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15 January 2021, Volume 16 Issue 1 Previous Issue    Next Issue

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Oxidative stress battles neuronal Bcl-xL in a fight to the death Han-A Park, , Katheryn Broman, Elizabeth A. Jonas 2021, 16 (1):  12-15.  doi: 10.4103/1673-5374.286946 Abstract ( 129 )   PDF (431KB) ( 145 )   Save Bcl-xL is a pro-survival protein of the Bcl2 family found in the mitochondrial membrane. Bcl-xL supports growth, development, and maturation of neurons, and it also prevents neuronal death during neurotoxic stimulation. This article reviews the mechanisms and upstream signaling that regulate the activity and abundance of Bcl-xL. Our team and others have reported that oxidative stress is a key regulator of intracellular Bcl-xL balance in neurons. Oxidative stress regulates synthesis, degradation, and activity of Bcl-xL and therefore neuronal function. During apoptosis, pro-apoptotic Bcl2 proteins such as Bax and Bak translocate to and oligomerize in the mitochondrial membrane. Formation of oligomers causes release of cytochrome c and activation of caspases that lead to neuronal death. Bcl-xL binds directly to pro-apoptotic Bcl2 proteins to block apoptotic signaling. Although anti-apoptotic roles of Bcl-xL have been well documented, an increasing number of studies in recent decades show that protein binding partners of Bcl-xL are not limited to Bcl2 proteins. Bcl-xL forms a complex with F1Fo ATP synthase, DJ-1, DRP1, IP3R, and the ryanodine receptor. These proteins support physiological processes in neurons such as growth and development and prevent neuronal damage by regulating mitochondrial ATP production, synapse formation, synaptic vesicle recycling, neurotransmission, and calcium signaling. However, under conditions of oxidative stress, Bcl-xL undergoes proteolytic cleavage thus lowering the abundance of functional Bcl-xL in neurons. Additionally, oxidative stress alters formation of Bcl-xL-mediated multiprotein complexes by regulating post-translational phosphorylation. Finally, oxidative stress regulates transcription factors that target the Bcl-x gene and alter accessibility of microRNA to mRNA influencing mRNA levels of Bcl-xL. In this review, we discussed how Bcl-xL supports the normal physiology of neurons, and how oxidative stress contributes to pathology by manipulating the dynamics of Bcl-xL production, degradation, and activity.  Related Articles | Metrics

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Microglia-associated neuroinflammation is a potential therapeutic target for ischemic stroke Wan Zhang, Tian Tian, Shao-Xin Gong, Wen-Qian Huang, Qin-Yi Zhou, Ai-Ping Wang, Ying Tian 2021, 16 (1):  6-11.  doi: 10.4103/1673-5374.286954 Abstract ( 231 )   PDF (700KB) ( 234 )   Save Microglia-associated neuroinflammation plays an important role in the pathophysiology of ischemic stroke. Microglial activation and polarization, and the inflammatory response mediated by these cells play important roles in the development, progression and outcome of brain injury after ischemic stroke. Currently, there is no effective strategy for treating ischemic stroke in clinical practice. Therefore, it is clinically important to study the role and regulation of microglia in stroke. In this review, we discuss the involvement of microglia in the neuroinflammatory process in ischemic stroke, with the aim of providing a better understanding of the relationship between ischemic stroke and microglia. Related Articles | Metrics

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Development and postnatal neurogenesis in the retina: a comparison between altricial and precocial bird species Guadalupe Álvarez-Hernán, José Antonio de Mera-Rodríguez, Yolanda Gañán, Jorge Solana-Fajardo, Gervasio Martín-Partido, Joaquín Rodríguez-León, Javier Francisco-Morcillo 2021, 16 (1):  16-20.  doi: 10.4103/1673-5374.286947 Abstract ( 110 )   PDF (2916KB) ( 374 )   Save The visual system is affected by neurodegenerative diseases caused by the degeneration of specific retinal neurons, the leading cause of irreversible blindness in humans. Throughout vertebrate phylogeny, the retina has two kinds of specialized niches of constitutive neurogenesis: the retinal progenitors located in the circumferential marginal zone and Müller glia. The proliferative activity in the retinal progenitors located in the circumferential marginal zone in precocial birds such as the chicken, the commonest bird model used in developmental and regenerative studies, is very low. This region adds only a few retinal cells to the peripheral edge of the retina during several months after hatching, but does not seem to be involved in retinal regeneration. Müller cells in the chicken retina are not proliferative under physiological conditions, but after acute damage some of them undergo a reprogramming event, dedifferentiating into retinal stem cells and generating new retinal neurons. Therefore, regenerative response after injury occurs with low efficiency in the precocial avian retina. In contrast, it has recently been shown that neurogenesis is intense in the retina of altricial birds at hatching. In particular, abundant proliferative activity is detected both in the circumferential marginal zone and in the outer half of the inner nuclear layer. Therefore, stem cell niches are very active in the retina of altricial birds. Although more extensive research is needed to assess the potential of proliferating cells in the adult retina of altricial birds, it emerges as an attractive model for studying different aspects of neurogenesis and neural regeneration in vertebrates. Related Articles | Metrics

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The role of peptidase neurolysin in neuroprotection and neural repair after stroke Vardan T. Karamyan 2021, 16 (1):  21-25.  doi: 10.4103/1673-5374.284904 Abstract ( 122 )   PDF (486KB) ( 166 )   Save Current experimental stroke research has evolved to focus on detailed understanding of the brain’s self-protective and restorative mechanisms, and harness this knowledge for development of new therapies. In this context, the role of peptidases and neuropeptides is of growing interest. In this focused review, peptidase neurolysin (Nln) and its extracellular peptide substrates are briefly discussed in relation to pathophysiology of ischemic stroke. Upregulation of Nln following stroke is viewed as a compensatory cerebroprotective mechanism in the acute phase of stroke, because the main neuropeptides inactivated by Nln are neuro/cerebrotoxic (bradykinin, substance P, neurotensin, angiotensin II, hemopressin), whereas the peptides generated by Nln are neuro/cerebroprotective (angiotensin-(1–7), Leu-/Met-enkephalins). This notion is confirmed by experimental studies documenting aggravation of stroke outcomes in mice after inhibition of Nln following stroke, and dramatic improvement of stroke outcomes in mice overexpressing Nln in the brain. The role of Nln in the (sub)chronic phase of stroke is less clear and it is likely, that this peptidase does not have a major role in neural repair mechanisms. This is because, the substrates of Nln are less uniform in modulating neurorestorative mechanisms in one direction, some appearing to have neural repair enhancing/stimulating potential, whereas others doing the opposite. Future studies focusing on the role of Nln in pathophysiology of stroke should determine its potential as a cerebroprotective target for stroke therapy, because its unique ability to modulate multiple neuropeptide systems critically involved in brain injury mechanisms is likely advantageous over modulation of one pathogenic pathway for stroke pharmacotherapy.  Related Articles | Metrics

