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15 May 2023, Volume 18 Issue 5 Previous Issue   

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Chx10+V2a interneurons in spinal motor regulation and spinal cord injury Wen-Yuan Li, Ling-Xiao Deng, Feng-Guo Zhai, Xiao-Yu Wang, Zhi-Gang Li, Ying Wang 2023, 18 (5):  933-939.  doi: 10.4103/1673-5374.355746 Abstract ( 279 )   PDF (2829KB) ( 205 )   Save Chx10-expressing V2a (Chx10+V2a) spinal interneurons play a large role in the excitatory drive of motoneurons. Chemogenetic ablation studies have demonstrated the essential nature of Chx10+V2a interneurons in the regulation of locomotor initiation, maintenance, alternation, speed, and rhythmicity. The role of Chx10+V2a interneurons in locomotion and autonomic nervous system regulation is thought to be robust, but their precise role in spinal motor regulation and spinal cord injury have not been fully explored. The present paper reviews the origin, characteristics, and functional roles of Chx10+V2a interneurons with an emphasis on their involvement in the pathogenesis of spinal cord injury. The diverse functional properties of these cells have only been substantiated by and are due in large part to their integration in a variety of diverse spinal circuits. Chx10+V2a interneurons play an integral role in conferring locomotion, which integrates various corticospinal, mechanosensory, and interneuron pathways. Moreover, accumulating evidence suggests that Chx10+V2a interneurons also play an important role in rhythmic patterning maintenance, left-right alternation of central pattern generation, and locomotor pattern generation in higher order mammals, likely conferring complex locomotion. Consequently, the latest research has focused on postinjury transplantation and noninvasive stimulation of Chx10+V2a interneurons as a therapeutic strategy, particularly in spinal cord injury. Finally, we review the latest preclinical study advances in laboratory derivation and stimulation/transplantation of these cells as a strategy for the treatment of spinal cord injury. The evidence supports that the Chx10+V2a interneurons act as a new therapeutic target for spinal cord injury. Future optimization strategies should focus on the viability, maturity, and functional integration of Chx10+V2a interneurons transplanted in spinal cord injury foci. Related Articles | Metrics

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Clemastine in remyelination and protection of neurons and skeletal muscle after spinal cord injury Ali Myatich, Azizul Haque, Christopher Sole, Naren L. Banik 2023, 18 (5):  940-946.  doi: 10.4103/1673-5374.355749 Abstract ( 191 )   PDF (720KB) ( 158 )   Save Spinal cord injuries affect nearly five to ten individuals per million every year. Spinal cord injury causes damage to the nerves, muscles, and the tissue surrounding the spinal cord. Depending on the severity, spinal injuries are linked to degeneration of axons and myelin, resulting in neuronal impairment and skeletal muscle weakness and atrophy. The protection of neurons and promotion of myelin regeneration during spinal cord injury is important for recovery of function following spinal cord injury. Current treatments have little to no effect on spinal cord injury and neurogenic muscle loss. Clemastine, an Food and Drug Administration-approved antihistamine drug, reduces inflammation, protects cells, promotes remyelination, and preserves myelin integrity. Recent clinical evidence suggests that clemastine can decrease the loss of axons after spinal cord injury, stimulating the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes that are capable of myelination. While clemastine can aid not only in the remyelination and preservation of myelin sheath integrity, it also protects neurons. However, its role in neurogenic muscle loss remains unclear. This review discusses the pathophysiology of spinal cord injury, and the role of clemastine in the protection of neurons, myelin, and axons as well as attenuation of skeletal muscle loss following spinal cord injury. Related Articles | Metrics

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The effects and potential of microglial polarization and crosstalk with other cells of the central nervous system in the treatment of Alzheimer’s disease Yi-Ge Wu, Li-Juan Song, Li-Jun Yin, Jun-Jun Yin, Qing Wang, Jie-Zhong Yu, Bao-Guo Xiao, Cun-Gen Ma 2023, 18 (5):  947-954.  doi: 10.4103/1673-5374.355747 Abstract ( 360 )   PDF (3469KB) ( 280 )   Save Microglia are resident immune cells in the central nervous system. During the pathogenesis of Alzheimer’s disease, stimulatory factors continuously act on the microglia causing abnormal activation and unbalanced phenotypic changes; these events have become a significant and promising area of research. In this review, we summarize the effects of microglial polarization and crosstalk with other cells in the central nervous system in the treatment of Alzheimer’s disease. Our literature search found that phenotypic changes occur continuously in Alzheimer’s disease and that microglia exhibit extensive crosstalk with astrocytes, oligodendrocytes, neurons, and penetrated peripheral innate immune cells via specific signaling pathways and cytokines. Collectively, unlike previous efforts to modulate microglial phenotypes at a single level, targeting the phenotypes of microglia and the crosstalk with other cells in the central nervous system may be more effective in reducing inflammation in the central nervous system in Alzheimer’s disease. This would establish a theoretical basis for reducing neuronal death from central nervous system inflammation and provide an appropriate environment to promote neuronal regeneration in the treatment of Alzheimer’s disease. Related Articles | Metrics

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Patient-specific monocyte-derived microglia as a screening tool for neurodegenerative diseases Hazel Quek, Anthony R. White 2023, 18 (5):  955-958.  doi: 10.4103/1673-5374.355740 Abstract ( 112 )   PDF (1912KB) ( 55 )   Save Microglia, the main driver of neuroinflammation, play a central role in the initiation and exacerbation of various neurodegenerative diseases and are now considered a promising therapeutic target. Previous studies on in vitro human microglia and in vivo rodent models lacked scalability, consistency, or physiological relevance, which deterred successful therapeutic outcomes for the past decade. Here we review human blood monocyte-derived microglia-like cells as a robust and consistent approach to generate a patient-specific microglia-like model that can be used in extensive cohort studies for drug testing. We will highlight the strength and applicability of human blood monocyte-derived microglia-like cells to increase translational outcomes by reviewing the advantages of human blood monocyte-derived microglia-like cells in addressing patient heterogeneity and stratification, the basis of personalized medicine. Related Articles | Metrics

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Molecular hallmarks of long non-coding RNAs in aging and its significant effect on aging-associated diseases Syed Aoun Mehmood Sherazi, Asim Abbasi, Abdullah Jamil, Mohammad Uzair, Ayesha Ikram, Shanzay Qamar, Adediji Ayomide Olamide, Muhammad Arshad, Peter J. Fried, Milos Ljubisavljevic, Ran Wang, Shahid Bashir 2023, 18 (5):  959-968.  doi: 10.4103/1673-5374.355751 Abstract ( 187 )   PDF (803KB) ( 81 )   Save Aging is linked to the deterioration of many physical and cognitive abilities and is the leading risk factor for Alzheimer’s disease. The growing aging population is a significant healthcare problem globally that researchers must investigate to better understand the underlying aging processes. Advances in microarrays and sequencing techniques have resulted in deeper analyses of diverse essential genomes (e.g., mouse, human, and rat) and their corresponding cell types, their organ-specific transcriptomes, and the tissue involved in aging. Traditional gene controllers such as DNA- and RNA-binding proteins significantly influence such programs, causing the need to sort out long non-coding RNAs, a new class of powerful gene regulatory elements. However, their functional significance in the aging process and senescence has yet to be investigated and identified. Several recent researchers have associated the initiation and development of senescence and aging in mammals with several well-reported and novel long non-coding RNAs. In this review article, we identified and analyzed the evolving functions of long non-coding RNAs in cellular processes, including cellular senescence, aging, and age-related pathogenesis, which are the major hallmarks of long non-coding RNAs in aging. Related Articles | Metrics

