochondrial membrane potential of hippocampal neurons. Additionally, we have demonstrated that (D-Ser2) Oxm improves cognitive decline and reduces the deposition of amyloid-beta in Alzheimer’s disease model mice. However, the protective mechanism remains unclear. In this study, we showed that 2 weeks of intraperitoneal administration of (D-Ser2) Oxm ameliorated the working memory and fear memory impairments of 9-month-old 3×Tg Alzheimer’s disease model mice. In addition, electrophysiological data recorded by a wireless multichannel neural recording system implanted in the hippocampal CA1 region showed that (D-Ser2) Oxm increased the power of the theta rhythm. In addition, (D-Ser2) Oxm treatment greatly increased the expression level of synaptic-associated proteins SYP and PSD-95 and increased the number of dendritic spines in 3×Tg Alzheimer’s disease model mice. These findings suggest that (D-Ser2) Oxm improves the cognitive function of Alzheimer’s disease transgenic mice by recovering hippocampal synaptic function and theta rhythm.  Related Articles | Metrics

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Aquaporin 4 deficiency eliminates the beneficial effects of voluntary exercise in a mouse model of Alzheimer’s disease Yun Liu, Pan-Pan Hu, Shuang Zhai, Wei-Xi Feng, Rui Zhang, Qian Li, Charles Marshall, Ming Xiao, Ting Wu 2022, 17 (9):  2079-2088.  doi: 10.4103/1673-5374.335169 Abstract ( 178 )   PDF (9923KB) ( 74 )   Save Regular exercise has been shown to reduce the risk of Alzheimer’s disease (AD). Our previous study showed that the protein aquaporin 4 (AQP4), which is specifically expressed on the paravascular processes of astrocytes, is necessary for glymphatic clearance of extracellular amyloid beta (Aβ) from the brain, which can delay the progression of Alzheimer’s disease. However, it is not known whether AQP4-regulated glymphatic clearance of extracellular Aβ is involved in beneficial effects of exercise in AD patients. Our results showed that after 2 months of voluntary wheel exercise, APP/PS1 mice that were 3 months old at the start of the intervention exhibited a decrease in Aβ burden, glial activation, perivascular AQP4 mislocalization, impaired glymphatic transport, synapse protein loss, and learning and memory defects compared with mice not subjected to the exercise intervention. In contrast, APP/PS1 mice that were 7 months old at the start of the intervention exhibited impaired AQP4 polarity and reduced glymphatic clearance of extracellular Aβ, and the above-mentioned impairments were not alleviated after the 2-month exercise intervention. Compared with age-matched APP/PS1 mice, AQP4 knockout APP/PS1 mice had more serious defects in glymphatic function, Aβ plaque deposition, and cognitive impairment, which could not be alleviated after the exercise intervention. These findings suggest that AQP4-dependent glymphatic transport is the neurobiological basis for the beneficial effects of voluntary exercises that protect against the onset of AD.  Related Articles | Metrics