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15 July 2022, Volume 17 Issue 7 Previous Issue    Next Issue

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Rethinking the necessity of low glucose intervention for cerebral ischemia/reperfusion injury Jiahua Xie, Farooqahmed S. Kittur, P. Andy Li, Chiu-Yueh Hung 2022, 17 (7):  1397-1403.  doi: 10.4103/1673-5374.330592 Abstract ( 155 )   PDF (1619KB) ( 125 )   Save Glucose is the essential and almost exclusive metabolic fuel for the brain. Ischemic stroke caused by a blockage in one or more cerebral arteries quickly leads to a lack of regional cerebral blood supply resulting in severe glucose deprivation with subsequent induction of cellular homeostasis disturbance and eventual neuronal death. To make up ischemia-mediated adenosine 5′-triphosphate depletion, glucose in the ischemic penumbra area rapidly enters anaerobic metabolism to produce glycolytic adenosine 5′-triphosphate for cell survival. It appears that an increase in glucose in the ischemic brain would exert favorable effects. This notion is supported by in vitro studies, but generally denied by most in vivo studies. Clinical studies to manage increased blood glucose levels after stroke also failed to show any benefits or even brought out harmful effects while elevated admission blood glucose concentrations frequently correlated with poor outcomes. Surprisingly, strict glycaemic control in clinical practice also failed to yield any beneficial outcome. These controversial results from glucose management studies during the past three decades remain a challenging question of whether glucose intervention is needed for ischemic stroke care. This review provides a brief overview of the roles of cerebral glucose under normal and ischemic conditions and the results of managing glucose levels in non-diabetic patients. Moreover, the relationship between blood glucose and cerebral glucose during the ischemia/reperfusion processes and the potential benefits of low glucose supplements for non-diabetic patients are discussed.  Related Articles | Metrics

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Microglia activation, classification and microglia-mediated neuroinflammatory modulators in subarachnoid hemorrhage Junfan Chen, Zhiyuan Vera Zheng, Gang Lu, Wai Yee Chan, Yisen Zhang, George Kwok Chu Wong 2022, 17 (7):  1404-1411.  doi: 10.4103/1673-5374.330589 Abstract ( 338 )   PDF (2627KB) ( 146 )   Save Subarachnoid hemorrhage is a devastating disease with significant mortality and morbidity, despite advances in treating cerebral aneurysms. There has been recent progress in the intensive care management and monitoring of patients with subarachnoid hemorrhage, but the results remain unsatisfactory. Microglia, the resident immune cells of the brain, are increasingly recognized as playing a significant role in neurological diseases, including subarachnoid hemorrhage. In early brain injury following subarachnoid hemorrhage, microglial activation and neuroinflammation have been implicated in the development of disease complications and recovery. To understand the disease processes following subarachnoid hemorrhage, it is important to focus on the modulators of microglial activation and the pro-inflammatory/anti-inflammatory cytokines and chemokines. In this review, we summarize research on the modulators of microglia-mediated inflammation in subarachnoid hemorrhage, including transcriptome changes and the neuroinflammatory signaling pathways. We also describe the latest developments in single-cell transcriptomics for microglia and summarize advances that have been made in the transcriptome-based classification of microglia and the implications for microglial activation and neuroinflammation. Related Articles | Metrics

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MicroRNA biomarkers in frontotemporal dementia and to distinguish from Alzheimer’s disease and amyotrophic lateral sclerosis Bridget Martinez, Philip V. Peplow 2022, 17 (7):  1412-1422.  doi: 10.4103/1673-5374.330591 Abstract ( 203 )   PDF (615KB) ( 77 )   Save Frontotemporal lobar degeneration describes a group of progressive brain disorders that primarily are associated with atrophy of the prefrontal and anterior temporal lobes. Frontotemporal lobar degeneration is considered to be equivalent to frontotemporal dementia. Frontotemporal dementia is characterized by progressive impairments in behavior, executive function, and language. There are two main clinical subtypes: behavioral-variant frontotemporal dementia and primary progressive aphasia. The early diagnosis of frontotemporal dementia is critical for developing management strategies and interventions for these patients. Without validated biomarkers, the clinical diagnosis depends on recognizing all the core or necessary neuropsychiatric features, but misdiagnosis often occurs due to overlap with a range of neurologic and psychiatric disorders. In the studies reviewed a very large number of microRNAs were found to be dysregulated but with limited overlap between individual studies. Measurement of specific miRNAs singly or in combination, or as miRNA pairs (as a ratio) in blood plasma, serum, or cerebrospinal fluid enabled frontotemporal dementia to be discriminated from healthy controls, Alzheimer’s disease, and amyotrophic lateral sclerosis. Furthermore, upregulation of miR-223-3p and downregulation of miR-15a-5p, which occurred both in blood serum and cerebrospinal fluid, distinguished behavioral-variant frontotemporal dementia from healthy controls. Downregulation of miR-132-3p in frontal and temporal cortical tissue distinguished frontotemporal lobar degeneration and frontotemporal dementia, respectively, from healthy controls. Possible strong miRNA biofluid biomarker contenders for behavioral-variant frontotemporal dementia are miR-223-3p, miR-15a-5p, miR-22-3p in blood serum and cerebrospinal fluid, and miR-124 in cerebrospinal fluid. No miRNAs were identified able to distinguish between behavioral-variant frontotemporal dementia and primary progressive aphasia subtypes. Further studies are warranted on investigating miRNA expression in biofluids and frontal/temporal cortical tissue to validate and extend these findings. Related Articles | Metrics

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Protein synthesis modulation as a therapeutic approach for amyotrophic lateral sclerosis and frontotemporal dementia Santiago E. Charif, M. Florencia Vassallu, Lara Salvañal, Lionel M. Igaz 2022, 17 (7):  1423-1430.  doi: 10.4103/1673-5374.330593 Abstract ( 265 )   PDF (469KB) ( 49 )   Save Protein synthesis is essential for cells to perform life metabolic processes. Pathological alterations of protein content can lead to particular diseases. Cells have an intrinsic array of mechanisms and pathways that are activated when protein misfolding, accumulation, aggregation or mislocalization occur. Some of them (like the unfolded protein response) represent complex interactions between endoplasmic reticulum sensors and elongation factors that tend to increase expression of chaperone proteins and/or repress translation in order to restore protein homeostasis (also known as proteostasis). This is even more important in neurons, as they are very susceptible to harmful effects associated with protein overload and proteostatic mechanisms are less effective with age. Several neurodegenerative pathologies such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, amyotrophic lateral sclerosis and frontotemporal dementia exhibit a particular molecular signature of distinct, unbalanced protein overload. In amyotrophic lateral sclerosis and frontotemporal dementia, the majority of cases present intracellular inclusions of ubiquitinated transactive response DNA-binding protein of 43 kDa (TDP-43). TDP-43 is an RNA binding protein that participates in RNA metabolism, among other functions. Dysregulation of TDP-43 (e.g. aggregation and mislocalization) can dramatically affect neurons, and this has been linked to disease development. Expression of amyotrophic lateral sclerosis/frontotemporal dementia TDP-43-related mutations in cellular and animal models has been shown to recapitulate key features of the amyotrophic lateral sclerosis/frontotemporal dementia disease spectrum. These variants can be causative of degeneration onset and progression. Most neurodegenerative diseases (including amyotrophic lateral sclerosis and frontotemporal dementia) have no cure at the moment; however, modulating translation has recently emerged as an attractive approach that can be performed at several steps (i.e. regulating activation of initiation and elongation factors, inhibiting unfolded protein response activation or inducing chaperone expression and activity). This review focuses on the features of protein imbalance in neurodegenerative disorders and the relevance of developing therapeutical compounds aiming at restoring proteostasis. We strive to highlight the importance of research on drugs that, not only restore protein imbalance without compromising translational activity of cells, but are also as safe as possible for the patients. Related Articles | Metrics