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Vimentin as a potential target for diverse nervous system diseases Kang-Zhen Chen, Shu-Xian Liu, Yan-Wei Li, Tao He, Jie Zhao, Tao Wang, Xian-Xiu Qiu, Hong-Fu Wu 2023, 18 (5):  969-975.  doi: 10.4103/1673-5374.355744 Abstract ( 344 )   PDF (1990KB) ( 124 )   Save Vimentin is a major type III intermediate filament protein that plays important roles in several basic cellular functions including cell migration, proliferation, and division. Although vimentin is a cytoplasmic protein, it also exists in the extracellular matrix and at the cell surface. Previous studies have shown that vimentin may exert multiple physiological effects in different nervous system injuries and diseases. For example, the studies of vimentin in spinal cord injury and stroke mainly focus on the formation of reactive astrocytes. Reduced glial scar, increased axonal regeneration, and improved motor function have been noted after spinal cord injury in vimentin and glial fibrillary acidic protein knockout (GFAP–/–VIM–/–) mice. However, attenuated glial scar formation in post-stroke in GFAP–/– VIM–/– mice resulted in abnormal neuronal network restoration and worse neurological recovery. These opposite results have been attributed to the multiple roles of glial scar in different temporal and spatial conditions. In addition, extracellular vimentin may be a neurotrophic factor that promotes axonal extension by interaction with the insulin-like growth factor 1 receptor. In the pathogenesis of bacterial meningitis, cell surface vimentin is a meningitis facilitator, acting as a receptor of multiple pathogenic bacteria, including E. coli K1, Listeria monocytogenes, and group B streptococcus. Compared with wild type mice, VIM–/– mice are less susceptible to bacterial infection and exhibit a reduced inflammatory response, suggesting that vimentin is necessary to induce the pathogenesis of meningitis. Recently published literature showed that vimentin serves as a double-edged sword in the nervous system, regulating axonal regrowth, myelination, apoptosis, and neuroinflammation. This review aims to provide an overview of vimentin in spinal cord injury, stroke, bacterial meningitis, gliomas, and peripheral nerve injury and to discuss the potential therapeutic methods involving vimentin manipulation in improving axonal regeneration, alleviating infection, inhibiting brain tumor progression, and enhancing nerve myelination. Related Articles | Metrics

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Inflammation in diabetic retinopathy: possible roles in pathogenesis and potential implications for therapy Lei Tang, Guo-Tong Xu, Jing-Fa Zhang 2023, 18 (5):  976-982.  doi: 10.4103/1673-5374.355743 Abstract ( 515 )   PDF (5219KB) ( 217 )   Save Diabetic retinopathy, characterized as a microangiopathy and neurodegenerative disease, is the leading cause of visual impairment in diabetic patients. Many clinical features observed in diabetic retinopathy, such as capillary occlusion, acellular capillaries and retinal non-perfusion, aggregate retinal ischemia and represent relatively late events in diabetic retinopathy. In fact, retinal microvascular injury is an early event in diabetic retinopathy involving multiple biochemical alterations, and is manifested by changes to the retinal neurovascular unit and its cellular components. Currently, intravitreal anti-vascular endothelial growth factor therapy is the first-line treatment for diabetic macular edema, and benefits the patient by decreasing the edema and improving visual acuity. However, a significant proportion of patients respond poorly to anti-vascular endothelial growth factor treatments, indicating that factors other than vascular endothelial growth factor are involved in the pathogenesis of diabetic macular edema. Accumulating evidence confirms that low-grade inflammation plays a critical role in the pathogenesis and development of diabetic retinopathy as multiple inflammatory factors, such as interleukin-1β, monocyte chemotactic protein-1 and tumor necrosis factor -α, are increased in the vitreous and retina of diabetic retinopathy patients. These inflammatory factors, together with growth factors such as vascular endothelial growth factor, contribute to blood-retinal barrier breakdown, vascular damage and neuroinflammation, as well as pathological angiogenesis in diabetic retinopathy, complicated by diabetic macular edema and proliferative diabetic retinopathy. In addition, retinal cell types including microglia, Müller glia, astrocytes, retinal pigment epithelial cells, and others are activated, to secrete inflammatory mediators, aggravating cell apoptosis and subsequent vascular leakage. New therapies, targeting these inflammatory molecules or related signaling pathways, have the potential to inhibit retinal inflammation and prevent diabetic retinopathy progression. Here, we review the relevant literature to date, summarize the inflammatory mechanisms underlying the pathogenesis of diabetic retinopathy, and propose inflammation-based treatments for diabetic retinopathy and diabetic macular edema. Related Articles | Metrics

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The critical role of the endolysosomal system in cerebral ischemia Hui-Yi Zhang, Ye Tian, Han-Yan Shi, Ya Cai, Ying Xu 2023, 18 (5):  983-990.  doi: 10.4103/1673-5374.355745 Abstract ( 203 )   PDF (745KB) ( 63 )   Save Cerebral ischemia is a serious disease that triggers sequential pathological mechanisms, leading to significant morbidity and mortality. Although most studies to date have typically focused on the lysosome, a single organelle, current evidence supports that the function of lysosomes cannot be separated from that of the endolysosomal system as a whole. The associated membrane fusion functions of this system play a crucial role in the biodegradation of cerebral ischemia-related products. Here, we review the regulation of and the changes that occur in the endolysosomal system after cerebral ischemia, focusing on the latest research progress on membrane fusion function. Numerous proteins, including N-ethylmaleimide-sensitive factor and lysosomal potassium channel transmembrane protein 175, regulate the function of this system. However, these proteins are abnormally expressed after cerebral ischemic injury, which disrupts the normal fusion function of membranes within the endolysosomal system and that between autophagosomes and lysosomes. This results in impaired “maturation” of the endolysosomal system and the collapse of energy metabolism balance and protein homeostasis maintained by the autophagy-lysosomal pathway. Autophagy is the final step in the endolysosomal pathway and contributes to maintaining the dynamic balance of the system. The process of autophagosome-lysosome fusion is a necessary part of autophagy and plays a crucial role in maintaining energy homeostasis and clearing aging proteins. We believe that, in cerebral ischemic injury, the endolysosomal system should be considered as a whole rather than focusing on the lysosome. Understanding how this dynamic system is regulated will provide new ideas for the treatment of cerebral ischemia. Related Articles | Metrics

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Novel therapeutic strategies targeting mitochondria as a gateway in neurodegeneration Diogo Trigo, José João Vitória, Odete A. B. da Cruz e Silva 2023, 18 (5):  991-995.  doi: 10.4103/1673-5374.355750 Abstract ( 130 )   PDF (1006KB) ( 80 )   Save In recent years, multiple disciplines have focused on mitochondrial biology and contributed to understanding its relevance towards adult-onset neurodegenerative disorders. These are complex dynamic organelles that have a variety of functions in ensuring cellular health and homeostasis. The plethora of mitochondrial functionalities confers them an intrinsic susceptibility to internal and external stressors (such as mutation accumulation or environmental toxins), particularly so in long-lived postmitotic cells such as neurons. Thus, it is reasonable to postulate an involvement of mitochondria in aging-associated neurological disorders, notably neurodegenerative pathologies including Alzheimer’s disease and Parkinson’s disease. On the other hand, biological effects resulting from neurodegeneration can in turn affect mitochondrial health and function, promoting a feedback loop further contributing to the progression of neuronal dysfunction and cellular death. This review examines state-of-the-art knowledge, focus on current research exploring mitochondrial health as a contributing factor to neuroregeneration, and the development of therapeutic approaches aimed at restoring mitochondrial homeostasis in a pathological setting. Related Articles | Metrics