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Cathepsins in neuronal plasticity Amanda Phuong Tran, Jerry Silver 2021, 16 (1):  26-35.  doi: 10.4103/1673-5374.286948 Abstract ( 92 )   PDF (1481KB) ( 220 )   Save Proteases comprise a variety of enzymes defined by their ability to catalytically hydrolyze the peptide bonds of other proteins, resulting in protein lysis. Cathepsins, specifically, encompass a class of at least twenty proteases with potent endopeptidase activity. They are located subcellularly in lysosomes, organelles responsible for the cell’s degradative and autophagic processes, and are vital for normal lysosomal function. Although cathepsins are involved in a multitude of cell signaling activities, this chapter will focus on the role of cathepsins (with a special emphasis on Cathepsin B) in neuronal plasticity. We will broadly define what is known about regulation of cathepsins in the central nervous system and compare this with their dysregulation after injury or disease. Importantly, we will delineate what is currently known about the role of cathepsins in axon regeneration and plasticity after spinal cord injury. It is well established that normal cathepsin activity is integral to the function of lysosomes. Without normal lysosomal function, autophagy and other homeostatic cellular processes become dysregulated resulting in axon dystrophy. Furthermore, controlled activation of cathepsins at specialized neuronal structures such as axonal growth cones and dendritic spines have been positively implicated in their plasticity. This chapter will end with a perspective on the consequences of cathepsin dysregulation versus controlled, localized regulation to clarify how cathepsins can contribute to both neuronal plasticity and neurodegeneration. Related Articles | Metrics

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Cognitive impairment in multiple sclerosis: lessons from cerebrospinal fluid biomarkers Lorenzo Gaetani, Nicola Salvadori, Elena Chipi, Lucia Gentili, Angela Borrelli, Lucilla Parnetti, Massimiliano Di Filippo 2021, 16 (1):  36-42.  doi: 10.4103/1673-5374.286949 Abstract ( 98 )   PDF (606KB) ( 174 )   Save Cognitive impairment is a common clinical manifestation of multiple sclerosis, but its pathophysiology is not completely understood. White and grey matter injury together with synaptic dysfunction do play a role. The measurement of biomarkers in the cerebrospinal fluid and the study of their association with cognitive impairment may provide interesting in vivo evidence of the biological mechanisms underlying multiple sclerosis-related cognitive impairment. So far, only a few studies on this topic have been published, giving interesting results that deserve further investigation. Cerebrospinal fluid biomarkers of different pathophysiological mechanisms seem to reflect different neuropsychological patterns of cognitive deficits in multiple sclerosis. The aim of this review is to discuss the studies that have correlated cerebrospinal fluid markers of immune, glial and neuronal pathology with cognitive impairment in multiple sclerosis. Although preliminary, these findings suggest that cerebrospinal fluid biomarkers show some correlation with cognitive performance in multiple sclerosis, thus providing interesting insights into the mechanisms underlying the involvement of specific cognitive domains.  Related Articles | Metrics

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Progenies of NG2 glia: what do we learn from transgenic mouse models ? Qilin Guo, Anja Scheller, Wenhui Huang 2021, 16 (1):  43-48.  doi: 10.4103/1673-5374.286950 Abstract ( 110 )   PDF (1652KB) ( 156 )   Save In the mammalian central nervous system, nerve-glia antigen 2 (NG2) glia are considered the fourth glial population in addition to astrocytes, oligodendrocytes and microglia. The fate of NG2 glia in vivo has been carefully studied in several transgenic mouse models using the Cre/loxP strategy. There is a clear agreement that NG2 glia mainly serve as progenitors for oligodendrocytes and a subpopulation of astrocytes mainly in the ventral forebrain, whereas the existence of a neurogenic potential of NG2 glia is lack of adequate evidence. This mini review summarizes the findings from recent studies regarding the fate of NG2 glia during development. We will highlight the age-and-region-dependent heterogeneity of the NG2 glia differentiation potential. We will also discuss putative reasons for inconsistent findings in various transgenic mouse lines of previous studies.  Related Articles | Metrics

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The NLRP3 inflammasome: a potential therapeutic target for traumatic brain injury Saifudeen Ismael, Heba A. Ahmed, Tusita Adris, Kehkashan Parveen, Parth Thakor, Tauheed Ishrat 2021, 16 (1):  49-57.  doi: 10.4103/1673-5374.286951 Abstract ( 105 )   PDF (664KB) ( 231 )   Save Although the precise mechanisms contributing to secondary brain injury following traumatic brain injury are complex and obscure, a number of studies have demonstrated that inflammatory responses are an obvious and early feature in the pathogenesis of traumatic brain injury. Inflammasomes are multiprotein complexes that prompt the stimulation of caspase-1 and subsequently induce the maturation and secretion of proinflammatory cytokines, such as interleukin-1β and interleukin-18. These cytokines play a pivotal role in facilitating innate immune responses and inflammation. Among various inflammasome complexes, the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is the best characterized, a crucial role for NLRP3 has been demonstrated in various brain diseases, including traumatic brain injury. Several recent studies have revealed the contribution of NLRP3 inflammasome in identifying cellular damage and stimulating inflammatory responses to aseptic tissue injury after traumatic brain injury. Even more important, blocking or inhibiting the activation of the NLRP3 inflammasome may have substantial potential to salvage tissue damage during traumatic brain injury. In this review, we summarize recently described mechanisms that are involved in the activation and regulation of the NLRP3 inflammasome. Moreover, we review the recent investigations on the contribution of the NLRP3 inflammasome in the pathophysiology of TBI, and current advances and challenges in potential NLRP3-targeted therapies. A significant contribution of NLRP3 inflammasome activation to traumatic brain injury implies that therapeutic approaches focused on targeting specific inflammasome components could significantly improve the traumatic brain injury outcomes. Related Articles | Metrics

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Mechanisms of neuroplasticity and brain degeneration: strategies for protection during the aging process Mariana Toricelli, Arthur Antonio Ruiz Pereira, Guilherme Souza Abrao, Helena Nascimento Malerba, Julia Maia, Hudson Sousa Buck, Tania Araujo Viel 2021, 16 (1):  58-67.  doi: 10.4103/1673-5374.286952 Abstract ( 157 )   PDF (781KB) ( 252 )   Save Aging is a dynamic and progressive process that begins at conception and continues until death. This process leads to a decrease in homeostasis and morphological, biochemical and psychological changes, increasing the individual’s vulnerability to various diseases. The growth in the number of aging populations has increased the prevalence of chronic degenerative diseases, impairment of the central nervous system and dementias, such as Alzheimer’s disease, whose main risk factor is age, leading to an increase of the number of individuals who need daily support for life activities. Some theories about aging suggest it is caused by an increase of cellular senescence and reactive oxygen species, which leads to inflammation, oxidation, cell membrane damage and consequently neuronal death. Also, mitochondrial mutations, which are generated throughout the aging process, can lead to changes in energy production, deficiencies in electron transport and apoptosis induction that can result in decreased function. Additionally, increasing cellular senescence and the release of proinflammatory cytokines can cause irreversible damage to neuronal cells. Recent reports point to the importance of changing lifestyle by increasing physical exercise, improving nutrition and environmental enrichment to activate neuroprotective defense mechanisms. Therefore, this review aims to address the latest information about the different mechanisms related to neuroplasticity and neuronal death and to provide strategies that can improve neuroprotection and decrease the neurodegeneration caused by aging and environmental stressors. Related Articles | Metrics