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A novel viewpoint in glaucoma therapeutics: enriched environment María F. González Fleitas, Damián Dorfman, Ruth E. Rosenstein 2022, 17 (7):  1431-1439.  doi: 10.4103/1673-5374.330594 Abstract ( 144 )   PDF (877KB) ( 79 )   Save Glaucoma is one of the world’s most frequent visual impairment causes and leads to selective damage to retinal ganglion cells and their axons. Despite glaucoma’s most accepted risk factor is increased intraocular pressure (IOP), the mechanisms behind the disease have not been fully elucidated. To date, IOP lowering remains the gold standard; however, glaucoma patients may still lose vision regardless of effective IOP management. Therefore, the exclusive IOP control apparently is not enough to stop the disease progression, and developing new resources to protect the retina and optic nerve against glaucoma is a goal of vast clinical importance. Besides pharmacological treatments, environmental conditions have been shown to prevent neurodegeneration in the central nervous system. In this review, we discuss current concepts on key pathogenic mechanisms involved in glaucoma, the effect of enriched environment on these mechanisms in different experimental models, as well as recent evidence supporting the preventive and therapeutic effect of enriched environment exposure against experimental glaucomatous damage. Finally, we postulate that stimulating vision may become a non-invasive and rehabilitative therapy that could be eventually translated to the human disease, preventing glaucoma-induced terrible sequelae resulting in permanent visual disability. Related Articles | Metrics

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Neuronal reprogramming in treating spinal cord injury Xuanyu Chen, Hedong Li 2022, 17 (7):  1440-1445.  doi: 10.4103/1673-5374.330590 Abstract ( 165 )   PDF (509KB) ( 86 )   Save Spinal cord injury represents a devastating central nervous system injury that could impair the mobility and sensory function of afflicted patients. The hallmarks of spinal cord injury include neuroinflammation, axonal degeneration, neuronal loss, and reactive gliosis. Furthermore, the formation of a glial scar at the injury site elicits an inhibitory environment for potential neuroregeneration. Besides axonal regeneration, a significant challenge in treating spinal cord injury is to replenish the neurons lost during the pathological process. However, despite decades of research efforts, current strategies including stem cell transplantation have not resulted in a successful clinical therapy. Furthermore, stem cell transplantation faces serious hurdles such as immunorejection of the transplanted cells and ethical issues. In vivo neuronal reprogramming is a recently developed technology and leading a major breakthrough in regenerative medicine. This innovative technology converts endogenous glial cells into functional neurons for injury repair in the central nervous system. The feasibility of in vivo neuronal reprogramming has been demonstrated successfully in models of different neurological disorders including spinal cord injury by numerous laboratories. Several reprogramming factors, mainly the pro-neural transcription factors, have been utilized to reprogram endogenous glial cells into functional neurons with distinct phenotypes. So far, the literature on in vivo neuronal reprogramming in the model of spinal cord injury is still small. In this review, we summarize a limited number of such reports and discuss several questions that we think are important for applying in vivo neuronal reprogramming in the research field of spinal cord injury as well as other central nervous system disorders. Related Articles | Metrics

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The role of L-arginine metabolism in neurocritical care patients Marius Marc-Daniel Mader, Patrick Czorlich 2022, 17 (7):  1446-1453.  doi: 10.4103/1673-5374.327331 Abstract ( 168 )   PDF (1883KB) ( 102 )   Save Nitric oxide is an important mediator of vascular autoregulation and is involved in pathophysiological changes after acute neurological disorders. Nitric oxide is generated by nitric oxide synthases from the amino acid L-arginine. L-arginine can also serve as a substrate for arginases or lead to the generation of dimethylarginines, asymmetric dimethylarginine, and symmetric dimethylarginine, by methylation. Asymmetric dimethylarginine is an endogenous inhibitor of nitric oxide synthase and can lead to endothelial dysfunction. This review discusses the role of L-arginine metabolism in patients suffering from acute and critical neurological disorders often requiring neuro-intensive care treatment. Conditions addressed in this review include intracerebral hemorrhage, aneurysmal subarachnoid hemorrhage, and traumatic brain injury. Recent therapeutic advances in the field are described including current randomized controlled trials for traumatic brain injuries and hemorrhagic stroke. Related Articles | Metrics

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Homer signaling pathways as effective therapeutic targets for ischemic and traumatic brain injuries and retinal lesions Xiu-Quan Wu, Ning Su, Zhou Fei, Fei Fei 2022, 17 (7):  1454-1461.  doi: 10.4103/1673-5374.330588 Abstract ( 126 )   PDF (38353KB) ( 32 )   Save Ischemic and traumatic insults to the central nervous system account for most serious acute and fatal brain injuries and are usually characterized by primary and secondary damage. Secondary damage presents the greatest challenge for medical staff; however, there are currently few effective therapeutic targets for secondary damage. Homer proteins are postsynaptic scaffolding proteins that have been implicated in ischemic and traumatic insults to the central nervous system. Homer signaling can exert either positive or negative effects during such insults, depending on the specific subtype of Homer protein. Homer 1b/c couples with other proteins to form postsynaptic densities, which form the basis of synaptic transmission, while Homer1a expression can be induced by harmful external factors. Homer 1c is used as a unique biomarker to reveal alterations in synaptic connectivity before and during the early stages of apoptosis in retinal ganglion cells, mediated or affected by extracellular or intracellular signaling or cytoskeletal processes. This review summarizes the structural features, related signaling pathways, and diverse roles of Homer proteins in physiological and pathological processes. Upregulating Homer1a or downregulating Homer1b/c may play a neuroprotective role in secondary brain injuries. Homer also plays an important role in the formation of photoreceptor synapses. These findings confirm the neuroprotective effects of Homer, and support the future design of therapeutic drug targets or gene therapies for ischemic and traumatic brain injuries and retinal disorders based on Homer proteins. Related Articles | Metrics

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Is activation of GDNF/RET signaling the answer for successful treatment of Parkinson’s disease? A discussion of data from the culture dish to the clinic James A. Conway, Edgar R. Kramer 2022, 17 (7):  1462-1467.  doi: 10.4103/1673-5374.327330 Abstract ( 335 )   PDF (540KB) ( 141 )   Save The neurotrophic signaling of glial cell line-derived neurotrophic factor (GDNF) with its canonical receptor, the receptor tyrosine kinase RET, coupled together with the GDNF family receptor alpha 1 is important for dopaminergic neuron survival and physiology in cell culture experiments and animal models. This prompted the idea to try GDNF/RET signaling as a therapeutic approach to treat Parkinson’s disease with the hallmark of dopaminergic cell death in the substantia nigra of the midbrain. Despite several clinical trials with GDNF in Parkinson’s disease patients, which mainly focused on optimizing the GDNF delivery technique, benefits were only seen in a few patients. In general, the endpoints did not show significant improvements. This suggests that it will be helpful to learn more about the basic biology of this fascinating but complicated GDNF/RET signaling system in the dopaminergic midbrain and about recent developments in the field to facilitate its use in the clinic. Here we will refer to the latest publications and point out important open questions in the field. Related Articles | Metrics

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Optogenetic neuroregeneration Harald Janovjak, Sonja Kleinlogel 2022, 17 (7):  1468-1470.  doi: 10.4103/1673-5374.330596 Abstract ( 221 )   PDF (739KB) ( 112 )   Save Optogenetics is a powerful technology that employs light and genetics to manipulate physiology and behavior with unprecedented precision. The high acuity of light stimulation permits fine control both in space (e.g., to target just one tissue in an animal) and in time (e.g., to interfere with a specific disease stage), whilst genetic targeting restricts manipulation to a functionally-relevant cell population (Figure 1A). These unique capabilities have laid the ground for answering previously unresolvable questions in neuroscience and for new treatment avenues. Already shortly after its inception, optogenetics was harnessed to understand neural circuit function in animal models of neurological and neurodegenerative disorders, including spinal cord injury, stroke, and Parkinson’s disease (PD). Notably, in some of these models, optically-evoked neuronal activity was sufficient to elicit a functional improvement, e.g. through the formation of new microcircuitries or release of neurotrophic factors (Ordaz et al., 2017). These initial discoveries were recently followed by targeted neuroregeneration strategies. These generally aim at either replacement of degenerated sensory functions by optogenetic actuators or site-specific optical delivery of pro-survival signals to counter neurodegeneration (Kleinlogel et al., 2020; Ingles-Prieto et al., 2021). It is these two optogenetic neuroregeneration strategies that we discuss here, from the origins of the field of optogenetics to the recent pioneering clinical application (Sahel et al., 2021). Related Articles | Metrics