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Targeting the nitric oxide/cGMP signaling pathway to treat chronic pain Dan-Yang Li, Shao-Jie Gao, Jia Sun, Long-Qing Zhang, Jia-Yi Wu, Fan-He Song, Dai-Qiang Liu, Ya-Qun Zhou, Wei Mei 2023, 18 (5):  996-1003.  doi: 10.4103/1673-5374.355748 Abstract ( 446 )   PDF (4846KB) ( 165 )   Save Nitric oxide (NO)/cyclic guanosine 3′,5′-monophosphate (cGMP) signaling has been shown to act as a mediator involved in pain transmission and processing. In this review, we summarize and discuss the mechanisms of the NO/cGMP signaling pathway involved in chronic pain, including neuropathic pain, bone cancer pain, inflammatory pain, and morphine tolerance. The main process in the NO/cGMP signaling pathway in cells involves NO activating soluble guanylate cyclase, which leads to subsequent production of cGMP. cGMP then activates cGMP-dependent protein kinase (PKG), resulting in the activation of multiple targets such as the opening of ATP-sensitive K+ channels. The activation of NO/cGMP signaling in the spinal cord evidently induces upregulation of downstream molecules, as well as reactive astrogliosis and microglial polarization which participate in the process of chronic pain. In dorsal root ganglion neurons, natriuretic peptide binds to particulate guanylyl cyclase, generating and further activating the cGMP/PKG pathway, and it also contributes to the development of chronic pain. Upregulation of multiple receptors is involved in activation of the NO/cGMP signaling pathway in various pain models. Notably the NO/cGMP signaling pathway induces expression of downstream effectors, exerting both algesic and analgesic effects in neuropathic pain and inflammatory pain. These findings suggest that activation of NO/cGMP signaling plays a constituent role in the development of chronic pain, and this signaling pathway with dual effects is an interesting and promising target for chronic pain therapy. Related Articles | Metrics

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Neurosteroids as stress modulators and neurotherapeutics: lessons from the retina Yukitoshi Izumi, Makoto Ishikawa, Toru Nakazawa, Hiroshi Kunikata, Kota Sato, Douglas F. Covey, Charles F. Zorumski 2023, 18 (5):  1004-1008.  doi: 10.4103/1673-5374.355752 Abstract ( 112 )   PDF (3120KB) ( 60 )   Save Neurosteroids are rapidly emerging as important new therapies in neuropsychiatry, with one such agent, brexanolone, already approved for treatment of postpartum depression, and others on the horizon. These steroids have unique properties, including neuroprotective effects that could benefit a wide range of brain illnesses including depression, anxiety, epilepsy, and neurodegeneration. Over the past 25 years, our group has developed ex vivo rodent models to examine factors contributing to several forms of neurodegeneration in the retina. In the course of this work, we have developed a model of acute closed angle glaucoma that involves incubation of ex vivo retinas under hyperbaric conditions and results in neuronal and axonal changes that mimic glaucoma. We have used this model to determine neuroprotective mechanisms that could have therapeutic implications. In particular, we have focused on the role of both endogenous and exogenous neurosteroids in modulating the effects of acute high pressure.  Endogenous allopregnanolone, a major stress-activated neurosteroid in the brain and retina, helps to prevent severe pressure-induced retinal excitotoxicity but is unable to protect against degenerative changes in ganglion cells and their axons under hyperbaric conditions. However, exogenous allopregnanolone, at a pharmacological concentration, completely preserves retinal structure and does so by combined effects on gamma-aminobutyric acid type A receptors and stimulation of the cellular process of macroautophagy. Surprisingly, the enantiomer of allopregnanolone, which is inactive at gamma-aminobutyric acid type A receptors, is equally retinoprotective and acts primarily via autophagy. Both enantiomers are also equally effective in preserving retinal structure and function in an in vivo glaucoma model. These studies in the retina have important implications for the ongoing development of allopregnanolone and other neurosteroids as therapeutics for neuropsychiatric illnesses. Related Articles | Metrics

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Myelinosome organelles in pathological retinas: ubiquitous presence and dual role in ocular proteostasis maintenance Marina G. Yefimova 2023, 18 (5):  1009-1016.  doi: 10.4103/1673-5374.355753 Abstract ( 136 )   PDF (3931KB) ( 39 )   Save The timely and efficient elimination of aberrant proteins and damaged organelles, formed in response to various genetic and environmental stressors, is a vital need for all cells of the body. Recent lines of evidence point out several non-classical strategies employed by ocular tissues to cope with aberrant constituents generated in the retina and in the retinal pigmented epithelium cells exposed to various stressors. Along with conventional strategies relying upon the intracellular degradation of aberrant constituents through ubiquitin-proteasome and/or lysosome-dependent autophagy proteolysis, two non-conventional mechanisms also contribute to proteostasis maintenance in ocular tissues. An exosome-mediated clearing and a myelinosome-driven secretion mechanism do not require intracellular degradation but provide the export of aberrant constituents and “waste proteins” outside of the cells. The current review is centered on the non-degradative myelinosome-driven secretion mechanism, which operates in the retina of transgenic Huntington’s disease R6/1 model mice. Myelinosome-driven secretion is supported by rare organelles myelinosomes that are detected not only in degenerative Huntington’s disease R6/1 retina but also in various pathological states of the retina and of the retinal pigmented epithelium. The intra-retinal traffic and inter-cellular exchange of myelinosomes was discussed in the context of a dual role of the myelinosome-driven secretion mechanism for proteostasis maintenance in different ocular compartments. Special focus was made on the interplay between degradative and non-degradative strategies in ocular pathophysiology, to delineate potential therapeutic approaches to counteract several vision diseases. Related Articles | Metrics

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Anti-IgLON5 disease: a novel topic beyond neuroimmunology Yi-ZongHeng Zhang, You Ni, Yi-Ning Gao, Ding-Ding Shen, Lu He, Dou Yin, Huan-Yu Meng, Qin-Ming Zhou, Ji Hu, Sheng Chen 2023, 18 (5):  1017-1022.  doi: 10.4103/1673-5374.355742 Abstract ( 250 )   PDF (3842KB) ( 127 )   Save Anti-IgLON5 disease is a recently defined autoimmune disorder of the nervous system associated with autoantibodies against IgLON5. Given its broad clinical spectrum and extremely complex pathogenesis, as well as difficulties in its early diagnosis and treatment, anti-IgLON5 disease has become the subject of considerable research attention in the field of neuroimmunology. Anti-IgLON5 disease has characteristics of both autoimmunity and neurodegeneration due to the unique activity of the anti-IgLON5 antibody. Neuropathologic examination revealed the presence of a tauopathy preferentially affecting the hypothalamus and brainstem tegmentum, potentially broadening our understanding of tauopathies. In contrast to that seen with other autoimmune encephalitis-related antibodies, basic studies have demonstrated that IgLON5 antibody-induced neuronal damage and degeneration are irreversible, indicative of a potential link between autoimmunity and neurodegeneration in anti-IgLON5 disease. Herein, we comprehensively review and discuss basic and clinical studies relating to anti-IgLON5 disease to better understand this complicated disorder. Related Articles | Metrics

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Endocannabinoid control of neuroinflammation in traumatic brain injury by monoacylglycerol lipase in astrocytes Chu Chen 2023, 18 (5):  1023-1024.  doi: 10.4103/1673-5374.355755 Abstract ( 109 )   PDF (592KB) ( 50 )   Save Traumatic brain injury (TBI) is a temporary or permanent disruption of brain function caused by external forces. TBI has been recognized as an important risk factor for the development of Alzheimer’s disease  and dementia later in life. However, the mechanisms by which TBI contributes to developing Alzheimer’s disease are largely unknown. In particular, no effective therapies are currently available for the prevention and treatment of TBI-induced neurodegenerative disease. The acute brain damage after TBI results not only from primary injury, which is the result of the external mechanical force but also from secondary injury, which is associated with a complex cascade of molecular, cellular, and immune responses. Neuroinflammation associated with other processes plays a critical role in causing secondary injury following TBI (Simon et al., 2017). The extent of neuroinflammatory responses seems to be closely correlated with the outcome following TBI (Woodcock and Morganti-Kossmann, 2013). This means that while the primary injury immediately following TBI is not preventable, appropriate and timely intervention to resolve neuroinflammation following the primary injury would be the key to preventing further brain damage, neuropathological changes, and synaptic and cognitive impairments (Zhang et al., 2015).  Related Articles | Metrics