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Roles of the ocular pressure, pressure-sensitive ion channel, and elasticity in pressure-induced retinal diseases Ji-Jie Pang 2021, 16 (1):  68-72.  doi: 10.4103/1673-5374.286953 Abstract ( 101 )   PDF (599KB) ( 221 )   Save The intraocular pressure inside the human eye maintains 10–21 mmHg above the atmospheric pressure. Elevation of intraocular pressure is highly correlated with the retinopathy in glaucoma, and changes in the exterior pressure during mountain hiking, air traveling, and diving may also induce vision decline and retinopathy. The pathophysiological mechanism of these pressure-induced retinal disorders has not been completely clear. Retinal neurons express pressure-sensitive channels intrinsically sensitive to pressure and membrane stretch, such as the transient receptor potential channel (TRP) family permeable to Ca2+ and Na+ and the two-pore domain K channel family. Recent data have shown that pressure excites the primate retinal bipolar cell by opening TRP vanilloid 4 to mediate transient depolarizing currents, and TRP vanilloid 4 agonists enhance the membrane excitability of primate retinal ganglion cells. The eyeball wall is constructed primarily by the sclera and cornea of low elasticity, and the flow rate of the aqueous humor and intraocular pressure both fluctuate, but the mathematical relationship between the ocular elasticity, aqueous humor volume, and intraocular pressure has not been established. This review will briefly review recent literature on the pressure-related retinal pathophysiology in glaucoma and other pressure-induced retinal disorders, the elasticity of ocular tissues, and pressure-sensitive cation channels in retinal neurons. Emerging data support the global volume and the elasticity and thickness of the sclera and cornea as variables to affect the intraocular pressure level like the volume of the aqueous humor. Recent results also suggest some potential routes for TRPs to mediate retinal ganglion cell dysfunction: TRP opening upon intraocular pressure elevation and membrane stretch, enhancing glutamate release from bipolar cells, increasing intracellular Na+, Ca2+ concentration in retinal ganglion cells and extracellular glutamate concentration, inactivating voltage-gated Na+ channels, and causing excitotoxicity and dysfunction of retinal ganglion cells. Further studies on these routes likely identify novel targets and therapeutic strategies for the treatment of pressure-induced retinal disorders.   Related Articles | Metrics

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Application of modern neuroimaging technology in the diagnosis and study of Alzheimer’s disease Hong-Mei Zeng, Hua-Bo Han, Qi-Fang Zhang, Hua Bai 2021, 16 (1):  73-79.  doi: 10.4103/1673-5374.286957 Abstract ( 122 )   PDF (388KB) ( 285 )   Save Neurological abnormalities identified via neuroimaging are common in patients with Alzheimer’s disease. However, it is not yet possible to easily detect these abnormalities using head computed tomography in the early stages of the disease. In this review, we evaluated the ways in which modern imaging techniques such as positron emission computed tomography, single photon emission tomography, magnetic resonance spectrum imaging, structural magnetic resonance imaging, magnetic resonance diffusion tensor imaging, magnetic resonance perfusion weighted imaging, magnetic resonance sensitive weighted imaging, and functional magnetic resonance imaging have revealed specific changes not only in brain structure, but also in brain function in Alzheimer’s disease patients. The reviewed literature indicated that decreased fluorodeoxyglucose metabolism in the temporal and parietal lobes of Alzheimer’s disease patients is frequently observed via positron emission computed tomography. Furthermore, patients with Alzheimer’s disease often show a decreased N-acetylaspartic acid/creatine ratio and an increased myoinositol/creatine ratio revealed via magnetic resonance imaging. Atrophy of the entorhinal cortex, hippocampus, and posterior cingulate gyrus can be detected early using structural magnetic resonance imaging. Magnetic resonance sensitive weighted imaging can show small bleeds and abnormal iron metabolism. Task-related functional magnetic resonance imaging can display brain function activity through cerebral blood oxygenation. Resting functional magnetic resonance imaging can display the functional connection between brain neural networks. These are helpful for the differential diagnosis and experimental study of Alzheimer’s disease, and are valuable for exploring the pathogenesis of Alzheimer’s disease. Related Articles | Metrics

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Neuroregeneration and functional recovery after stroke: advancing neural stem cell therapy toward clinical application Yang Jiao, Yu-Wan Liu, Wei-Gong Chen, Jing Liu 2021, 16 (1):  80-92.  doi: 10.4103/1673-5374.286955 Abstract ( 530 )   PDF (1252KB) ( 453 )   Save Stroke is a main cause of death and disability worldwide. The ability of the brain to self-repair in the acute and chronic phases after stroke is minimal; however, promising stem cell-based interventions are emerging that may give substantial and possibly complete recovery of brain function after stroke. Many animal models and clinical trials have demonstrated that neural stem cells (NSCs) in the central nervous system can orchestrate neurological repair through nerve regeneration, neuron polarization, axon pruning, neurite outgrowth, repair of myelin, and remodeling of the microenvironment and brain networks. Compared with other types of stem cells, NSCs have unique advantages in cell replacement, paracrine action, inflammatory regulation and neuroprotection. Our review summarizes NSC origins, characteristics, therapeutic mechanisms and repair processes, then highlights current research findings and clinical evidence for NSC therapy. These results may be helpful to inform the direction of future stroke research and to guide clinical decision-making.  Related Articles | Metrics

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Interaction between Schwann cells and other cells during repair of peripheral nerve injury Wen-Rui Qu, Zhe Zhu, Jun Liu, De-Biao Song, Heng Tian, Bing-Peng Chen, Rui Li, Ling-Xiao Deng 2021, 16 (1):  93-98.  doi: 10.4103/1673-5374.286956 Abstract ( 123 )   PDF (919KB) ( 232 )   Save Peripheral nerve injury (PNI) is common and, unlike damage to the central nervous system injured nerves can effectively regenerate depending on the location and severity of injury. Peripheral myelinating glia, Schwann cells (SCs), interact with various cells in and around the injury site and are important for debris elimination, repair, and nerve regeneration. Following PNI, Wallerian degeneration of the distal stump is rapidly initiated by degeneration of damaged axons followed by morphologic changes in SCs and the recruitment of circulating macrophages. Interaction with fibroblasts from the injured nerve microenvironment also plays a role in nerve repair. The replication and migration of injury-induced dedifferentiated SCs are also important in repairing the nerve. In particular, SC migration stimulates axonal regeneration and subsequent myelination of regenerated nerve fibers. This mobility increases SC interactions with other cells in the nerve and the exogenous environment, which influence SC behavior post-injury. Following PNI, SCs directly and indirectly interact with other SCs, fibroblasts, and macrophages. In addition, the inter- and intracellular mechanisms that underlie morphological and functional changes in SCs following PNI still require further research to explain known phenomena and less understood cell-specific roles in the repair of the injured peripheral nerve. This review provides a basic assessment of SC function post-PNI, as well as a more comprehensive evaluation of the literature concerning the SC interactions with macrophages and fibroblasts that can influence SC behavior and, ultimately, repair of the injured nerve. Related Articles | Metrics

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A novel role for tissue-nonspecific alkaline phosphatase at the blood-brain barrier during sepsis Divine C. Nwafor, Candice M. Brown 2021, 16 (1):  99-100.  doi: 10.4103/1673-5374.286958 Abstract ( 121 )   PDF (1078KB) ( 141 )   Save Sepsis is a life threatening systemic inflammatory condition involving multi-organ dysfunction. The World Health Organization estimates that about 30 million people are affected by sepsis every year, and at least 6 million people die from sepsis each year. Out of approximately 24 million sepsis survivors, it is estimated that 70% of these individuals will experience some form of long-term neurological impairment (Iwashyna et al., 2010). Thus, when combined with prevention, diagnosis, and therapeutic management strategies, a functional understanding of the mechanisms that promote sepsis-associated neurological impairment is necessary to address the clinical challenges and economic burdens faced when treating sepsis.  Related Articles | Metrics