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Neuronal and endothelial transglutaminase-2 expression in experimental autoimmune encephalomyelitis and multiple sclerosis Damien D. Pearse, Mousumi Ghosh 2022, 17 (7):  1471-1472.  doi: 10.4103/1673-5374.330598 Abstract ( 117 )   PDF (288KB) ( 47 )   Save Multiple sclerosis (MS) is a neurological condition characterized by the disruption of the blood-brain barrier, immune system activation, and inflammation that is accompanied by glial reactivity, neuronal cell death, axon demyelination, and axotomy. Pathological changes result in functional loss including paralysis, migraine, vision problems, spasticity, and neuropathic pain. Although the causative factor responsible for triggering MS remains to be identified, anti-inflammatory treatments have been translated to clinical use with favorable reductions in the frequency, severity, and duration of relapses in the relapsing-remitting form of MS. Among the identified therapeutic targets in MS, transglutaminase-2 (TG2) has been reported to be involved in disease pathogenesis (Chrobok et al., 2018). Related Articles | Metrics

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Lycium barbarum polysaccharides and ferroptosis: jumping into the era of novel regulated cell death Amy Cheuk Yin Lo, Ming Yang 2022, 17 (7):  1473-1474.  doi: 10.4103/1673-5374.330600 Abstract ( 221 )   PDF (328KB) ( 134 )   Save Lycium barbarum polysaccharides (LBP) are the key bioactive components of Lycium barbarum (also named Gouqizi or Goji berry or wolfberry), a widely used Traditional Chinese herb for more than 2000 years. Believed to balance “yin” and “yang” within the body, Lycium barbarum is consumed for general health benefits. Besides, it also “nourishes” the eyes, kidneys, lungs, and liver. Indeed, Lycium barbarum has been considered as a “superfruit”, an inexpensive supplement for many oxidative stress-related diseases. It is currently included in the Pharmacopoeia of the People’s Republic of China. Related Articles | Metrics

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Morpholino studies shed light on the signaling pathways regulating axon regeneration in lampreys Daniel Sobrido-Cameán†, Antón Barreiro-Iglesias 2022, 17 (7):  1475-1477.  doi: 10.4103/1673-5374.330597 Abstract ( 146 )   PDF (645KB) ( 57 )   Save Lampreys are one of the most ancient extant vertebrates and they have become an animal model of interest for the study of spontaneous axon regeneration after a traumatic central nervous system injury. Contrary to most mammals, lampreys recover locomotion after a complete spinal cord injury (SCI). During recovery from SCI, some of the descending axons in lampreys regenerate through the injury site and reinnervate caudal levels of the spinal cord. Interestingly, the brainstem of lampreys contains 36 giant descending neurons that can be identified individually and that show very different survival and regenerative abilities after a complete SCI (Jacobs et al., 1997; see Barreiro-Iglesias, 2015), even when their axons are found in similar locations in a spinal cord that is permissive for axonal regrowth. Some of these identifiable neurons are considered “good” regenerators (they regenerate their axon more than 55% of the times) and others are considered “bad” regenerators (they regenerate their axon less than 50% of the times) (Figure 1). This offers a model in which the intrinsic mechanisms regulating neuronal survival and axonal regrowth can be studied in vivo and at the level of individual neurons. First, one can use this model to find genes showing differential expression between “good” and “bad” regenerator neurons, and then try to perform functional studies by manipulating their expression or their action. As in any other animal model, drugs can be used for this purpose (Fogerson et al., 2016; Romaus-Sanjurjo et al., 2018; Sobrido-Cameán et al., 2019, 2020), but ideally genetic manipulations are also needed to confirm drug effects or to manipulate the expression of genes for which no drugs are available. Related Articles | Metrics

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Quo vadis? Bioengineered polysaccharide-based hydrogel scaffolds for damaged central nervous system recovery and regeneration Isadora C. Carvalho, Herman S. Mansur 2022, 17 (7):  1478-1480.  doi: 10.4103/1673-5374.330599 Abstract ( 140 )   PDF (705KB) ( 60 )   Save Impairments in the central nervous system (CNS) are a prevalent cause of life-long disabilities worldwide, representing serious health, social, and economic concerns (Doblado et al., 2021). During the last decades, with the population eldering and the increase in the life span, we have experienced an increase in CNS-related disorders, like stroke and neurodegenerative diseases (Jarrin et al., 2021). Paralysis, cognitive function, and sensory losses (Jensen et al., 2020) are among the most predominant outcomes. Regrettably, there is still no effective therapy for CNS repair and regeneration (CNSRR), where most of the current therapeutics can only prevent continued damage in the affected area (Ali and Bhuiyan, 2021). The presence of the blood-brain barrier restricts the permeation of drugs through the circulation, and the difficulty of accessing the damaged regions, which usually demand invasive surgeries, compromise even more the effectiveness of the available treatments (Ojeda-Hernández et al., 2020). Thus, there is an urge to develop an effective therapy for CNSRR. Hopefully, a multidisciplinary strategy has been adopted for designing sophisticated multifunctional platforms based on nature-sourced materials capable of influencing cell fate, delivering therapeutics for the damaged area in a sustained manner, and supporting the adjacent brain parenchyma aiming at CNSRR: the polysaccharides. Here, we do not cover the overall properties of polysaccharide-based materials. Hence, we emphatically recommend the readers resort to state-of-the-art works referenced throughout this paper for further comprehension of the theme (Carvalho et al., 2021; Doblado et al., 2021; Tupone et al., 2021). Related Articles | Metrics

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CXCR4 signaling in central nervous system regeneration: friend or foe? Daniel Terheyden-Keighley, Alexander M. Hilla, Dietmar Fischer 2022, 17 (7):  1481-1483.  doi: 10.4103/1673-5374.330605 Abstract ( 155 )   PDF (3088KB) ( 39 )   Save The knockout of the chemokine C-X-C motif chemokine receptor 4 (CXCR4) in growth-stimulated retinal ganglion cells (RGCs) has a multiplicative effect on optic nerve regeneration. C-X-C motif chemokine ligand 12 (CXCL12), the exclusive ligand of CXCR4, is expressed and axonally transported by an RGC subpopulation, releasing the chemokine at the lesion site. CXCL12 attracts injured axons of a CXCR4-positive RGC subpopulation, mostly αRGC, thereby preventing extension into the distal nerve. Knockout of either CXCR4 or CXCL12 in RGCs overcomes the axonal entrapment at the lesion site and enables long-distance regeneration. Thus, CXCL12/CXCR4-dependent attraction of axons contributes to the failure of optic nerve regeneration. Here we briefly cover CXCR4-based neural motility, current mechanistic background, and future perspectives in central nervous system (CNS) regeneration. Related Articles | Metrics

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Therapeutic potential of prophylactic exercise for intracerebral hemorrhage Keita Kinoshita, Kelly K. Chung, Hiroshi Katsuki, Ken Arai 2022, 17 (7):  1484-1485.  doi: 10.4103/1673-5374.330606 Abstract ( 152 )   PDF (274KB) ( 64 )   Save Physical activity helps promote and maintain our brain health, including memory and cognitive performance. Research has shown that exercise is a safe behavioral intervention that reduces the risk of hypokinetic diseases, such as hypertension, diabetes, and lipid metabolic disorders. In addition, accumulating evidence now suggests that increased physical activity has positive effects in both preventing and ameliorating multiple brain diseases, including stroke. Although stroke is often accompanied by severe long-term disability and dementia, exercise is considered effective in enhancing neurological functions, even in stroke patients. Recent systematic reviews and meta-analyses indicate that aerobic physical activity promotes multiple health outcomes, including neurological behaviors and cognitive performance in stroke patients (Luo et al., 2020). Pre-clinical studies using rodent models of stroke have also demonstrated that exercise has therapeutic potential by influencing neuroinflammation, neuroprotection, remyelination, and astrogliosis (Svensson et al., 2015). Because aging is a major risk factor for stroke, and because polypharmacy among older adult patients has become a serious social issue around the world, it is worthwhile pursuing the potential of exercise as a non-pharmacological therapy for stroke. Related Articles | Metrics

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The role of lysosomes in alpha-synucleinopathies: a focus on glial cells Denise Balta, Friederike Zunke 2022, 17 (7):  1486-1488.  doi: 10.4103/1673-5374.330608 Abstract ( 140 )   PDF (479KB) ( 51 )   Save Lysosomes are the major degradative compartments within eukaryotic cells. Besides their role in the degradation and recycling of intra- and extracellular molecules, they further mediate important biological processes, such as immune signaling and perpetuation of nutrient- and energy homeostasis. Impairment of lysosomal function triggers the accumulation of catabolic products within the organelle resulting in lysosomal storage disorders (LSDs). Interestingly, clinical, molecular, and genetic studies further indicate a strong link between lysosomal dysfunction and neurodegenerative disorders, including Parkinson’s disease (PD). Because of the association of lysosomal dysfunction and protein aggregation of α-synuclein (α-Syn) in PD or multiple system atrophy (MSA), the role of lysosomal pathways has been a matter of recent studies, mostly focusing on neuronal cells. Although it is known that glial cells play an important role in disease pathology of PD and MSA, only few studies on the lysosomal pathways, within glial cells have been carried out. Hence, a better understanding of lysosomal function in glia is needed to elucidate disease pathogenesis and to search for novel therapeutic approaches. Related Articles | Metrics