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Neuroinflammation and glial activation in the central nervous system: a metabolic perspective Assunta Virtuoso, Ciro De Luca, Sohaib Ali Korai, Michele Papa, Giovanni Cirillo 2023, 18 (5):  1025-1026.  doi: 10.4103/1673-5374.355754 Abstract ( 138 )   PDF (1135KB) ( 55 )   Save Decades of research in glial biology have investigated mechanisms of neuro-glial interplay, demonstrating that neurons and glia intimately cooperate for energy metabolism in the central nervous system (CNS) (Magistretti and Allaman, 2018). As neurons invest their adenosine triphosphate in the neurotransmission, glial cells work to support neurons, providing metabolic substrates. Astrocytes, in particular, contribute largely to energy metabolism in CNS: they sense and shuttle nutrients (e.g., glucose and lipids) and hormones (e.g., insulin), accumulate and utilize glycogen for brain demands, influencing their own metabolism and neuronal activity by lactate transport (astrocyte-neuron lactate shuttle). Related Articles | Metrics

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LL-37 and CsgC exemplify the crosstalk between anti-amyloid, antimicrobial, and anti-biofilm protein activities Jaime Santos, Salvador Ventura, Irantzu Pallarès 2023, 18 (5):  1027-1028.  doi: 10.4103/1673-5374.355757 Abstract ( 100 )   PDF (1706KB) ( 31 )   Save Protein misfolding and aggregation into amyloid fibrils is the main pathological hallmark of neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s, and prion diseases (Chiti and Dobson, 2017). These insoluble fibrillar deposits possess a common structure characterized by a cross-β-sheet conformation in which β-strands run transversely to the fiber axis and form an intermolecular network of hydrogen bonds. However, amyloid formation is not only found in disease; the unique properties of this protein fold are also exploited by nature to perform a growing list of relevant and highly conserved cellular functions (Otzen and Riek, 2019). Pathogenic and functional amyloid formation needs to be regulated to sustain organism fitness, and a wide range of strategies have evolved to prevent uncontrolled aggregation. Importantly, we are not only exposed to our endogen amyloidogenic proteins, but we also face the threat of food and bacterial amyloids. For instance, many bacterial species in the gut microbiome can form an amyloid scaffolded biofilm, which facilitates bacterial proliferation, promotes the synergy between the host and the microbiome, and may eventually play a role in the pathogenesis of different diseases. It is then plausible to speculate that our own systemic defense against endogenous amyloids can work to fight this exogenic risk. Indeed, given the common structural properties shared by unrelated amyloids, it could be expected that the same cellular agents would mediate the response to human amyloids and those from other sources. In this perspective, we provide context for this idea by exploring the overlap between anti-microbial, anti-biofilm, and anti-amyloid activities, defining a framework for developing novel therapies for neurodegenerative diseases. Related Articles | Metrics

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Olfactory dysfunction as a common biomarker for neurodegenerative and neuropsychiatric disorders David Slabik, Olga Garaschuk 2023, 18 (5):  1029-1030.  doi: 10.4103/1673-5374.355756 Abstract ( 176 )   PDF (440KB) ( 72 )   Save The sense of smell supports the identification and the safety of food, warns of danger/predators, and plays a key role in mating (Croy and Hummel, 2017; Kondo et al., 2020; Tzeng et al., 2021). Via connection to the limbic system, it supports behavioral adaption and emotions and can detect fear, tears, and happiness in the body odor of others (Croy and Hummel, 2017; Tzeng et al., 2021). Sensory information is transmitted from the olfactory receptor neurons in the nose via the olfactory bulb (OB) to higher-order olfactory structures including the anterior olfactory nucleus, the piriform and entorhinal cortices, amygdala, hippocampus, orbitofrontal and prefrontal cortices, and nucleus accumbens (Croy and Hummel, 2017; Marin et al., 2018). In the OB, axons from olfactory receptor neurons synapse on the dendrites of OB projection neurons mitral (MCs) and tufted cells in so-called glomeruli (Marin et al., 2018).  Related Articles | Metrics

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Mechanotransduction mechanisms in central nervous system glia Brenan Cullimore, Jackson Baumann, Christopher N. Rudzitis, Andrew O. Jo, Denisa Kirdajova, David Križaj 2023, 18 (5):  1031-1032.  doi: 10.4103/1673-5374.355758 Abstract ( 95 )   PDF (637KB) ( 111 )   Save Mechanical forces shape the development, function, and survival of every cell within the central nervous system (CNS) but are particularly important for astroglia, a subtype of glial cell that mediates communication between neurons and blood vessels. Astrocytes utilize changes in intracellular concentration of the 2nd messenger calcium [Ca2+]i to integrate local electrical, chemical, and mechanical microenvironments, with Ca2+-dependent release of gliotransmitters and cytokines implicated in the regulation of neurovascular coupling, short- and long-term synaptic plasticity, and neuronal excitability. These functions may be perturbed by age, tissue swelling (edema), ischemia, physical trauma, and chronic elevations in intraocular or intracranial pressure, to produce a reactive response that manifests as increases in hypertrophy, cell proliferation, and proinflammatory signaling. Astroglial activation by acute and chronic mechanical trauma compromises the integrity of blood-CNS barriers and neuronal function yet information about molecular sensors that transduce mechanical forces into astroglial [Ca2+]i is surprisingly sparse. We know that large tissue deformations that activate astroglia and injure CNS induce [Ca2+]i  elevations (Rzigalinski et al., 1998; Lindqvist et al., 2010) but it is not known whether the cells are capable of responding to physiological deformations of the extracellular matrix (< 5% strain) and what such force transducers might be.  Related Articles | Metrics

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Blocking postsynaptic density-93 binding to C‑X3‑C motif chemokine ligand 1 promotes microglial phenotypic transformation during acute ischemic stroke Xiao-Wei Cao, Hui Yang, Xiao-Mei Liu, Shi-Ying Lou, Li-Ping Kong, Liang-Qun Rong, Jun-Jun Shan, Yun Xu, Qing-Xiu Zhang 2023, 18 (5):  1033-1039.  doi: 10.4103/1673-5374.355759 Abstract ( 125 )   PDF (13796KB) ( 54 )   Save We previously reported that postsynaptic density-93 mediates neuron-microglia crosstalk by interacting with amino acids 357–395 of C‑X3‑C motif chemokine ligand 1 (CX3CL1) to induce microglia polarization. More importantly, the peptide Tat-CX3CL1 (comprising amino acids 357–395 of CX3CL1) disrupts the interaction between postsynaptic density-93 and CX3CL1, reducing neurological impairment and exerting a protective effect in the context of acute ischemic stroke. However, the mechanism underlying these effects remains unclear. In the current study, we found that the pro-inflammatory M1 phenotype increased and the anti-inflammatory M2 phenotype decreased at different time points. The M1 phenotype increased at 6 hours after stroke and peaked at 24 hours after perfusion, whereas the M2 phenotype decreased at 6 and 24 hours following reperfusion. We found that the peptide Tat-CX3CL1 (357–395aa) facilitates microglial polarization from M1 to M2 by reducing the production of soluble CX3CL1. Furthermore, the a disintegrin and metalloprotease domain 17 (ADAM17) inhibitor GW280264x, which inhibits metalloprotease activity and prevents CX3CL1 from being sheared into its soluble form, facilitated microglial polarization from M1 to M2 by inhibiting soluble CX3CL1 formation. Additionally, Tat-CX3CL1 (357–395aa) attenuated long-term cognitive deficits and improved white matter integrity as determined by the Morris water maze test at 31–34 days following surgery and immunofluorescence staining at 35 days after stroke, respectively. In conclusion, Tat-CX3CL1 (357–395aa) facilitates functional recovery after ischemic stroke by promoting microglial polarization from M1 to M2. Therefore, the Tat-CX3CL1 (357–395aa) is a potential therapeutic agent for ischemic stroke.   Related Articles | Metrics