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Neuronal protein-tyrosine phosphatase 1B hinders sensory-motor functional recovery and causes affective disorders in two different focal ischemic stroke models Shelly A. Cruz, Zhaohong Qin, Konrad M. Ricke, Alexandre F.R. Stewart, Hsiao-Huei Chen 2021, 16 (1):  129-136.  doi: 10.4103/1673-5374.286970 Abstract ( 139 )   PDF (4413KB) ( 182 )   Save Ischemic brain injury causes neuronal death and inflammation. Inflammation activates protein-tyrosine phosphatase 1B (PTP1B). Here, we tested the significance of PTP1B activation in glutamatergic projection neurons on functional recovery in two models of stroke: by photothrombosis, focal ischemic lesions were induced in the sensorimotor cortex (SM stroke) or in the peri-prefrontal cortex (peri-PFC stroke). Elevated PTP1B expression was detected at 4 days and up to 6 weeks after stroke. While ablation of PTP1B in neurons of neuronal knockout (NKO) mice had no effect on the volume or resorption of ischemic lesions, markedly different effects on functional recovery were observed. SM stroke caused severe sensory and motor deficits (adhesive removal test) in wild type and NKO mice at 4 days, but NKO mice showed drastically improved sensory and motor functional recovery at 8 days. In addition, peri-PFC stroke caused anxiety-like behaviors (elevated plus maze and open field tests), and depression-like behaviors (forced swimming and tail suspension tests) in wild type mice 9 and 28 days after stroke, respectively, with minimal effect on sensory and motor function. Peri-PFC stroke-induced affective disorders were associated with fewer active (FosB+) neurons in the PFC and nucleus accumbens but more FosB+ neurons in the basolateral amygdala, compared to sham-operated mice. In contrast, mice with neuronal ablation of PTP1B were protected from anxiety-like and depression-like behaviors and showed no change in FosB+ neurons after peri-PFC stroke. Taken together, our study identifies neuronal PTP1B as a key component that hinders sensory and motor functional recovery and also contributes to the development of anxiety-like and depression-like behaviors after stroke. Thus, PTP1B may represent a novel therapeutic target to improve stroke recovery. All procedures for animal use were approved by the Animal Care and Use Committee of the University of Ottawa Animal Care and Veterinary Service (protocol 1806) on July 27, 2018. Related Articles | Metrics

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Resveratrol as an inductor of autophagy: is there a unique pathway of activation? Narayana Pineda-Ramírez, Penélope Aguilera 2021, 16 (1):  101-103.  doi: 10.4103/1673-5374.286959 Abstract ( 184 )   PDF (1170KB) ( 186 )   Save Autophagy is a process of cellular degradation for the removal of damaged components and eventual recycling of the resulting molecules that help to the maintenance of cellular homeostasis. Through this pathway, proteins with relatively long half-life and whole organelles (e.g., mitochondria, peroxisomes, and ribosomes) are degraded in the cytoplasm for the continuous turnover of cellular structures to facilitate their renewal. However, the beneficial effect of autophagy goes beyond cellular “cleaning” and resides to a large extent on its ability to recycle cell components back into the cytosol. Thus, autophagy is a fundamental mechanism to regulate cellular functions, including DNA repair, proliferation, differentiation, embryonic development, and the immune response.  Related Articles | Metrics

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Mending the broken in amyotrophic lateral sclerosis: DNA damage and repair in motor neuron degeneration Byung Woo Kim, Lee J. Martin 2021, 16 (1):  104-105.  doi: 10.4103/1673-5374.286960 Abstract ( 107 )   PDF (1139KB) ( 176 )   Save Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes paralysis and respiratory failure (Petrov et al., 2017). The driving mechanisms are unknown, and there are no effective treatments (Petrov et al., 2017). Aging and a few gene mutations, a common one being missense mutations in superoxide dismutase-1 (SOD1), are risk factors for ALS (Figure 1). The recent Food and Drug Administration approval of edaravone for the treatment of ALS putatively supports a role for oxidative and nitrative stresses in the disease processes (Figure 1A). DNA damage, abnormalities in DNA repair, and other nuclear abnormalities are implicated also in the pathogenesis of human ALS (Bradley and Krasin, 1982; Kim et al., 2020). DNA damage as an upstream pathogenic event in human ALS is supported by evidence for p53 activation and its import into the nucleus of motor neurons (Martin, 2000), and hyperactivation and nuclear accumulation of apurinic/apyrimidinic endodeoxyribonuclease-1 (Shaikh and Martin, 2002). Kim et al. (2020) discovered that upper and lower motor neurons in postmortem central nervous system (CNS) from ALS patients, mostly sporadic ALS in comparison to age-matched controls, accumulate several different types of DNA lesions and engage a prominent DNA damage response (DDR), as evidenced by accumulation of nuclear Abelson non-receptor tyrosine kinase and breast cancer type 1 susceptibility protein, and the serine/threonine protein kinase ataxia telangiectasia mutated activation (Figure 1A). Apyriminidinic sites, single-stranded DNA, oxidized DNA, and DDR proteins are present in motor neurons at pre-attritional stages and throughout the somatodendritic attritional stages of neurodegeneration (Kim et al., 2020). Motor neurons with DNA damage are also positive for activated p53 and cleaved caspase-3 (Figure 1A). These recent findings support the concept that, in human ALS, the motor neuron degeneration is a cell-autonomous form of programmed cell death (Martin, 1999).  Related Articles | Metrics

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Sigma-1 receptor: culprit and rescuer in motor neuron diseases Jean-Charles Liévens, Tangui Maurice 2021, 16 (1):  106-107.  doi: 10.4103/1673-5374.286961 Abstract ( 146 )   PDF (401KB) ( 145 )   Save Initially, the Sigma-1 receptor (S1R) was incorrectly categorized as one of the opioid receptors. But it has since become clear that S1R is a non-opioid non-phencyclidine receptor with molecular chaperone activity. S1R is a 223 amino-acid long protein that shares no clear homology with any other known mammalian proteins, its closest homolog being the fungal ERG2 sterol isomerase. Even its pharmacological counterpart, the Sigma-2 receptor that was only recently cloned, is genetically distinct. S1R is more likely considered as an atypical ligand-modulated chaperone protein. S1R is widely expressed in many organs including brain where its function has mainly been explored. In the brain, S1R is found in neurons as well in astrocytes, microglia or oligodendrocytes. While S1R regulates important glial functions like inflammatory response or supply of neurotrophic factors, this perspective article mostly focuses on the various roles of S1R in neurons. At cellular level, S1R resides mainly as a transmembrane protein in the endoplasmic reticulum (ER) and more particularly in the vicinity of mitochondria. At this subdomain, called mitochondrial associated ER-membranes (MAM), S1R regulates calcium exchange between the two organelles through inositol triphosphate receptor type 3 (IP3R type 3). S1R prevents proteosomal degradation of IP3R but also activates its opening for calcium efflux by dissociating IP3R from the scaffolding protein ankyrin G (Su et al., 2016). As a consequence, increased calcium influx in mitochondria boosts production of the nicotinamide adenine dinucleotide cofactor, stimulates the respiratory complex 1 activity and hence increases ATP biosynthesis (Figure 1). MAM are particularly enriched in cholesterol and supply mitochondria with this precursor for steroidogenesis. S1R can promote cholesterol transfer by interaction with steroidogenic acute regulatory protein and voltage dependant anion channel, both facilitating escort of ER-derived cholesterol across the mitochondrial outer membrane (Su et al., 2016) (Figure 1). Moreover, in normal condition, cognate co-chaperone GRP78/Bip is associated to S1R and the ER stress sensor, inositol requiring enzyme 1 (IRE1), keeping them inactive. But when facing stress condition, GRP78/Bip dissociates from S1R and IRE1. Then S1R can stabilize the proper folding of IRE1 and promotes long lasting dimerization and trans-autophosphorylation of IRE1 (Su et al., 2016). This leads to activation of its ribonuclease function and the subsequent expression of the spliced/active transcription factor X-box binding protein 1, which regulates nuclear production of antioxidant proteins and chaperone proteins. On the other hand, over-expression of S1R or binding of S1R by exogenous or putative endogenous agonists can promote its interaction with ion channels, receptors and kinases, and then finely tunes neuronal excitability and plasticity (Su et al., 2016). Among endogenous agonists are neuroactive steroids such as sulfate esters of pregnenolone or dehydroepiandrosterone, the hallucinogenic N,N-dimethyltryptamine and choline. Nevertheless, it is unclear whether  endogenous agonists have a true physiological role through S1R in vivo. Finally, upon stimulation by cocaine, S1R protein can translocate to the nuclear envelope, where it binds Emerin to regulate gene transcription by recruiting chromatin-remodelling factors (Su et al., 2016). Related Articles | Metrics