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Targeting the motor cortex to restore walking after incomplete spinal cord injury Marina Martinez 2022, 17 (7):  1489-1490.  doi: 10.4103/1673-5374.330603 Abstract ( 152 )   PDF (727KB) ( 46 )   Save Spinal cord injury (SCI), second only to stroke, is the leading cause of paralysis. The ability to walk is often lost after SCI, reducing independence and quality of life. Restoration of walking is cited as a priority among persons with SCI of all degrees of severity, chronicity, or age at injury. As 70% of SCIs are anatomically incomplete, some neural connections relaying information to and from the brain are spared. Even in severe SCI, clinically deemed motor complete, these residual descending pathways might participate in the recovery of motor function. Specifically, direct and indirect pathways originating from the motor cortex are crucial for planning, controlling, and executing voluntary movements. Studies performed by my team in rats (Brown and Martinez, 2018, 2021; Bonizzato and Martinez, 2021) and by others in humans (Smith et al., 2000; Thomas and Gorassini, 2005; Pulverenti et al., 2021) indicate that recovery of walking following incomplete SCI depends largely on activation, strengthening, and plasticity of these pathways. Directly engaging these spared connections through targeted cortical neurostimulation led to previously unseen acute alleviation of locomotor deficits and long-term improvement of voluntary control of movements in rats (Bonizzato and Martinez, 2021). Related Articles | Metrics

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Impact of alpha-synuclein pathology on adult neurogenesis: evidence for multilayered mechanisms Jana Bonsberger, Franziska Richter, Milos Stanojlovic 2022, 17 (7):  1491-1492.  doi: 10.4103/1673-5374.330601 Abstract ( 150 )   PDF (353KB) ( 48 )   Save Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting 8–10 million people worldwide. Moreover, PD is the fastest-growing neurodegenerative disease and it is predicted that the number of patients will double in the next thirty years. Neuropathologically, PD is characterized by the presence of protein aggregations called Lewy bodies (LB) and by degeneration of dopaminergic neurons in the substantia nigra pars compacta, which give rise to classical motor symptoms. However, overwhelming scientific evidence shows that PD is a multilayered disease. LB pathology affects different brain regions and neuronal populations leading to various non-motor symptoms, such as cognitive, sleep, and sensory impairments, mood and metabolic disorders, etc., some of which, interestingly, appear long before the hallmark motor symptoms. A main component of LB is the protein alpha-synuclein (α-syn). Accumulation and aggregation of α-syn is a characteristic feature that can be observed in synucleinopathies, a group of diseases which PD, dementia with Lewy bodies (DLB), and multiple system atrophy belongs to. While DLB is characterized by progressive dementia, about 80% of PD patients experience some form of cognitive impairment. Therefore, PD and DLB together constitute the second leading cause of neurodegenerative dementias. Moreover, it is proposed that α-syn-associated pathology in cortical and hippocampal (Hipp) brain areas is causing cognitive deficits and dementia in PD and DLB. Alterations in adult neurogenesis may represent a potential pathomechanism. Related Articles | Metrics

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Neurotrophin receptοrs, gamma-secretase inhibitors, and neurodegeneration of basal forebrain cholinergic neurons Marçal Vilar 2022, 17 (7):  1493-1494.  doi: 10.4103/1673-5374.330607 Abstract ( 160 )   PDF (402KB) ( 32 )   Save The amyloid hypothesis of Alzhemer’s disease (AD) postulates that the generation of amyloid-beta (Aβ) peptide from the amyloid precursor protein (APP) by the action of the γ-secretase complex is one of the principal causes of AD. This idea is supported by the identification of several hereditary mutations in the APP gene or in the PSEN1 and PSEN2 genes that encode Presenilin-1 and Presenilin-2, the catalytic component of the γ-secretase complex. The assumption at that time was that familial AD (FAD), mutations lead to a gain of function phenotype, increasing the ratio between the levels of the toxic Aβ1–42, and the less toxic Aβ1–40 peptide (Kuperstein et al., 2010). Actually, the ratio Aβ1–42/Aβ1–40 is the principal cause of the toxic effect as some FAD mutations in APP decrease the levels of Aβ1–40 without changing the total levels of Aβ1–42 (Ancolio et al., 1997). Pharmaceutical companies started the race to design new highly specific γ-secretase inhibitors (GSIs)with good pharmacological properties to jump into the clinic. The reduction of the circulating levels of Aβ1–42 in AD mouse models rapidly supported this approximation, and one of the lead compounds, Semagacestat (Lilly), entered the phase III clinical trials. However, results were not as good as initially expected, and the appearance of several skin cancer problems and a reduction, rather than an improvement, in the cognitive performance of the patients lead the FDA to stop the clinical trials. Meanwhile, it was reported that inhibition of the γ-secretase could lead to skin problems in the mice (Li et al., 2007), and that FAD mutations are actually the loss of function mutations (Chávez-Gutiérrez et al., 2012). The molecular mechanism of γ-secretase activity showed that FAD mutations alter its proteolytic processing leading to an increase in the long toxic peptides Aβ1–42 and a reduction of the shorter Aβ1–37 species (Chávez-Gutiérrez et al., 2012). Nowadays, it is clear that the goal is to increase the processing with the identification of new γ-secretase modulators. Related Articles | Metrics

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Vibrotactile coordinated reset stimulation for the treatment of Parkinson’s disease Peter A. Tass 2022, 17 (7):  1495-1497.  doi: 10.4103/1673-5374.329001 Abstract ( 194 )   PDF (33197KB) ( 83 )   Save Regular deep brain stimulation (rDBS) is the standard therapy for the treatment of medically refractory Parkinson’s disease (PD) (Benabid et al., 2009). Notwithstanding its significant therapeutic effects, rDBS may cause side effects, characterized as rDBS-induced movement disorders (Baizabal-Carvallo and Jankovic, 2016). Abnormal neuronal synchrony is a hallmark of Parkinson’s disease (Hammond et al., 2007). Coordinated reset (CR) stimulation was computationally developed to cause an “unlearning” of pathologically persistent synchrony and synaptic connectivity, thereby inducing long-lasting therapeutic effects (Tass and Majtanik, 2006; Tass, 2017). The CR approach was initially developed for DBS (Tass and Majtanik, 2006; Tass et al., 2012; Adamchic et al., 2014) and thereafter, employing vibratory CR stimuli enabled the development of vibrotactile CR (vCR) fingertip stimulation (Tass, 2017). Two recent clinical feasibility studies with vCR in PD patients demonstrated that delivery of vCR for four hours per day for 3+ months is feasible, has no side effects, and leads to a clinically and statistically significant reduction of Movement Disorders Society-Unified Parkinson’s Disease Rating Scale part III (MDS-UPRDS III) scores (Pfeifer et al., 2012). In one of these feasibility studies, electroencephalography (EEG) recordings demonstrated that cortical sensorimotor high beta power (21–30 Hz) at rest was significantly reduced after three months of daily vCR therapy (Pfeifer et al., 2021). Remarkably, in both studies MDS-UPDRS exams as well as EEG recordings were performed off medication, where PD medication was properly withdrawn for 12–48 hours prior to the patients’ morning MDS-UPDRS exams and EEG recordings, depending on the PD medication’s half-life. These encouraging results enable the development of a proof-of-concept study with vCR for the treatment of PD. In addition, these results highlight the potential for vibrotactile, non-invasive neuromodulation approaches employing dedicated multichannel stimulus patterns for the treatment of PD. Related Articles | Metrics