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Ischemic accumulation of succinate induces Cdc42 succinylation and inhibits neural stem cell proliferation after cerebral ischemia/reperfusion Lin-Yan Huang, Ju-Yun Ma, Jin-Xiu Song, Jing-Jing Xu, Rui Hong, Hai-Di Fan, Heng Cai, Wan Wang, Yan-Ling Wang, Zhao-Li Hu, Jian-Gang Shen, Su-Hua Qi 2023, 18 (5):  1040-1045.  doi: 10.4103/1673-5374.355821 Abstract ( 213 )   PDF (2377KB) ( 108 )   Save Ischemic accumulation of succinate causes cerebral damage by excess production of reactive oxygen species. However, it is unknown whether ischemic accumulation of succinate affects neural stem cell proliferation. In this study, we established a rat model of cerebral ischemia/reperfusion injury by occlusion of the middle cerebral artery. We found that succinate levels increased in serum and brain tissue (cortex and hippocampus) after ischemia/reperfusion injury. Oxygen-glucose deprivation and reoxygenation stimulated primary neural stem cells to produce abundant succinate. Succinate can be converted into diethyl succinate in cells. Exogenous diethyl succinate inhibited the proliferation of mouse-derived C17.2 neural stem cells and increased the infarct volume in the rat model of cerebral ischemia/reperfusion injury. Exogenous diethyl succinate also increased the succinylation of the Rho family GTPase Cdc42 but repressed Cdc42 GTPase activity in C17.2 cells. Increasing Cdc42 succinylation by knockdown of the desuccinylase Sirt5 also inhibited Cdc42 GTPase activity in C17.2 cells. Our findings suggest that ischemic accumulation of succinate decreases Cdc42 GTPase activity by induction of Cdc42 succinylation, which inhibits the proliferation of neural stem cells and aggravates cerebral ischemia/reperfusion injury.  Related Articles | Metrics

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Neutrophil-derived interleukin-17A participates in neuroinflammation induced by traumatic brain injury Xiao-Jian Xu, Qian-Qian Ge, Meng-Shi Yang, Yuan Zhuang, Bin Zhang, Jin-Qian Dong, Fei Niu, Hao Li, Bai-Yun Liu 2023, 18 (5):  1046-1051.  doi: 10.4103/1673-5374.355767 Abstract ( 205 )   PDF (6183KB) ( 86 )   Save After brain injury, infiltration and abnormal activation of neutrophils damages brain tissue and worsens inflammation, but the mediators that connect activated neutrophils with neuroinflammation have not yet been fully clarified. To identify regulators of neutrophil-mediated neuroinflammation after traumatic brain injury, a mouse model of traumatic brain injury was established by controlled cortical impact. At 7 days post-injury (sub-acute phase), genome-wide transcriptomic data showed that interleukin 17A-associated signaling pathways were markedly upregulated, suggesting that interleukin 17A may be involved in neuroinflammation. Double immunofluorescence staining showed that interleukin 17A was largely secreted by neutrophils rather than by glial cells and neurons. Furthermore, nuclear factor-kappaB and Stat3, both of which are important effectors in interleukin 17A-mediated proinflammatory responses, were significantly activated. Collectively, our findings suggest that neutrophil-derived interleukin 17A participates in neutrophil-mediated neuroinflammation during the subacute phase of traumatic brain injury. Therefore, interleukin 17A may be a promising therapeutic target for traumatic brain injury. Related Articles | Metrics

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Integrin binding peptides facilitate growth and interconnected vascular-like network formation of rat primary cortical vascular endothelial cells in vitro Ram Kuwar, Xuejun Wen, Ning Zhang, Dong Sun 2023, 18 (5):  1052-1056.  doi: 10.4103/1673-5374.355760 Abstract ( 187 )   PDF (2109KB) ( 67 )   Save Neovascularization and angiogenesis in the brain are important physiological processes for normal brain development and repair/regeneration following insults. Integrins are cell surface adhesion receptors mediating important function of cells such as survival, growth and development during tissue organization, differentiation and organogenesis. In this study, we used an integrin-binding array platform to identify the important types of integrins and their binding peptides that facilitate adhesion, growth, development, and vascular-like network formation of rat primary brain microvascular endothelial cells. Brain microvascular endothelial cells were isolated from rat brain on post-natal day 7. Cells were cultured in a custom-designed integrin array system containing short synthetic peptides binding to 16 types of integrins commonly expressed on cells in vertebrates. After 7 days of culture, the brain microvascular endothelial cells were processed for immunostaining with markers for endothelial cells including von Willibrand factor and platelet endothelial cell adhesion molecule. 5-Bromo-2′-dexoyuridine was added to the culture at 48 hours prior to fixation to assess cell proliferation. Among 16 integrins tested, we found that α5β1, αvβ5 and αvβ8 greatly promoted proliferation of endothelial cells in culture. To investigate the effect of integrin-binding peptides in promoting neovascularization and angiogenesis, the binding peptides to the above three types of integrins were immobilized to our custom-designed hydrogel in three-dimensional (3D) culture of brain microvascular endothelial cells with the addition of vascular endothelial growth factor. Following a 7-day 3D culture, the culture was fixed and processed for double labeling of phalloidin with von Willibrand factor or platelet endothelial cell adhesion molecule and assessed under confocal microscopy. In the 3D culture in hydrogels conjugated with the integrin-binding peptide, brain microvascular endothelial cells formed interconnected vascular-like network with clearly discernable lumens, which is reminiscent of brain microvascular network in vivo. With the novel integrin-binding array system, we identified the specific types of integrins on brain microvascular endothelial cells that mediate cell adhesion and growth followed by functionalizing a 3D hydrogel culture system using the binding peptides that specifically bind to the identified integrins, leading to robust growth and lumenized microvascular-like network formation of brain microvascular endothelial cells in 3D culture. This technology can be used for in vitro and in vivo vascularization of transplants or brain lesions to promote brain tissue regeneration following neurological insults.   Related Articles | Metrics

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A benchtop brain injury model using resected donor tissue from patients with Chiari malformation Jacqueline A. Tickle, Jon Sen, Christopher Adams, David N. Furness, Rupert Price, Viswapathi Kandula, Nikolaos Tzerakis, Divya M. Chari 2023, 18 (5):  1057-1061.  doi: 10.4103/1673-5374.355761 Abstract ( 122 )   PDF (8573KB) ( 27 )   Save The use of live animal models for testing new therapies for brain and spinal cord repair is a controversial area. Live animal models have associated ethical issues and scientific concerns regarding the predictability of human responses. Alternative models that replicate the 3D architecture of the central nervous system have prompted the development of organotypic neural injury models. However, the lack of reliable means to access normal human neural tissue has driven reliance on pathological or post-mortem tissue which limits their biological utility. We have established a protocol to use donor cerebellar tonsillar tissue surgically resected from patients with Chiari malformation (cerebellar herniation towards the foramen magnum, with ectopic rather than diseased tissue) to develop an in vitro organotypic model of traumatic brain injury. Viable tissue was maintained for approximately 2 weeks with all the major neural cell types detected. Traumatic injuries could be introduced into the slices with some cardinal features of post-injury pathology evident. Biomaterial placement was also feasible within the in vitro lesions. Accordingly, this ‘proof-of-concept’ study demonstrates that the model offers potential as an alternative to the use of animal tissue for preclinical testing in neural tissue engineering. To our knowledge, this is the first demonstration that donor tissue from patients with Chiari malformation can be used to develop a benchtop model of traumatic brain injury. However, significant challenges in relation to the clinical availability of tissue were encountered, and we discuss logistical issues that must be considered for model scale-up.   Related Articles | Metrics