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cAMP/PKA pathway and mitochondrial protection in oxidative stress-induced optic nerve head astrocytes Keun-Young Kim, Won-Kyu Ju 2021, 16 (1):  108-109.  doi: 10.4103/1673-5374.286962 Abstract ( 134 )   PDF (665KB) ( 551 )   Save Glaucoma is a leading cause of blindness worldwide in individuals 60 years of age and older. Despite the widely appreciated disease relevance of structural and functional abnormalities of astrocyte in the optic nerve head (ONH) that is associated with retinal ganglion cell (RGC) axon degeneration, the molecular mechanisms underlying astrocyte dysfunction in glaucomatous ONH degeneration are poorly understood. Oxidative stress is strongly linked to glaucoma pathogenesis, and astrocytes are the responsible cell type that is mostly related to oxidative stress and glaucomatous ONH degeneration.  Related Articles | Metrics

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Fused in sarcoma-amyotrophic lateral sclerosis as a novel member of DNA single strand break diseases with pure neurological phenotypes Marcel Naumann, Julian Laubenthal, Andreas Hermann 2021, 16 (1):  110-112.  doi: 10.4103/1673-5374.286963 Abstract ( 81 )   PDF (472KB) ( 166 )   Save Accumulation of DNA damage and genomic instability are believed to have crucial effects in neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, premature aging diseases as well as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Until recently these studies were largely correlative in nature, though raising the possibility that defects in the DNA damage response (DDR) underlie neurodegenerative diseases. However, more light needs to be shed on (a) the identification of specific lesions, if existing, and their propensity to accumulate in the affected neurons of a given neurodegenerative disease; (b) the underlying mechanisms that impede the repair of these lesions; and based on that (c) the development of animal model systems harboring these identified lesions that are central to progression of neurodegenerative disease in order to see, if interventional strategies that promote DNA repair can alleviate these effects and lead to novel mechanism-driven approaches in drug development to combat neurodegenerative diseases (Madabhushi et al., 2014). It is established that the nervous system requires the largest part of the oxygen consumption producing higher levels of reactive oxygen species (ROS) as a side product, which are known for their oxidative stress on cells in general. Focussing on neurons, ROS are one of the major sources for genotoxic stress producing more than 100 different oxidative base modifications with strong mutagenic potential, which can easily be converted to single strand breaks (SSB) (Madabhushi et al., 2014). Therefore, neurons are particularly dependent on efficient base excision repair and single strand repair processes (Figure 1), which is reflected by the volume of neurological disorders caused by defects in these repair pathways (Madabhushi et al., 2014). This highlights the pivotal role of DNA damage and the biological response mechanisms to it as a presumably early event in the process of neurodegeneration. Pathophysiological studies on ALS have particularly drawn attention on its relevance in the recent years. Related Articles | Metrics

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Thrombolysis in acute stroke under dual antiplatelet therapy: perspectives arising from ranslational studies Franziska Lieschke, Yi Zheng, Christian Foerch, Klaus van Leyen 2021, 16 (1):  113-114.  doi: 10.4103/1673-5374.284906 Abstract ( 115 )   PDF (322KB) ( 187 )   Save We have recently established a mouse model of focal stroke under dual antiplatelet therapy (DAPT) to study tissue plasminogen activator (tPA)-associated hemorrhagic transformation. The purpose of this short perspective is to discuss the rationale for establishing the model, highlighting its relevance for addressing unresolved clinical questions. Hemorrhagic conversion of the ischemic stroke remains one of the major liabilities of thrombolytic therapy with tPA, contributing to unfavorable outcomes and failed regeneration. This was recognized early on, and the resulting restrictions on tPA usage have led to only a minor percentage of stroke patients receiving any kind of drug treatment to limit ischemic injury. Broadening the patient population eligible for thrombolytic therapy is a major goal, and thus efforts are being directed at optimally defining inclusion criteria based on prior drug treatment status, among other factors. DAPT with aspirin and clopidogrel (ASA + CPG) is commonly given to patients at high risk for atherothrombotic events. However, clinical data to date has not been entirely clear as to whether the increased likelihood of bleeding following thrombolysis in patients on DAPT is indeed detrimental to patient outcome, and many see this potential downside outweighed by the benefits of recanalization of the blocked vessel. Accordingly, current guidelines allow for tPA thrombolysis in patients under DAPT. Nonetheless, doubts remain if on balance tPA is actually beneficial in these patients, and these doubts may lead to undertreatment. Final clarity might be achieved with a prospective, randomized clinical trial, but it appears unlikely that this will ever occur. In this situation, modeling the process in animals subjected to experimental ischemic stroke under DAPT can provide insights into mechanisms of hemorrhagic transformation (HT). Even more importantly, establishing such a model enables researchers to test possible strategies to mitigate the bleeding risk in patients on DAPT. If the safety of tPA thrombolysis can be increased by reducing hemorrhage, this could clearly tilt the balance towards favoring tPA treatment, and thus improve long-term outcomes of ischemic strokes. Testing such an approach in the animal model is the best first step in evaluating the utility of such an adjuvant. Related Articles | Metrics

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Neuromuscular junction mitochondrial enrichment: a “double-edged sword” underlying the selective motor neuron vulnerability in amyotrophic lateral sclerosis Topaz Altman, Eran Perlson 2021, 16 (1):  115-116.  doi: 10.4103/1673-5374.286964 Abstract ( 130 )   PDF (1059KB) ( 157 )   Save Motor neurons are highly polarized cells, with long axons that extend to more than 1 m in the adult human. The axons further arborize into a specialized synaptic compartment, the motor unit, containing up to 2000 neuromuscular junctions (NMJs). While the size of other neuronal synapses can be up to 1 µm, the NMJ is much larger and can reach 10–30 µm (Jones et al., 2017). The vast size of the motor unit requires motor neurons to evolutionally adapt and supply this distal portion with a sufficient amount of ATP, as well as to replenish the axonal protein pool in order to maintain their synapses. To address its substantial energetic needs, the NMJ is enriched with a vast network of mitochondria. This is supported by ultrastructural studies using electron and confocal microscopy, which revealed that only ~50% of active synapses in the adult rodent central nervous system (CNS) contain any mitochondria, whereas all NMJs are enriched with a tightly packed mitochondrial network (Misgeld and Schwarz, 2017; Altman et al., 2019). The mechanisms leading to this distinct enrichment, as well as its implications and functional meaning in the context of neurodegeneration, remain poorly understood. Here, we discuss and suggest a possible explanation for how the mitochondrial enrichment of the NMJ can be relevant to the selective vulnerability of motor neurons in motor neuron diseases, and in particular amyotrophic lateral sclerosis (ALS). Related Articles | Metrics