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Propagation of TDP-43 proteinopathy in neurodegenerative disorders Rachel Keszycki, Pouya Jamshidi, Allegra Kawles, Grace Minogue, Margaret E. Flanagan, Colleen R. Zaccard, M.-Marsel Mesulam, Tamar Gefen, Changiz Geula 2022, 17 (7):  1498-1500.  doi: 10.4103/1673-5374.330609 Abstract ( 135 )   PDF (1032KB) ( 55 )   Save Neurodegenerative disorders are characterized by disruptions to neuronal function and circuitry, leading to a variety of clinical syndromes depending on the affected neuroanatomic regions (Geula, 1998). Many proteinopathies implicated in neurodegenerative diseases are characterized by the pathologic accumulation of proteins into inclusions that are initially deposited in specific areas of the brain and spread widely with disease progression, leading to significant neuronal loss and gliosis (Brettschneider et al., 2013, 2014; Josephs et al., 2016; Jamshidi et al., 2020). There is substantial evidence that amyloid-β, phosphorylated tau, and α-synuclein spread through cell-to-cell propagation of pathological seeds in a prion-like manner, most likely involving trans-synaptic spread of pathology (Brettschneider et al., 2013). In recent years, research has begun to address the mechanism of propagation underlying the transactive response DNA-binding protein 43-kDa (TDP-43) abnormal species of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) (Brettschneider et al., 2013). In a recent study, our laboratory produced evidence suggesting that TDP-43 inclusions spread throughout the hippocampus in a manner that supports transsynaptic propagation along axonal pathways (Jamshidi et al., 2020). Here, we briefly review prior research on the propagation of TDP-43 pathology and suggest putative mechanisms. Related Articles | Metrics

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View on microRNAs as a potential tool to fight blindness: focus on Müller glia and gliosis Stefanie Gabriele Wohl 2022, 17 (7):  1501-1502.  doi: 10.4103/1673-5374.330610 Abstract ( 123 )   PDF (3184KB) ( 48 )   Save The neural retina is a part of the central nervous system. As it lacks regenerative capacity, in an event of injury or disease, neuronal loss leads to visual impairment and often to blindness. Moreover, Müller glia (MG), the predominant glia in the retina, undergo a variety of molecular and cellular changes and discontinue to carry out their important regular functions in the tissue (e.g., maintaining tissue homeostasis and nurturing neurons). They form the glial scar, a barrier that prevents any form of regeneration and represents a big obstacle for regenerative medicine, in particular for transplantation approaches (Bringmann et al., 2006). For decades, researchers have studied the processes of neurodegeneration and gliosis in the retina, which are very similar to the degenerative events in other brain areas. To this end, urgent questions are: What is happening in MG during gliosis and can the glial scar be prevented or reversed, and if so, how. MG have been monitored and described in different injury/disease models including acute and chronic phases. Various cell markers, cell signaling molecules and pathways have been identified. However, in order to understand which factors are regulating the expression of these molecules, transcriptional and translational regulators need also to be included. A molecule group that gains more and more importance, not only in understanding the regulatory network of particular cellular processes, but also in manipulating them, are microRNAs (miRNAs). miRNAs are inhibitors of protein translation. They bind to mRNA molecules and induce either their destabilization or their decay. Since miRNAs regulate cell cycle events as well as cell death, they play a significant role in cell degeneration and predominantly in cancer (64,345 PubMed entries from 2002–2021). In cancer research, miRNAs did not only gain substantial importance as biomarkers for diagnostics, there is also an increasing interest in the pharmaceutical industry of this “young and relatively immature field of utilizing miRNAs as a therapeutic tool”, with first clinical trials on their way (Bonneau et al., 2019). Related Articles | Metrics

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Alpha-synuclein as a biomarker in Parkinson’s disease: focus on neural derived extracelluar vesicles Cristina Agliardi, Franca R. Guerini, Mario Meloni, Mario Clerici 2022, 17 (7):  1503-1504.  doi: 10.4103/1673-5374.330604 Abstract ( 187 )   PDF (1755KB) ( 108 )   Save The prevalence of Parkinson’s disease (PD) is rapidly increasing, and more than 12 million people are expected to suffer from PD by 2040. PD is a highly invalidating neurodegenerative condition that arises from the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. The main cause for such degeneration is the formation of cytoplasmic inclusions known as Lewy bodies, which include both misfolded α-synuclein (α-syn) protein and a multitude of fragmented membranes, organelles, and vesicles (Shahmoradian et al., 2019; Lashuel, 2020). No reliable biomarkers that can predict the onset of PD in its prodromal phase or could assess disease progression are currently available. α-Syn plays a pivotal role in the pathogenesis of PD and is present in peripheral tissues and biofluids; this led to the investigation of α-syn as a possible PD biomarker. Related Articles | Metrics

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Critical role of mitochondrial aldehyde dehydrogenase 2 in acrolein sequestering in rat spinal cord injury Seth A. Herr, Liangqin Shi, Thomas Gianaris, Yucheng Jiao, Siyuan Sun, Nick Race, Scott Shapiro, Riyi Shi 2022, 17 (7):  1505-1511.  doi: 10.4103/1673-5374.330613 Abstract ( 166 )   PDF (2224KB) ( 108 )   Save Lipid peroxidation-derived aldehydes, such as acrolein, the most reactive aldehyde, have emerged as key culprits in sustaining post-spinal cord injury (SCI) secondary pathologies leading to functional loss. Strong evidence suggests that mitochondrial aldehyde dehydrogenase-2 (ALDH2), a key oxidoreductase and powerful endogenous anti-aldehyde machinery, is likely important for protecting neurons from aldehydes-mediated degeneration. Using a rat model of spinal cord contusion injury and recently discovered ALDH2 activator (Alda-1), we planned to validate the aldehyde-clearing and neuroprotective role of ALDH2. Over an acute 2 day period post injury, we found that ALDH2 expression was significantly lowered post-SCI, but not so in rats given Alda-1. This lower enzymatic expression may be linked to heightened acrolein-ALDH2 adduction, which was revealed in co-immunoprecipitation experiments. We have also found that administration of Alda-1 to SCI rats significantly lowered acrolein in the spinal cord, and reduced cyst pathology. In addition, Alda-1 treatment also resulted in significant improvement of motor function and attenuated post-SCI mechanical hypersensitivity up to 28 days post-SCI. Finally, ALDH2 was found to play a critical role in in vitro protection of PC12 cells from acrolein exposure. It is expected that the outcome of this study will broaden and enhance anti-aldehyde strategies in combating post-SCI neurodegeneration and potentially bring treatment to millions of SCI victims. All animal work was approved by Purdue Animal Care and Use Committee (approval No. 1111000095) on January 1, 2021. Related Articles | Metrics

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Hypothermia selectively protects the anterior forebrain mesocircuit during global cerebral ischemia Xiao-Hua Wang, Wei Jiang, Si-Yuan Zhang, Bin-Bin Nie, Yi Zheng, Feng Yan, Jian-Feng Lei, Tian-Long Wang 2022, 17 (7):  1512-1517.  doi: 10.4103/1673-5374.330616 Abstract ( 171 )   PDF (1133KB) ( 57 )   Save Hypothermia is an important protective strategy against global cerebral ischemia following cardiac arrest. However, the mechanisms of hypothermia underlying the changes in different regions and connections of the brain have not been fully elucidated. This study aims to identify the metabolic nodes and connection integrity of specific brain regions in rats with global cerebral ischemia that are most affected by hypothermia treatment. 18F-fluorodeoxyglucose positron emission tomography was used to quantitatively determine glucose metabolism in different brain regions in a rat model of global cerebral ischemia established at 31–33°C. Diffusion tensor imaging was also used to reconstruct and explore the brain connections involved. The results showed that, compared with the model rats established at 37–37.5°C, the rat models of global cerebral ischemia established at 31–33°C had smaller hypometabolic regions in the thalamus and primary sensory areas and sustained no obvious thalamic injury. Hypothermia selectively preserved the integrity of the anterior forebrain mesocircuit, exhibiting protective effects on the brain during the global cerebral ischemia. The study was approved by the Institutional Animal Care and Use Committee at Capital Medical University (approval No. XW-AD318-97-019) on December 15, 2019. Related Articles | Metrics