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Double-target neural circuit-magnetic stimulation improves motor function in spinal cord injury by attenuating astrocyte activation Dan Zhao, Ye Zhang, Ya Zheng, Xu-Tong Li, Cheng-Cheng Sun, Qi Yang, Qing Xie, Dong-Sheng Xu 2023, 18 (5):  1062-1066.  doi: 10.4103/1673-5374.355768 Abstract ( 177 )   PDF (2555KB) ( 83 )   Save Multi-target neural circuit-magnetic stimulation has been clinically shown to improve rehabilitation of lower limb motor function after spinal cord injury. However, the precise underlying mechanism remains unclear. In this study, we performed double-target neural circuit-magnetic stimulation on the left motor cortex and bilateral L5 nerve root for 3 successive weeks in a rat model of incomplete spinal cord injury caused by compression at T10. Results showed that in the injured spinal cord, the expression of the astrocyte marker glial fibrillary acidic protein and inflammatory factors interleukin 1β, interleukin-6, and tumor necrosis factor-α had decreased, whereas that of neuronal survival marker microtubule-associated protein 2 and synaptic plasticity markers postsynaptic densification protein 95 and synaptophysin protein had increased. Additionally, neural signaling of the descending corticospinal tract was markedly improved and rat locomotor function recovered significantly. These findings suggest that double-target neural circuit-magnetic stimulation improves rat motor function by attenuating astrocyte activation, thus providing a theoretical basis for application of double-target neural circuit-magnetic stimulation in the clinical treatment of spinal cord injury.  Related Articles | Metrics

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Bone marrow mesenchymal stem cells and exercise restore motor function following spinal cord injury by activating PI3K/AKT/mTOR pathway Xin Sun, Li-Yi Huang, Hong-Xia Pan, Li-Juan Li, Lu Wang, Gai-Qin Pei, Yang Wang, Qing Zhang, Hong-Xin Cheng, Cheng-Qi He, Quan Wei 2023, 18 (5):  1067-1075.  doi: 10.4103/1673-5374.355762 Abstract ( 163 )   PDF (17378KB) ( 106 )   Save Although many therapeutic interventions have shown promise in treating spinal cord injury, focusing on a single aspect of repair cannot achieve successful and functional regeneration in patients following spinal cord injury . In this study, we applied a combinatorial approach for treating spinal cord injury involving neuroprotection and rehabilitation, exploiting cell transplantation and functional sensorimotor training to promote nerve regeneration and functional recovery. Here, we used a mouse model of thoracic contusive spinal cord injury to investigate whether the combination of bone marrow mesenchymal stem cell transplantation and exercise training has a synergistic effect on functional restoration. Locomotor function was evaluated by the Basso Mouse Scale, horizontal ladder test, and footprint analysis. Magnetic resonance imaging, histological examination, transmission electron microscopy observation, immunofluorescence staining, and western blotting were performed 8 weeks after spinal cord injury to further explore the potential mechanism behind the synergistic repair effect. In vivo, the combination of bone marrow mesenchymal stem cell transplantation and exercise showed a better therapeutic effect on motor function than the single treatments. Further investigations revealed that the combination of bone marrow mesenchymal stem cell transplantation and exercise markedly reduced fibrotic scar tissue, protected neurons, and promoted axon and myelin protection. Additionally, the synergistic effects of bone marrow mesenchymal stem cell transplantation and exercise on spinal cord injury recovery occurred via the PI3K/AKT/mTOR pathway. In vitro, experimental evidence from the PC12 cell line and primary cortical neuron culture also demonstrated that blocking of the PI3K/AKT/mTOR pathway would aggravate neuronal damage. Thus, bone marrow mesenchymal stem cell transplantation combined with exercise training can effectively restore motor function after spinal cord injury by activating the PI3K/AKT/mTOR pathway.  Related Articles | Metrics

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Alterations in gut microbiota are related to metabolite profiles in spinal cord injury Jian-Ning Kang, Zheng-Fang Sun, Xin-Yu Li, Xiao-Di Zhang, Zheng-Xin Jin, Ce Zhang, Ying Zhang, Hui-Yun Wang, Na-Na Huang, Jian-Hao Jiang, Bin Ning 2023, 18 (5):  1076-1083.  doi: 10.4103/1673-5374.355769 Abstract ( 235 )   PDF (3184KB) ( 168 )   Save Studies have shown that gut microbiota metabolites can enter the central nervous system via the blood-spinal cord barrier and cause neuroinflammation, thus constituting secondary injury after spinal cord injury. To investigate the correlation between gut microbiota and metabolites and the possible mechanism underlying the effects of gut microbiota on secondary injury after spinal cord injury, in this study, we established mouse models of T8–T10 traumatic spinal cord injury. We used 16S rRNA gene amplicon sequencing and metabolomics to reveal the changes in gut microbiota and metabolites in fecal samples from the mouse model. Results showed a severe gut microbiota disturbance after spinal cord injury, which included marked increases in pro-inflammatory bacteria, such as Shigella, Bacteroides, Rikenella, Staphylococcus, and Mucispirillum and decreases in anti-inflammatory bacteria, such as Lactobacillus, Allobaculum, and Sutterella. Meanwhile, we identified 27 metabolites that decreased and 320 metabolites that increased in the injured spinal cord. Combined with pathway enrichment analysis, five markedly differential amino acids (L-leucine, L-methionine, L-phenylalanine, L-isoleucine and L-valine) were screened out, which play a pivotal role in activating oxidative stress and inflammatory responses following spinal cord injury. Integrated correlation analysis indicated that the alteration of gut microbiota was related to the differences in amino acids, which suggests that disturbances in gut microbiota might participate in the secondary injury through the accumulation of partial metabolites that activate oxidative stress and inflammatory responses. Findings from this study provide a new theoretical basis for improving the secondary injury after spinal cord injury through fecal microbial transplantation.  Related Articles | Metrics

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Neural progenitor cells derived from fibroblasts induced by small molecule compounds under hypoxia for treatment of Parkinson’s disease in rats Yu Guo, Yuan-Yuan Wang, Ting-Ting Sun, Jia-Jia Xu, Pan Yang, Cai-Yun Ma, Wei-Jun Guan, Chun-Jing Wang, Gao-Feng Liu, Chang-Qing Liu 2023, 18 (5):  1090-1098.  doi: 10.4103/1673-5374.355820 Abstract ( 164 )   PDF (17522KB) ( 34 )   Save Neural progenitor cells (NPCs) capable of self-renewal and differentiation into neural cell lineages offer broad prospects for cell therapy for neurodegenerative diseases. However, cell therapy based on NPC transplantation is limited by the inability to acquire sufficient quantities of NPCs. Previous studies have found that a chemical cocktail of valproic acid, CHIR99021, and Repsox (VCR) promotes mouse fibroblasts to differentiate into NPCs under hypoxic conditions. Therefore, we used VCR (0.5 mM valproic acid, 3 μM CHIR99021, and 1 μM Repsox) to induce the reprogramming of rat embryonic fibroblasts into NPCs under a hypoxic condition (5%). These NPCs exhibited typical neurosphere-like structures that can express NPC markers, such as Nestin, SRY-box transcription factor 2, and paired box 6 (Pax6), and could also differentiate into multiple types of functional neurons and astrocytes in vitro. They had similar gene expression profiles to those of rat brain-derived neural stem cells. Subsequently, the chemically-induced NPCs (ciNPCs) were stereotactically transplanted into the substantia nigra of 6-hydroxydopamine-lesioned parkinsonian rats. We found that the ciNPCs exhibited long-term survival, migrated long distances, and differentiated into multiple types of functional neurons and glial cells in vivo. Moreover, the parkinsonian behavioral defects of the parkinsonian model rats grafted with ciNPCs showed remarkable functional recovery. These findings suggest that rat fibroblasts can be directly transformed into NPCs using a chemical cocktail of VCR without introducing exogenous factors, which may be an attractive donor material for transplantation therapy for Parkinson’s disease.  Related Articles | Metrics