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Neuroprotective therapy for retinal neurodegenerative diseases by stem cell secretome Ricardo Usategui-Martín, Ivan Fernandez-Bueno 2021, 16 (1):  117-118.  doi: 10.4103/1673-5374.283498 Abstract ( 112 )   PDF (1398KB) ( 135 )   Save Retinal neurodegenerative diseases like age-related macular degeneration, glaucoma, diabetic retinopathy or retinitis pigmentosa are the most frequent causes of incurable low vision and blindness worldwide. It had been estimated that the prevalence of these diseases varies between 1/750 and 1/5000 depending on the region, the level of consanguinity or ethnicity (Na et al., 2017). The functional and structural complexity of the retina makes it susceptible to multiple types of pathogenic damage. The retinal neurodegeneration may be caused by genetic defects, increased intraocular pressure, high levels of blood glucose or other types of stress or aging. All of them cause progressive neuronal death which is accompanied by a response of glial cells. Although the etiology, pathogenesis and clinical characteristics of retinal neurodegenerative diseases are very different, they have common features because the cellular and molecular response to retinal neurodegeneration is closely similar (Cuenca et al., 2014). Thus, it had been proposed that several neuroprotective therapeutic approaches may be adequate for the retinal neurodegenerative process. Retinal neurodegeneration is characterized by an inflammatory response, oxidative stress and activation of cell death pathways (Cuenca et al., 2014). Besides, the neurodegenerative process of the retina is commonly divided into four different phases and changes that occur during the retina degeneration can be associated with the stage of neurodegeneration (Vugler, 2010; Cuenca et al., 2014; Gagliardi et al., 2019). During phase 1 the function and morphology of the retina appear normal but cell stress induces molecular changes and eventual cell death. In phase 2, cellular stress and the activation of apoptotic pathways leads to progressive cell loss and activation of glial cells. In phase 3, it could be observed a large-scale neuronal cell death which leads glial cells hypertrophy and microglial activation. Phase 4 is characterized by the global retinal alteration with the neuronal cell death, hypertrophy of glial cells, epiretinal membrane formation, invasion by blood vessels and by the migration of the retinal pigment epithelium cells (Cuenca et al., 2014). Related Articles | Metrics

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Dual targeting nano-approaches for Alzheimer’s disease etiology Sajini D. Hettiarachchi, Roger M. Leblanc 2021, 16 (1):  119-120.  doi: 10.4103/1673-5374.286965 Abstract ( 85 )   PDF (639KB) ( 187 )   Save Alzheimer’s disease (AD) is the most common progressive neurodegenerative disorder of aging. The characteristic features of AD begin as mild cognitive dysfunctions, which gradually progress to the fatal delirium through a total loss of cognition and executive motor functions (Pimplikar et al., 2010). Three decades later from now, more than 100 million people will suffer from AD worldwide by making it the most expensive disease (Prince et al., 2013; Bloom, 2014). The major pathological hallmarks of the AD is the extracellular amyloid-beta (Aβ) plaques deposition and the intracellular neurofibrillary tangle-aggregation of hyperphosphorylated tau-proteins. Despite the fact that Aβ and tau-phosphorylation is the primary etiology for the AD, the recent concern developed on anti-amyloid mechanisms, such as cholinergic dysfunction and reactive oxygen species (ROS) generation. The current most prevalent clinical arena is, treating amyloid or non-amyloid hypothesis individually. However, the intercorrelated nature of amyloid and non-amyloid hypothesis governs the need of the intervention of combined diagnostic approaches.     Related Articles | Metrics

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Neuroprotective effects of metalosalen complexes against oxidative stress Lara Rouco, Marcelino Maneiro 2021, 16 (1):  121-122.  doi: 10.4103/1673-5374.286966 Abstract ( 88 )   PDF (403KB) ( 161 )   Save Neurodegenerative diseases and oxidative stress: During the metabolic processes, O2 can accept unpaired electrons to form superoxide radical species (O2•–), which are able to generate hydrogen peroxide (H2O2) with a fast dismutation, therefore increasing the hydroxyl radical (HO•) levels. These species and other radicals (•OOH, ROO•, RO•, CO3•–), which can be produced through a sequence of reactions, constitute the designated reactive species of oxygen (ROS). Oxidative stress is caused by a disequilibrium between the ROS produced and the antioxidant defence against them (catalase enzymes, superoxide dismutase (SOD) and glutathione peroxidases, in addition to other non-enzymatic antioxidants, such as α-tocopherol, ascorbic acid and carotenes). The consequences of oxidative stress are the increase in the formation of oxidized cellular macromolecules, the activation of phagocytes, the release of cytokines or the activation of oncogenes. These processes lead to different pathologies in humans, such as carcinogenesis, inflammatory illnesses, diabetes type II, cellular senescence and different neurodegenerative diseases (Zhao et al., 2019). The brain is prone to oxidative stress since neurons consume large amounts of oxygen (20% of oxygen uptake when brain accounts for only 2% of body weight) due to the high rate of energy consumption (4 × 1012 ATP/min) to maintain neuronal intracellular ion homeostasis (Miller et al., 2017). Furthermore, neural mitochondria generate large amounts of hydrogen peroxide compared to skeletal muscle mitochondria. Additionally, neuronal membranes have high concentrations of polyunsaturated fatty acids like arachidonic acid, docosahexaenoic acid or eicosapentaenoic acid; all of them with unsaturated double bonds which are susceptible to oxidation, giving rise to lipid hydroperoxides as the primary oxidation products. Thus, unsaturated lipid peroxidation also contributes to the progression of disbalanced redox homeostasis, generating reactive oxygen species. The effects of oxidative stress are implicated in the progression of several neurodegenerative diseases: chronic diseases like Parkinson’s or Alzheimer’s diseases, acute injury of the brain like brain trauma or cerebral ischemia, and psychiatric disorders like depression, schizophrenia or autism (Chen et al., 2012). Related Articles | Metrics

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Neurogenesis similarities in different human adult stem cells Carlos Bueno, Salvador Martínez 2021, 16 (1):  123-124.  Abstract ( 72 )   PDF (969KB) ( 112 )   Save Human neurological disorders and spinal cord injuries are caused by a loss of neurons and glial cells in the brain or spinal cord. The proof-of-principle of cell therapy is that replacing damaged cells with new healthy ones will restore the lost function. Isolating and manipulating autologous neural stem cells (NSCs) could provide an ideal source of cells for use in cell replacement and the transfer of genes to a diseased central nervous system. NSCs are immature cells present, not only during embryonic development, but also in the adult brain of all mammalian species, including humans. The presence of NSCs in the adult mammalian brain has been described in two neurogenic niches, the ventricular-subventricular zone (V-SVZ) of the anterolateral ventricle wall and the subgranular zone of the hippocampal dentate gyrus. Typically, NSCs are defined as self-renewing multipotent cells that can generate neurons, astrocytes and oligodendrocytes. The major barrier to isolating adult NSCs in humans is the inaccessibility of living tissue. For this reason, an enormous effort has been made to derive neurons from human adult stem cells isolated from various tissue sources.  Related Articles | Metrics