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Silencing the enhancer of zeste homologue 2, Ezh2, represses axon regeneration of dorsal root ganglion neurons Ting-Ting Guo, Ying Zhao, Wei-Xiao Huang, Tao Zhang, Li-Li Zhao, Xiao-Song Gu, Song-Lin Zhou 2022, 17 (7):  1518-1525.  doi: 10.4103/1673-5374.330623 Abstract ( 309 )   PDF (131963KB) ( 106 )   Save Recovery from injury to the peripheral nervous system is different from that of the central nervous system in that it can lead to gene reprogramming that can induce the expression of a series of regeneration-associated genes. This eventually leads to axonal regeneration of injured neurons. Although some regeneration-related genes have been identified, the regulatory network underlying axon regeneration remains largely unknown. To explore the regulator of axon regeneration, we performed RNA sequencing of lumbar L4 and L5 dorsal root ganglion (DRG) neurons at different time points (0, 3, 6, 12 hours, 1, 3 and 7 days) after rat sciatic nerve crush. The isolation of neurons was carried out by laser capture microscopy combined with NeuN immunofluorescence staining. We found 1228 differentially expressed genes in the injured sciatic nerve tissue. The hub genes within these differentially expressed genes include Atf3, Jun, Myc, Ngf, Fgf2, Ezh2, Gfap and Il6. We verified that the expression of the enhancer of zeste homologue 2 gene (Ezh2) was up-regulated in DRG neurons after injury, and this up-regulation differed between large- and small-sized dorsal root ganglion neurons. To investigate whether the up-regulation of Ezh2 impacts axonal regeneration, we silenced Ezh2 with siRNA in cultured DRG neurons and found that the growth of the newborn axons was repressed. In our investigation into the regulatory network of Ezh2 by interpretive phenomenal analysis, we found some regulators of Ezh2 (including Erk, Il6 and Hif1a) and targets (including Atf3, Cdkn1a and Smad1). Our findings suggest that Ezh2, as a nerve regeneration-related gene, participates in the repair of the injured DRG neurons, and knocking down the Ezh2 in vitro inhibits the axonal growth of DRG neurons. All the experimental procedures approved by the Administration Committee of Experimental Animals of Jiangsu Province of China (approval No. S20191201-201) on March 21, 2019. Related Articles | Metrics

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Unexpected BrdU inhibition on astrocyte-to-neuron conversion Tao Wang, Jian-Cheng Liao, Xu Wang, Qing-Song Wang, Kai-Ying Wan, Yi-Yi Yang, Qing He, Jia-Xuan Zhang, Gong Chen, Wen Li 2022, 17 (7):  1526-1534.  doi: 10.4103/1673-5374.325747 Abstract ( 242 )   PDF (8727KB) ( 74 )   Save 5-Bromo-2′-deoxyuridine (BrdU) is a halogenated pyrimidine that can be incorporated into newly synthesized DNA during the S phase of the cell cycle. BrdU is widely used in fate-mapping studies of embryonic and adult neurogenesis to identify newborn neurons, however side effects on neural stem cells and their progeny have been reported. In vivo astrocyte-to-neuron (AtN) conversion is a new approach for generating newborn neurons by directly converting endogenous astrocytes into neurons. The BrdU-labeling strategy has been used to trace astrocyte-converted neurons, but whether BrdU has any effect on the AtN conversion is unknown. Here, while conducting a NeuroD1-mediated AtN conversion study using BrdU to label dividing reactive astrocytes following ischemic injury, we accidentally discovered that BrdU inhibited AtN conversion. We initially found a gradual reduction in BrdU-labeled astrocytes during NeuroD1-mediated AtN conversion in the mouse cortex. Although most NeuroD1-infected astrocytes were converted into neurons, the number of BrdU-labeled neurons was surprisingly low. To exclude the possibility that this BrdU inhibition was caused by the ischemic injury, we conducted an in vitro AtN conversion study by overexpressing NeuroD1 in cultured cortical astrocytes in the presence or absence of BrdU. Surprisingly, we also found a significantly lower conversion rate and a smaller number of converted neurons in the BrdU-treated group compared with the untreated group. These results revealed an unexpected inhibitory effect of BrdU on AtN conversion, suggesting more caution is needed when using BrdU in AtN conversion studies and in data interpretation. Related Articles | Metrics

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Optogenetics stimulates nerve reorganization in the contralesional anterolateral primary motor cortex in a mouse model of ischemic stroke Bei-Yao Gao, Yi-Xing Cao, Peng-Fei Fu, Ying Xing, Dan Liang, Shan Jiang, Yu-Xiao Xie, Min Li 2022, 17 (7):  1535-1544.  doi: 10.4103/1673-5374.330615 Abstract ( 186 )   PDF (20514KB) ( 42 )   Save The anterolateral motor cortex of rodents is an important motor auxiliary area, and its function is similar to that of the premotor area in humans. Activation and inhibition of the contralesional anterolateral motor cortex (cALM) have been shown to have direct effects on motor behavior. However, the significance of cALM activation and inhibition in the treatment of stroke remains unclear. This study investigated the role of optogenetic cALM stimulation in a mouse model of cerebral stroke. The results showed that 21-day optogenetic cALM inhibition, but not activation, improved neurological function. In addition, optogenetic cALM stimulation substantially altered dendritic structural reorganization and dendritic spine plasticity, as optogenetic cALM inhibition resulted in increased dendritic length, number of dendritic spines, and number of perforated synapses, whereas optogenetic activation led to an increase in the number of multiple synapse boutons and the number of dendritic intersections. Furthermore, RNA-seq analysis showed that multiple biological processes regulated by the cALM were upregulated immediately after optogenetic cALM inhibition, and that several immediate-early genes (including cFOS, Erg1, and Sema3f) were expressed at higher levels after optogenetic inhibition than after optogenetic activation. These results were confirmed by quantitative reverse transcription-polymerase chain reaction. Finally, immunofluorescence analysis showed that the c-FOS signal in layer V of the primary motor cortex in the ischemic hemisphere was higher after optogenetic cALM activation than it was after optogenetic cALM inhibition. Taken together, these findings suggest that optogenetic cALM stimulation promotes neural reorganization in the primary motor cortex of the ischemic hemisphere, and that optogenetic cALM inhibition and activation have different effects on neural plasticity. The study was approved by the Experimental Animal Ethics Committee of Fudan University (approval No. 201802173S) on March 3, 2018. Related Articles | Metrics

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Electroacupuncture treatment improves motor function and neurological outcomes after cerebral ischemia/reperfusion injury Si-Si Li, Xu-Yun Hua, Mou-Xiong Zheng, Jia-Jia Wu, Zhen-Zhen Ma, Xiang-Xin Xing, Jie Ma, Chun-Lei Shan, Jian-Guang Xu 2022, 17 (7):  1545-1555.  doi: 10.4103/1673-5374.330617 Abstract ( 371 )   PDF (80237KB) ( 61 )   Save Electroacupuncture (EA) has been widely used for functional restoration after stroke. However, its role in post-stroke rehabilitation and the associated regulatory mechanisms remain poorly understood. In this study, we applied EA to the Zusanli (ST36) and Quchi (LI11) acupoints in rats with middle cerebral artery occlusion and reperfusion. We found that EA effectively increased the expression of brain-derived neurotrophic factor and its receptor tyrosine kinase B, synapsin-1, postsynaptic dense protein 95, and microtubule-associated protein 2 in the ischemic penumbra of rats with middle cerebral artery occlusion and reperfusion. Moreover, EA greatly reduced the expression of myelin-related inhibitors Nogo-A and NgR in the ischemic penumbra. Tyrosine kinase B inhibitor ANA-12 weakened the therapeutic effects of EA. These findings suggest that EA can improve neurological function after middle cerebral artery occlusion and reperfusion, possibly through regulating the activity of the brain-derived neurotrophic factor/tyrosine kinase B signal pathway. All procedures and experiments were approved by the Animal Research Committee of Shanghai University of Traditional Chinese Medicine, China (approval No. PZSHUTCM200110002) on January 10, 2020. Related Articles | Metrics

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Effects of electroacupuncture on the functionality of NG2-expressing cells in perilesional brain tissue of mice following ischemic stroke Hong Ju Lee, Da Hee Jung, Nam Kwen Kim, Hwa Kyoung Shin, Byung Tae Choi 2022, 17 (7):  1556-1565.  doi: 10.4103/1673-5374.330611 Abstract ( 204 )   PDF (5235KB) ( 541 )   Save Neural/glial antigen 2 (NG2)-expressing cells has multipotent stem cell activity under cerebral ischemia. Our study examined the effects of electroacupuncture (EA) therapy (2 Hz, 1 or 3 mA, 20 minutes) at the Sishencong acupoint on motor function after ischemic insult in the brain by investigating the rehabilitative potential of NG2-derived cells in a mouse model of ischemic stroke. EA stimulation alleviated motor deficits caused by ischemic stroke, and 1 mA EA stimulation was more efficacious than 3 mA EA stimulation or positive control treatment with edaravone, a free radical scavenger. The properties of NG2-expressing cells were altered with 1 mA EA stimulation, enhancing their survival in perilesional brain tissue via reduction of tumor necrosis factor alpha expression. EA stimulation robustly activated signaling pathways related to proliferation and survival of NG2-expressing cells and increased the expression of neurotrophic factors such as brain-derived neurotrophic factor, tumor growth factor beta, and neurotrophin 3. In the perilesional striatum, EA stimulation greatly increased the number of NG2-expressing cells double-positive for oligodendrocyte, endothelial cell, and microglia/macrophage markers (CC1, CD31, and CD68). EA therapy also greatly activated brain-derived neurotrophic factor/tropomyosin receptor kinase B and glycogen synthase kinase 3 beta signaling. Our results indicate that EA therapy may prevent functional loss at the perilesional site by enhancing survival and differentiation of NG2-expressing cells via the activation of brain-derived neurotrophic factor -induced signaling, subsequently ameliorating motor dysfunction. The animal experiments were approved by the Animal Ethics Committee of Pusan National University (approval Nos. PNU2019-2199 and PNU2019-2884) on April 8, 2019 and June 19, 2019. Related Articles | Metrics