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Neuroprotective effects of insulin-like growth factor-2 in 6-hydroxydopamine-induced cellular and mouse models of Parkinson’s disease Hai-Ying Zhang, Yong-Cheng Jiang, Jun-Rui Li, Jia-Nan Yan, Xin-Jue Wang, Jia-Bing Shen, Kai-Fu Ke, Xiao-Su Gu 2023, 18 (5):  1099-1106.  doi: 10.4103/1673-5374.355815 Abstract ( 182 )   PDF (6278KB) ( 100 )   Save Skin-derived precursor Schwann cells have been reported to play a protective role in the central nervous system. The neuroprotective effects of skin-derived precursor Schwann cells may be attributable to the release of growth factors that nourish host cells. In this study, we first established a cellular model of Parkinson’s disease using 6-hydroxydopamine. When SH-SY5Y cells were pretreated with conditioned medium from skin-derived precursor Schwann cells, their activity was greatly increased. The addition of insulin-like growth factor-2 neutralizing antibody markedly attenuated the neuroprotective effects of skin-derived precursor Schwann cells. We also found that insulin-like growth factor-2 levels in the peripheral blood were greatly increased in patients with Parkinson’s disease and in a mouse model of Parkinson’s disease. Next, we pretreated cell models of Parkinson’s disease with insulin-like growth factor-2 and administered insulin-like growth factor-2 intranasally to a mouse model of Parkinson’s disease induced by 6-hydroxydopamine and found that the level of tyrosine hydroxylase, a marker of dopamine neurons, was markedly restored, α-synuclein aggregation decreased, and insulin-like growth factor-2 receptor down-regulation was alleviated. Finally, in vitro experiments showed that insulin-like growth factor-2 activated the phosphatidylinositol 3 kinase (PI3K)/AKT pathway. These findings suggest that the neuroprotective effects of skin-derived precursor Schwann cells on the central nervous system were achieved through insulin-like growth factor-2, and that insulin-like growth factor-2 may play a neuroprotective role through the insulin-like growth factor-2 receptor/PI3K/AKT pathway. Therefore, insulin-like growth factor-2 may be an useful target for Parkinson’s disease treatment. Related Articles | Metrics

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Blunt dopamine transmission due to decreased GDNF in the PFC evokes cognitive impairment in Parkinson’s disease Chuan-Xi Tang, Jing Chen, Kai-Quan Shao, Ye-Hao Liu, Xiao-Yu Zhou, Cheng-Cheng Ma, Meng-Ting Liu, Ming-Yu Shi, , Piniel Alphayo Kambey, Wei Wang, Abiola Abdulrahman Ayanlaja, Yi-Fang Liu, Wei Xu, Gang Chen, Jiao Wu, Xue Li, Dian-Shuai Gao 2023, 18 (5):  1107-1117.  doi: 10.4103/1673-5374.355816 Abstract ( 164 )   PDF (6212KB) ( 82 )   Save Studies have found that the absence of glial cell line-derived neurotrophic factor may be the primary risk factor for Parkinson’s disease. However, there have not been any studies conducted on the potential relationship between glial cell line-derived neurotrophic factor and cognitive performance in Parkinson’s disease. We first performed a retrospective case-control study at the Affiliated Hospital of Xuzhou Medical University between September 2018 and January 2020 and found that a decreased serum level of glial cell line-derived neurotrophic factor was a risk factor for cognitive disorders in patients with Parkinson’s disease. We then established a mouse model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and analyzed the potential relationships among glial cell line-derived neurotrophic factor in the prefrontal cortex, dopamine transmission, and cognitive function. Our results showed that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex weakened dopamine release and transmission by upregulating the presynaptic membrane expression of the dopamine transporter, which led to the loss and primitivization of dendritic spines of pyramidal neurons and cognitive impairment. In addition, magnetic resonance imaging data showed that the long-term lack of glial cell line-derived neurotrophic factor reduced the connectivity between the prefrontal cortex and other brain regions, and exogenous glial cell line-derived neurotrophic factor significantly improved this connectivity. These findings suggested that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex leads to neuroplastic degeneration at the level of synaptic connections and circuits, which results in cognitive impairment in patients with Parkinson’s disease. Related Articles | Metrics

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Artificial nerve graft constructed by coculture of activated Schwann cells and human hair keratin for repair of peripheral nerve defects Han-Jun Qin, Hang Li, Jun-Ze Chen, Kai-Rui Zhang, Xing-Qi Zhao, Jian-Qiang Qin, Bin Yu, Jun Yang 2023, 18 (5):  1118-1123.  doi: 10.4103/1673-5374.355817 Abstract ( 158 )   PDF (5209KB) ( 110 )   Save Studies have shown that human hair keratin (HHK) has no antigenicity and excellent mechanical properties. Schwann cells, as unique glial cells in the peripheral nervous system, can be induced by interleukin-1β to secrete nerve growth factor, which promotes neural regeneration. Therefore, HHK with Schwann cells may be a more effective approach to repair nerve defects than HHK without Schwann cells. In this study, we established an artificial nerve graft by loading an HHK skeleton with activated Schwann cells. We found that the longitudinal HHK microfilament structure provided adhesion medium, space and direction for Schwann cells, and promoted Schwann cell growth and nerve fiber regeneration. In addition, interleukin-1β not only activates Schwann cells, but also strengthens their activity and increases the expression of nerve growth factors. Activated Schwann cells activate macrophages, and activated macrophages secrete interleukin-1β, which maintains the activity of Schwann cells. Thus, a beneficial cycle forms and promotes nerve repair. Furthermore, our studies have found that the newly constructed artificial nerve graft promotes the improvements in nerve conduction function and motor function in rats with sciatic nerve injury, and increases the expression of nerve injury repair factors fibroblast growth factor 2 and human transforming growth factor B receptor 2. These findings suggest that this artificial nerve graft effectively repairs peripheral nerve injury. Related Articles | Metrics

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Overexpressing NeuroD1 reprograms Müller cells into various types of retinal neurons Di Xu, Li-Ting Zhong, Hai-Yang Cheng, Zeng-Qiang Wang, Xiong-Min Chen, Ai-Ying Feng, Wei-Yi Chen, Gong Chen, Ying Xu 2023, 18 (5):  1124-1134.  doi: 10.4103/1673-5374.355818 Abstract ( 304 )   PDF (6040KB) ( 147 )   Save The onset of retinal degenerative disease is often associated with neuronal loss. Therefore, how to regenerate new neurons to restore vision is an important issue. NeuroD1 is a neural transcription factor with the ability to reprogram brain astrocytes into neurons in vivo. Here, we demonstrate that in adult mice, NeuroD1 can reprogram Müller cells, the principal glial cell type in the retina, to become retinal neurons. Most strikingly, ectopic expression of NeuroD1 using two different viral vectors converted Müller cells into different cell types. Specifically, AAV7m8 GFAP681::GFP-ND1 converted Müller cells into inner retinal neurons, including amacrine cells and ganglion cells. In contrast, AAV9 GFAP104::ND1-GFP converted Müller cells into outer retinal neurons such as photoreceptors and horizontal cells, with higher conversion efficiency. Furthermore, we demonstrate that Müller cell conversion induced by AAV9 GFAP104::ND1-GFP displayed clear dose- and time-dependence. These results indicate that Müller cells in adult mice are highly plastic and can be reprogrammed into various subtypes of retinal neurons.  Related Articles | Metrics