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Brains, bacteria and behaviors: the role of interferon-gamma in the pathogenesis of pneumococcal meningitis Lay Khoon Too, Andrew Mitchell 2021, 16 (1):  125-126.  doi: 10.4103/1673-5374.286968 Abstract ( 99 )   PDF (506KB) ( 145 )   Save Pneumococcal meningitis is a highly lethal form of bacterial meningitis that occurs following brain infection by the Gram-positive cocci Streptococcus pneumoniae. Not only does it cause acute mortality, but pneumococcal meningitis also accounts for the highest proportion of survivors living with neurological sequelae, including behavioral disorders, cognitive deficits, hearing loss, motor impairment and epilepsy. More than 90 distinct pneumococcal serotypes have been identified worldwide based on their capsular compositions and serological responses. Serotype replacement continually poses great challenge to costly vaccination programs in developed countries (Koelman et al., 2020), this has therefore emphasized the need to develop new treatment strategies in addition to improving vaccine coverage. Various immunomodulatory agents, such as complement system inhibitors and matrix metalloproteinase inhibitors, have been shown to improve disease severity and mortality when tested in animal models (Bewersdorf et al., 2018). Nevertheless, given the evidence of long-term cognitive deficits and behavioral problems in patients who were clinically well recovered from pneumococcal meningitis, it remains unclear how the protection at the early inflammatory stage may translate into long-term functional recovery. With this in mind, we have established an integrated approach to investigate the interplay between acute host inflammatory response and ensuing neurological deficits in a mouse model of pneumococcal meningitis in animals that survive the lethal disease due to antibiotic ceftriaxone treatment. This has enabled the identification of a nexus between the toll-like receptors (TLRs) 2 and 4, interferon-gamma (IFN-γ) and the enzyme indoleamine 2,3-dioxygenase-1 (IDO-1) that contributes to enduring neurological impairments. Here, we will highlight the findings of our systematic studies in the hope of opening avenues for future research relevant to both meningitis as well as other neurological diseases. Related Articles | Metrics

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Inosine: a novel treatment for sciatic nerve injury Fellipe Soares dos Santos Cardoso, Ana Maria Blanco Martinez, Fernanda Martins de Almeida 2021, 16 (1):  127-128.  doi: 10.4103/1673-5374.286969 Abstract ( 108 )   PDF (324KB) ( 211 )   Save Trauma to the peripheral nervous system often results in loss of motor and sensory functions of the affected area of the body, leading to a series of functional impairments (Allodi et al., 2012). Injuries to peripheral nerves initiate a series of complex events, known as Wallerian degeneration, which allows the injured axons to regenerate and reinnervate their targets (Allodi et al., 2012). Damage to a nerve induces multiple alterations, which include: axonal degeneration, breakdown of myelin sheath, Schwann cells (SC) proliferation and conversion to a repair phenotype which express cytokines and chemokines that allow the infiltration and activation of macrophages (Mietto et al., 2015; Jessen and Mirsky, 2016). Then, both macrophages and SC clean up axon and myelin debris, and promote in the distal degenerated portion of the axon, a favorable microenvironment that is required for regeneration. After clearance, SC forms the bands of Büngner, which will guide the regenerating axons to the target and will allow the reestablishment of new synapses with the muscle, followed by the process of axon remyelination (Allodi et al., 2012; Jessen and Mirsky, 2016). Concomitant with these events, the neuronal cell body turns into a pro-regenerative state, allowing the injured axons to grow. Some positive signals such as cyclic adenosine monophosphate (cAMP) increase and the entrance of extracellular Ca2+ to the axoplasm can trigger and maintain the pro-regenerative state. cAMP has a key role in the growth state of the neuronal soma, regulating axon attraction or repulsion by guidance cues from the environment. One example is the nerve growth factor and brain-derived neurotrophic factor. Low levels of cAMP turn the attractive effects of these neurotrophic factors, important for axonal growth, in repulsion. Moreover, these signals activate a cascade of mitogen-activated protein kinases, which induces the expression of transcriptions factors such as activating transcription factor 3 and signal transducers and activators of transcription, increasing the expression of neurotrophic factors, growth proteins such as growth associated protein-43, cytoskeleton proteins and extracellular matrix components (Allodi et al., 2012). Related Articles | Metrics

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Effect of electroacupuncture on glial fibrillary acidic protein and nerve growth factor in the hippocampus of rats with hyperlipidemia and middle cerebral artery thrombus Na-Ying Xue, Dong-Yu Ge, Rui-Juan Dong, Hyung-Hwan Kim, Xiu-Jun Ren, , Ya Tu 2021, 16 (1):  137-142.  doi: 10.4103/1673-5374.286973 Abstract ( 139 )   PDF (2443KB) ( 184 )   Save Electroacupuncture (EA) has been shown to reduce blood lipid level and improve cerebral ischemia in rats with hyperlipemia complicated by cerebral ischemia. However, there are few studies on the results and mechanism of the effect of EA in reducing blood lipid level or promoting neural repair after stroke in hyperlipidemic subjects. In this study, EA was applied to a rat model of hyperlipidemia and middle cerebral artery thrombosis and the condition of neurons and astrocytes after hippocampal injury was assessed. Except for the normal group, rats in other groups were fed a high-fat diet throughout the whole experiment. Hyperlipidemia models were established in rats fed a high-fat diet for 6 weeks. Middle cerebral artery thrombus models were induced by pasting 50% FeCl3 filter paper on the left middle cerebral artery for 20 minutes on day 50 as the model group. EA1 group rats received EA at bilateral ST40 (Fenglong) for 7 days before the thrombosis. Rats in the EA1 and EA2 groups received EA at GV20 (Baihui) and bilateral ST40 for 14 days after model establishment. Neuronal health was assessed by hematoxylin-eosin staining in the brain. Hyperlipidemia was assessed by biochemical methods that measured total cholesterol, triglyceride, low-density lipoprotein and high-density lipoprotein in blood sera. Behavioral analysis was used to confirm the establishment of the model. Immunohistochemical methods were used to detect the expression of glial fibrillary acidic protein and nerve growth factor in the hippocampal CA1 region. The results demonstrated that, compared with the model group, blood lipid levels significantly decreased, glial fibrillary acidic protein immunoreactivity was significantly weakened and nerve growth factor immunoreactivity was significantly enhanced in the EA1 and EA2 groups. The repair effect was superior in the EA1 group than in the EA2 group. These findings confirm that EA can reduce blood lipid, inhibit glial fibrillary acidic protein expression and promote nerve growth factor expression in the hippocampal CA1 region after hyperlipidemia and middle cerebral artery thrombosis. All experimental procedures and protocols were approved by the Animal Use and Management Committee of Beijing University of Chinese Medicine, China (approval No. BUCM-3-2018022802-1002) on April 12, 2018.  Related Articles | Metrics