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Exacerbated VEGF up-regulation accompanies diabetes-aggravated hemorrhage in mice after experimental cerebral ischemia and delayed reperfusion Angela Ka Wai Lai, Tsz Chung Ng, Victor Ka Lok Hung, Ka Cheung Tam, Chi Wai Cheung, Sookja Kim Chung, Amy Cheuk Yin Lo 2022, 17 (7):  1566-1575.  doi: 10.4103/1673-5374.330612 Abstract ( 192 )   PDF (2771KB) ( 61 )   Save Reperfusion therapy is the preferred treatment for ischemic stroke, but is hindered by its short treatment window, especially in patients with diabetes whose reperfusion after prolonged ischemia is often accompanied by exacerbated hemorrhage. The mechanisms underlying exacerbated hemorrhage are not fully understood. This study aimed to identify this mechanism by inducing prolonged 2-hour transient intraluminal middle cerebral artery occlusion in diabetic Ins2Akita/+ mice to mimic patients with diabetes undergoing delayed mechanical thrombectomy. The results showed that at as early as 2 hours after reperfusion, Ins2Akita/+ mice exhibited rapid development of neurological deficits, increased infarct and hemorrhagic transformation, together with exacerbated down-regulation of tight-junction protein ZO-1 and up-regulation of blood-brain barrier-disrupting matrix metallopeptidase 2 and matrix metallopeptidase 9 when compared with normoglycemic Ins2+/+ mice. This indicated that diabetes led to the rapid compromise of vessel integrity immediately after reperfusion, and consequently earlier death and further aggravation of hemorrhagic transformation 22 hours after reperfusion. This observation was associated with earlier and stronger up-regulation of pro-angiogenic vascular endothelial growth factor (VEGF) and its downstream phospho-Erk1/2 at 2 hours after reperfusion, which was suggestive of premature angiogenesis induced by early VEGF up-regulation, resulting in rapid vessel disintegration in diabetic stroke. Endoplasmic reticulum stress-related pro-apoptotic C/EBP homologous protein was overexpressed in challenged Ins2Akita/+ mice, which suggests that the exacerbated VEGF up-regulation may be caused by overwhelming endoplasmic reticulum stress under diabetic conditions. In conclusion, the results mimicked complications in patients with diabetes undergoing delayed mechanical thrombectomy, and diabetes-induced accelerated VEGF up-regulation is likely to underlie exacerbated hemorrhagic transformation. Thus, suppression of the VEGF pathway could be a potential approach to allow reperfusion therapy in patients with diabetic stroke beyond the current treatment window. Experiments were approved by the Committee on the Use of Live Animals in Teaching and Research of the University of Hong Kong [CULATR 3834-15 (approval date January 5, 2016); 3977-16 (approval date April 13, 2016); and 4666-18 (approval date March 29, 2018)]. Related Articles | Metrics

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Survivors of COVID-19 exhibit altered amplitudes of low frequency fluctuation in the brain: a resting-state functional magnetic resonance imaging study at 1-year follow-up Yan-Yao Du, Wei Zhao, Xiang-Lin Zhou, Mu Zeng, Dan-Hui Yang, Xing-Zhi Xie, Si-Hong Huang, Ying-Jia Jiang, Wen-Han Yang, Hu Guo, Hui Sun, Ji-Yang Liu, Ping Liu, Zhi-Guo Zhou, Hong Luo, Jun Liu 2022, 17 (7):  1576-1581.  doi: 10.4103/1673-5374.327361 Abstract ( 322 )   PDF (821KB) ( 123 )   Save Although some short-term follow-up studies have found that individuals recovering from coronavirus disease 2019 (COVID-19) exhibit anxiety, depression, and altered brain microstructure, their long-term physical problems, neuropsychiatric sequelae, and changes in brain function remain unknown. This observational cohort study collected 1-year follow-up data from 22 patients who had been hospitalized with COVID-19 (8 males and 11 females, aged 54.2 ± 8.7 years). Fatigue and myalgia were persistent symptoms at the 1-year follow-up. The resting state functional magnetic resonance imaging revealed that compared with 29 healthy controls (7 males and 18 females, aged 50.5 ± 11.6 years), COVID-19 survivors had greatly increased amplitude of low-frequency fluctuation (ALFF) values in the left precentral gyrus, middle frontal gyrus, inferior frontal gyrus of operculum, inferior frontal gyrus of triangle, insula, hippocampus, parahippocampal gyrus, fusiform gyrus, postcentral gyrus, inferior parietal angular gyrus, supramarginal gyrus, angular gyrus, thalamus, middle temporal gyrus, inferior temporal gyrus, caudate, and putamen. ALFF values in the left caudate of the COVID-19 survivors were positively correlated with their Athens Insomnia Scale scores, and those in the left precentral gyrus were positively correlated with neutrophil count during hospitalization. The long-term follow-up results suggest that the ALFF in brain regions related to mood and sleep regulation were altered in COVID-19 survivors. This can help us understand the neurobiological mechanisms of COVID-19-related neuropsychiatric sequelae. This study was approved by the Ethics Committee of the Second Xiangya Hospital of Central South University (approval No. 2020S004) on March 19, 2020. Related Articles | Metrics

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Efficacy of Lycium barbarum polysaccharide in adolescents with subthreshold depression: interim analysis of a randomized controlled study Xiaoyue Li, Xuan Mo, Tao Liu, Robin Shao, Kayla Teopiz, Roger S. McIntyre, Kwok-Fai So, Kangguang Lin 2022, 17 (7):  1582-1587.  doi: 10.4103/1673-5374.330618 Abstract ( 294 )   PDF (588KB) ( 166 )   Save Subthreshold depression is a highly prevalent condition in adolescents who are at high risk for developing major depressive disorder. In preclinical models of neurological and psychiatric diseases, Lycium barbarum polysaccharide (LBP) extracted from Goji berries had anti-depressant effects including but not limited to anti-oxidative and anti-inflammatory properties. However, the effect of LBP on subthreshold depression is unclear. To investigate the clinical efficacy and safety of LBP for treating subthreshold depression in adolescents, we conducted a randomized, double-blind, placebo-controlled trial (RCT) with 29 adolescents with subthreshold depression recruited at The Fifth Affiliated Hospital of Guangzhou Medical University. The participants were randomly assigned to groups where they received either 300 mg LBP (LBP group, n = 15, 3 boys and 12 girls aged 15.13 ± 2.17 years) or a placebo (placebo group, n = 14, 2 boys and 12 girls aged 15 ± 1.71 years) for 6 successive weeks. Interim analyses revealed that the LBP group exhibited a greater change in Hamilton Depression Scale (HAMD-24) scores relative to the baseline and a higher remission rate (HAMD-24 total score ≤ 7) at 6 weeks compared with the placebo group. Scores on the Beck Depression Inventory-II (BDI-II), Pittsburgh Sleep Quality Index (PSQI), Kessler Psychological Distress Scale (Kessler), and Screen for Child Anxiety-Related Emotional Disorders (SCARED) were similar between the LBP and placebo groups. No side effects related to the intervention were reported in either group. These results indicate that LBP administration reduced depressive symptoms in adolescents with subthreshold depression. Furthermore, LBP was well tolerated with no treatment-limiting adverse events. Clinical trials involving a larger sample size are needed to further confirm the anti-depressive effects of LBP in adolescents with subthreshold depression. This study was approved by the Medical Ethics Committee of the Fifth Affiliated Hospital of Guangzhou Medical University (Guangzhou, China; approval No. L2019-08) on April 4, 2019 and was registered on ClinicalTrials.gov (identifier: NCT04032795) on July 25, 2019. Related Articles | Metrics