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Mechanism of piR-1245/PIWI-like protein-2 regulating Janus kinase-2/signal transducer and activator of transcription-3/vascular endothelial growth factor signaling pathway in retinal neovascularization Yong Yu, Li-Kun Xia, Yu Di, Qing-Zhu Nie, Xiao-Long Chen 2023, 18 (5):  1132-1138.  doi: 10.4103/1673-5374.355819 Abstract ( 168 )   PDF (4678KB) ( 80 )   Save Inhibiting retinal neovascularization is the optimal strategy for the treatment of retina-related diseases, but there is currently no effective treatment for retinal neovascularization. P-element-induced wimpy testis (PIWI)-interacting RNA (piRNA) is a type of small non-coding RNA implicated in a variety of diseases. In this study, we found that the expression of piR-1245 and the interacting protein PIWIL2 were remarkably increased in human retinal endothelial cells cultured in a hypoxic environment, and cell apoptosis, migration, tube formation and proliferation were remarkably enhanced in these cells. Knocking down piR-1245 inhibited the above phenomena. After intervention by a p-JAK2 activator, piR-1245 decreased the expression of hypoxia inducible factor-1α and vascular endothelial growth factor through the JAK2/STAT3 pathway. For in vivo analysis, 7-day-old newborn mice were raised in 75 ± 2% hyperoxia for 5 days and then piR-1245 in the retina was knocked down. In these mice, the number of newly formed vessels in the retina was decreased, the expressions of inflammation-related proteins were reduced, the number of apoptotic cells in the retina was decreased, the JAK2/STAT3 pathway was inhibited, and the expressions of hypoxia inducible factor-1α and vascular endothelial growth factor were decreased. Injection of the JAK2 inhibitor JAK2/TYK2-IN-1 into the vitreous cavity inhibited retinal neovascularization in mice and reduced expression of hypoxia inducible factor-1α and vascular endothelial growth factor. These findings suggest that piR-1245 activates the JAK2/STAT3 pathway, regulates the expression of hypoxia inducible factor-1α and vascular endothelial growth factor, and promotes retinal neovascularization. Therefore, piR-1245 may be a new therapeutic target for retinal neovascularization.  Related Articles | Metrics

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Ocular manifestations of central insulin resistance Muneeb A. Faiq, Trina Sengupta, Madhu Nath, Thirumurthy Velpandian, Daman Saluja, Rima Dada, Tanuj Dada, Kevin C. Chan 2023, 18 (5):  1139-1146.  doi: 10.4103/1673-5374.355765 Abstract ( 160 )   PDF (3486KB) ( 174 )   Save Central insulin resistance, the diminished cellular sensitivity to insulin in the brain, has been implicated in diabetes mellitus, Alzheimer’s disease and other neurological disorders. However, whether and how central insulin resistance plays a role in the eye remains unclear. Here, we performed intracerebroventricular injection of S961, a potent and specific blocker of insulin receptor in adult Wistar rats to test if central insulin resistance leads to pathological changes in ocular structures. 80 mg of S961 was stereotaxically injected into the lateral ventricle of the experimental group twice at 7 days apart, whereas buffer solution was injected to the sham control group. Blood samples, intraocular pressure, trabecular meshwork morphology, ciliary body markers, retinal and optic nerve integrity, and whole genome expression patterns were then evaluated. While neither blood glucose nor serum insulin level was significantly altered in the experimental or control group, we found that injection of S961 but not buffer solution significantly increased intraocular pressure at 14 and 24 days after first injection, along with reduced porosity and aquaporin 4 expression in the trabecular meshwork, and increased tumor necrosis factor α and aquaporin 4 expression in the ciliary body. In the retina, cell density and insulin receptor expression decreased in the retinal ganglion cell layer upon S961 injection. Fundus photography revealed peripapillary atrophy with vascular dysregulation in the experimental group. These retinal changes were accompanied by upregulation of pro-inflammatory and pro-apoptotic genes, downregulation of anti-inflammatory, anti-apoptotic, and neurotrophic genes, as well as dysregulation of genes involved in insulin signaling. Optic nerve histology indicated microglial activation and changes in the expression of glial fibrillary acidic protein, tumor necrosis factor α, and aquaporin 4. Molecular pathway architecture of the retina revealed the three most significant pathways involved being inflammation/cell stress, insulin signaling, and extracellular matrix regulation relevant to neurodegeneration. There was also a multimodal crosstalk between insulin signaling derangement and inflammation-related genes. Taken together, our results indicate that blocking insulin receptor signaling in the central nervous system can lead to trabecular meshwork and ciliary body dysfunction, intraocular pressure elevation, as well as inflammation, glial activation, and apoptosis in the retina and optic nerve. Given that central insulin resistance may lead to neurodegenerative phenotype in the visual system, targeting insulin signaling may hold promise for vision disorders involving the retina and optic nerve. Related Articles | Metrics

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Long noncoding RNA Pvt1 promotes the proliferation and migration of Schwann cells by sponging microRNA-214 and targeting c-Jun following peripheral nerve injury Bin Pan, Di Guo, Li Jing, Ke Li, Xin Li, Gen Li, Xiao Gao, Zhi-Wen Li, Wei Zhao, Hu Feng, Meng-Han Cao 2023, 18 (5):  1147-1153.  doi: 10.4103/1673-5374.353497 Abstract ( 111 )   PDF (3080KB) ( 88 )   Save Research has shown that long-chain noncoding RNAs (lncRNAs) are involved in the regulation of a variety of biological processes, including peripheral nerve regeneration, in part by acting as competing endogenous RNAs. c-Jun plays a key role in the repair of peripheral nerve injury. However, the precise underlying mechanism of c-Jun remains unclear. In this study, we performed microarray and bioinformatics analysis of mouse crush-injured sciatic nerves and found that the lncRNA Pvt1 was overexpressed in Schwann cells after peripheral nerve injury. Mechanistic studies revealed that Pvt1 increased c-Jun expression through sponging miRNA-214. We overexpressed Pvt1 in Schwann cells cultured in vitro and found that the proliferation and migration of Schwann cells were enhanced, and overexpression of miRNA-214 counteracted the effects of Pvt1 overexpression on Schwann cell proliferation and migration. We conducted in vivo analyses and injected Schwann cells overexpressing Pvt1 into injured sciatic nerves of mice. Schwann cells overexpressing Pvt1 enhanced the regeneration of injured sciatic nerves following peripheral nerve injury and the locomotor function of mice was improved. Our findings reveal the role of lncRNAs in the repair of peripheral nerve injury and highlight lncRNA Pvt1 as a novel potential treatment target for peripheral nerve injury.  Related Articles | Metrics

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Impact of cognition-related single nucleotide polymorphisms on brain imaging phenotype in Parkinson’s disease Ting Shen, Jia-Li Pu, Ya-Si Jiang, Yu-Mei Yue, Ting-Ting He, Bo-Yi Qu, Shuai Zhao, Ya-Ping Yan, Hsin-Yi Lai, Bao-Rong Zhang 2023, 18 (5):  1154-1160.  doi: 10.4103/1673-5374.355764 Abstract ( 127 )   PDF (18834KB) ( 39 )   Save Multiple single nucleotide polymorphisms may contribute to cognitive decline in Parkinson’s disease. However, the mechanism by which these single nucleotide polymorphisms modify brain imaging phenotype remains unclear. The aim of this study was to investigate the potential effects of multiple single nucleotide polymorphisms on brain imaging phenotype in Parkinson’s disease. Forty-eight Parkinson’s disease patients and 39 matched healthy controls underwent genotyping and 7T magnetic resonance imaging. A cognitive-weighted polygenic risk score model was designed, in which the effect sizes were determined individually for 36 single nucleotide polymorphisms. The correlations between polygenic risk score, neuroimaging features, and clinical data were analyzed. Furthermore, individual single nucleotide polymorphism analysis was performed to explore the main effects of genotypes and their interactive effects with Parkinson’s disease diagnosis. We found that, in Parkinson’s disease, the polygenic risk score was correlated with the neural activity of the hippocampus, parahippocampus, and fusiform gyrus, and with hippocampal-prefrontal and fusiform-temporal connectivity, as well as with gray matter alterations in the orbitofrontal cortex. In addition, we found that single nucleotide polymorphisms in α-synuclein (SNCA) were associated with white matter microstructural changes in the superior corona radiata, corpus callosum, and external capsule. A single nucleotide polymorphism in catechol-O-methyltransferase was associated with the neural activities of the lingual, fusiform, and occipital gyri, which are involved in visual cognitive dysfunction. Furthermore, DRD3 was associated with frontal and temporal lobe function and structure. In conclusion, imaging genetics is useful for providing a better understanding of the genetic pathways involved in the pathophysiologic processes underlying Parkinson’s disease. This study provides evidence of an association between genetic factors, cognitive functions, and multi-modality neuroimaging biomarkers in Parkinson’s disease. Related Articles | Metrics