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Robust temporal changes of cellular senescence and proliferation after sciatic nerve injury Yin-Ying Shen, Rui-Rui Zhang, Qian-Yan Liu, Shi-Ying Li, Sheng Yi 2022, 17 (7):  1588-1595.  doi: 10.4103/1673-5374.330619 Abstract ( 188 )   PDF (28115KB) ( 100 )   Save Cellular senescence and proliferation are essential for wound healing and tissue remodeling. However, senescence-proliferation cell fate after peripheral nerve injury has not been clearly revealed. Here, post-injury gene expression patterns in rat sciatic nerve stumps (SRP113121) and L4–5 dorsal root ganglia (SRP200823) obtained from the National Center for Biotechnology Information were analyzed to decipher cellular senescence and proliferation-associated genetic changes. We first constructed a rat sciatic nerve crush model. Then, β-galactosidase activities were determined to indicate the existence of cellular senescence in the injured sciatic nerve. Ki67 and EdU immunostaining was performed to indicate cellular proliferation in the injured sciatic nerve. Both cellular senescence and proliferation were less vigorous in the dorsal root ganglia than in sciatic nerve stumps. These results reveal the dynamic changes of injury-induced cellular senescence and proliferation from both genetic and morphological aspects, and thus extend our understanding of the biological processes following peripheral nerve injury. The study was approved by the Animal Ethics Committee of Nantong University, China (approval No. 20190226-001) on February 26, 2019. Related Articles | Metrics

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Lutein delays photoreceptor degeneration in a mouse model of retinitis pigmentosa Hui-Jun Zhang, Xiao-Bin Liu, Xiong-Min Chen, Qi-Hang Kong, Yu-Sang Liu, Kwok-Fai So, Jian-Su Chen, Ying Xu, Xue-Song Mi, Shi-Bo Tang 2022, 17 (7):  1596-1603.  doi: 10.4103/1673-5374.330622 Abstract ( 345 )   PDF (4035KB) ( 152 )   Save Retinitis pigmentosa is a retinal disease characterized by photoreceptor degeneration. There is currently no effective treatment for retinitis pigmentosa. Although a mixture of lutein and other antioxidant agents has shown promising effects in protecting the retina from degeneration, the role of lutein alone remains unclear. In this study, we administered intragastric lutein to Pde6brd10 model mice, which display degeneration of retinal photoreceptors, on postnatal days 17 (P17) to P25, when rod apoptosis reaches peak. Lutein at the optimal protective dose of 200 mg/kg promoted the survival of photoreceptors compared with vehicle control. Lutein increased rhodopsin expression in rod cells and opsin expression in cone cells, in line with an increased survival rate of photoreceptors. Functionally, lutein improved visual behavior, visual acuity, and retinal electroretinogram responses in Pde6brd10 mice. Mechanistically, lutein reduced the expression of glial fibrillary acidic protein in Müller glial cells. The results of this study confirm the ability of lutein to postpone photoreceptor degeneration by reducing reactive gliosis of Müller cells in the retina and exerting anti-inflammatory effects. This study was approved by the Laboratory Animal Ethics Committee of Jinan University (approval No. LACUC-20181217-02) on December 17, 2018. Related Articles | Metrics

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Osteopontin is a biomarker for early autoimmune uveoretinitis Jeongtae Kim, Meejung Ahn, Yuna Choi, Jiyoon Chun, Kyungsook Jung, Akane Tanaka, Hiroshi Matsuda, Taekyun Shin 2022, 17 (7):  1604-1608.  doi: 10.4103/1673-5374.330614 Abstract ( 139 )   PDF (1817KB) ( 63 )   Save Osteopontin (OPN) is an extracellular matrix protein with a diverse range of functions, including roles in cell adhesion, migration, and immunomodulation, which are associated with the modulation of neuroinflammation in the central nervous system. The present study was performed to evaluate the involvement of OPN in the eyes of an experimental autoimmune uveoretinitis (EAU) model. The EAU model was developed by immunization of Lewis rats with interphotoreceptor retinoid-binding protein. The results showed the OPN level was remarkably upregulated in the eye of EAU rats on day 9 post-immunization. The level of CD44, a ligand of OPN, was increased in the ciliary body of EAU rats. Furthermore, OPN was also detected in the ciliary body and activated microglia/macrophages in the EAU retina. The results suggest that OPN was significantly upregulated in the eyes of EAU rats, and that it may be useful as an early biomarker of ocular autoimmune diseases. All animal experiments were approved by the Institutional Animal Care and Use Committee of Jeju National University (approval No. 2020-0012) on March 11, 2020. Related Articles | Metrics

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Phosphoinositide-3-kinase regulatory subunit 4 participates in the occurrence and development of amyotrophic lateral sclerosis by regulating autophagy Yue Liu, Cai-Hui Wei, Cheng Li, Wen-Zhi Chen, Yu Zhu, Ren-Shi Xu 2022, 17 (7):  1609-1616.  doi: 10.4103/1673-5374.330621 Abstract ( 112 )   PDF (2614KB) ( 112 )   Save The development of amyotrophic lateral sclerosis (ALS) may be related to the abnormal alterations of multiple proteins. Our previous study revealed that the expression of phosphoinositide-3-kinase regulatory subunit 4 (PIK3R4) was decreased in ALS. However, the role of PIK3R4 in ALS pathogenesis remains unknown. This study was the first to find that transfection of PC12 cells with small interfering RNA against the PIK3R4 gene significantly decreased the expression levels of PIK3R4 and the autophagy-related proteins p62 and LC3. Additionally, in vivo experiments revealed that the PIK3R4 protein was extensively expressed in the anterior horn, posterior horn, central canal, and areas surrounding the central canal in cervical, thoracic, and lumbar segments of the spinal cord in adult mice. PIK3R4 protein was mainly expressed in the neurons within the spinal lumbar segments. PIK3R4 and p62 expression levels were significantly decreased at both the pre-onset and onset stages of ALS disease in Tg(SOD1*G93A)1Gur mice compared with control mice, but these proteins were markedly increased at the progression stage. LC3 protein expression did not change during progression of ALS. These findings suggest that PIK3R4 likely participates in the prevention of ALS progression. This study was approved by the Ethics Committee for Animal Care and Use of Jiangxi Provincial People’s Hospital, Affiliated People’s Hospital of Nanchang University (approval No. 2020025) on March 26, 2020. Related Articles | Metrics

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MicroRNA is a potential target for therapies to improve the physiological function of skeletal muscle after trauma Xin-Yi Gu, Bo Jin, Zhi-Dan Qi, Xiao-Feng Yin 2022, 17 (7):  1617-1622.  doi: 10.4103/1673-5374.330620 Abstract ( 131 )   PDF (1640KB) ( 58 )   Save MicroRNAs can regulate the function of ion channels in many organs. Based on our previous study we propose that miR-142a-39, which is highly expressed in denervated skeletal muscle, might affect cell excitability through similar mechanisms. In this study, we overexpressed or knocked down miR-142a-3p in C2C12 cells using a lentivirus method. After 7 days of differentiation culture, whole-cell currents were recorded. The results showed that overexpression of miR-142a-3p reduced the cell membrane capacitance, increased potassium current density and decreased calcium current density. Knockdown of miR-142a-3p reduced sodium ion channel current density. The results showed that change in miR-142a-3p expression affected the ion channel currents in C2C12 cells, suggesting its possible roles in muscle cell electrophysiology. This study was approved by the Animal Ethics Committee of Peking University in July 2020 (approval No. LA2017128). Related Articles | Metrics

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Loss of smell in COVID-19: reasons for variable recovery patterns from anosmia Abdul Mannan Baig 2022, 17 (7):  1623-1624.  doi: 10.4103/1673-5374.330625 Abstract ( 279 )   PDF (692KB) ( 72 )   Save Anosmia, which coupled with altered or loss of taste, during the current pandemic in individuals has heralded the onset of coronavirus disease 2019 (COVID-19). The recovery from the anosmia has been seen to vary among individuals, which in some cases has been seen to take a protracted course, the causes of which is unknown. Direct damages to olfactory ensheathing cells (OECs) and extensive inflammation of the olfactory mucosa (OM) has been implicated as the cause of anosmia in patients with long-COVID. Here I debate the possible mechanisms underlying the variable recovery from anosmia in COVID-19 and reasons why it continues in some patients with long-COVID? Related Articles | Metrics