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A novel tissue engineered nerve graft constructed with autologous vein and nerve microtissue repairs a long-segment sciatic nerve defect Jing Wang, Ya-Qiong Zhu, Yu Wang, Hong-Guang Xu, Wen-Jing Xu, Yue-Xiang Wang, Xiao-Qing Cheng, Qi Quan, Yong-Qiang Hu, Chang-Feng Lu, Yan-Xu Zhao, Wen Jiang, Chen Liu, Liang Xiao, Wei Lu, Chen Zhu, Ai-Yuan Wang 2021, 16 (1):  143-149.  doi: 10.4103/1673-5374.286977 Abstract ( 129 )   PDF (4987KB) ( 178 )   Save Veins are easy to obtain, have low immunogenicity, and induce a relatively weak inflammatory response. Therefore, veins have the potential to be used as conduits for nerve regeneration. However, because of the presence of venous valves and the great elasticity of the venous wall, the vein is not conducive to nerve regeneration. In this study, a novel tissue engineered nerve graft was constructed by combining normal dissected nerve microtissue with an autologous vein graft for repairing 10-mm peripheral nerve defects in rats. Compared with rats given the vein graft alone, rats given the tissue engineered nerve graft had an improved sciatic static index, and a higher amplitude and shorter latency of compound muscle action potentials. Furthermore, rats implanted with the microtissue graft had a higher density and thickness of myelinated nerve fibers and reduced gastrocnemius muscle atrophy compared with rats implanted with the vein alone. However, the tissue engineered nerve graft had a lower ability to repair the defect than autogenous nerve transplantation. In summary, although the tissue engineered nerve graft constructed with autologous vein and nerve microtissue is not as effective as autologous nerve transplantation for repairing long-segment sciatic nerve defects, it may nonetheless have therapeutic potential for the clinical repair of long sciatic nerve defects. This study was approved by the Experimental Animal Ethics Committee of Chinese PLA General Hospital (approval No. 2016-x9-07) on September 7, 2016. Related Articles | Metrics

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Brain-derived neurotrophic factor protects against acrylamide-induced neuronal and synaptic injury via the TrkB-MAPK-Erk1/2 pathway Xiao Chen, Jing-Wei Xiao, Peng Cao, Yi Zhang, Wen-Jian Cai, Jia-Yang Song, Wei-Min Gao , Bin Li 2021, 16 (1):  150-157.  doi: 10.4103/1673-5374.286976 Abstract ( 104 )   PDF (3440KB) ( 211 )   Save Acrylamide has been shown to be neurotoxic. Brain-derived neurotrophic factor (BDNF) can alleviate acrylamide-induced synaptic injury; however, the underlying mechanism remains unclear. In this study, dibutyryl-cyclic adenosine monophosphate-induced mature human neuroblastoma (NB-1) cells were exposed with 0–100 μg/mL acrylamide for 24–72 hours. Acrylamide decreased cell viability and destroyed synapses. Exposure of co-cultured NB-1 cells and Schwann cells to 0–100 μg/mL acrylamide for 48 hours resulted in upregulated expression of synapsin I and BDNF, suggesting that Schwann cells can activate self-protection of neurons. Under co-culture conditions, activation of the downstream TrkB-MAPK-Erk1/2 pathway strengthened the protective effect. Exogenous BDNF can increase expression of TrkB, Erk1/2, and synapsin I, while exogenous BDNF or the TrkB inhibitor K252a could inhibit these changes. Taken together, Schwann cells may act through the BDNF-TrkB-MAPK-Erk1/2 signaling pathway, indicating that BDNF plays an important role in this process. Therefore, exogenous BDNF may be an effective treatment strategy for acrylamide-induced nerve injury. This study was approved by the Laboratory Animal Welfare and Ethics Committee of the National Institute of Occupational Health and Poison Control, a division of the Chinese Center for Disease Control and Prevention (approval No. EAWE-2017-008) on May 29, 2017. Related Articles | Metrics

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Neural plasticity secondary to carpal tunnel syndrome: a pseudo-continuous arterial spin labeling study Xue Deng, Phoebe Lai-Heung Chau, Suk-Yee Chiu, Kwok-Pui Leung, Yong Hu, Wing-Yuk Ip 2021, 16 (1):  158-165.  doi: 10.4103/1673-5374.286971 Abstract ( 90 )   PDF (2806KB) ( 167 )   Save Conventional neuroimaging techniques cannot truly reflect the change of regional cerebral blood flow in patients with carpal tunnel syndrome. Pseudo-continuous arterial spinning labeling (pCASL) as an efficient non-invasive neuroimaging technique can be applied to directly quantify the neuronal activities of individual brain regions that show the persistent symptoms owing to its better spatial resolution and increased signal-to-noise ratio. Therefore, this prospective observational study was conducted in 27 eligible female carpal tunnel syndrome, aged 57.7 ± 6.51 years. Psychometric tests, nerve conduction studies and pCASL neuroimaging assessment were performed. The results showed that the relevant activated brain regions in the cortical, subcrotical, and cerebral regions were correlated with numbness, pain, functionality, median nerve status and motor amplitude of median nerve (K = 21–2849, r = –0.77–0.76, P < 0.05). There was a tendency of pain processing which shifted from the nociceptive circuitry to the emotional and cognitive one during the process of chronic pain caused by carpal tunnel syndrome. It suggests the necessity of addressing the ignored cognitive or emotional state when managing patients with carpal tunnel syndrome. Approval for this study was obtained from the Institutional Review Board  of The University of Hong Kong/Hospital Authority Hong Kong West, China (HKU/HA HKW IRB, approval No. UW17-129) on April 11, 2017. This study was registered in Clinical Trial Registry of The University of Hong Kong, China (registration number: HKUCTR-2220) on April 24, 2017. Related Articles | Metrics

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Deletion of Krüppel-like factor-4 promotes axonal regeneration in mammals Jin-Hui Xu, Xu-Zhen Qin, Hao-Nan Zhang, Yan-Xia Ma, Shi-Bin Qi, Hong-Cheng Zhang, Jin-Jin Ma, Xin-Ya Fu, Ji-Le Xie, Saijilafu 2021, 16 (1):  166-171.  doi: 10.4103/1673-5374.286978 Abstract ( 117 )   PDF (2651KB) ( 234 )   Save Axonal regeneration plays an important role in functional recovery after nervous system damage. However, after axonal injury in mammals, regeneration is often poor. The deletion of Krüppel-like factor-4 (Klf4) has been shown to promote axonal regeneration in retinal ganglion cells. However, the effects of Klf4 deletion on the corticospinal tract and peripheral nervous system are unknown. In this study, using a mouse model of sciatic nerve injury, we show that the expression of Klf4 in dorsal root ganglion sensory neurons was significantly reduced after peripheral axotomy, suggesting that the regeneration of the sciatic nerve is associated with Klf4. In vitro, dorsal root ganglion sensory neurons with Klf4 knockout exhibited significantly enhanced axonal regeneration. Furthermore, the regeneration of the sciatic nerve was enhanced in vivo following Klf4 knockout. Finally, AAV-Cre virus was used to knockout the Klf4 gene in the cortex. The deletion of Klf4 enhanced regeneration of the corticospinal tract in mice with spinal cord injury. Together, our findings suggest that regulating KLF4 activity in neurons is a potential strategy for promoting axonal regeneration and functional recovery after nervous system injury. This study was approved by the Animal Ethics Committee at Soochow University, China (approval No. SUDA20200316A01). Related Articles | Metrics

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Insights into stem cell therapy for diabetic retinopathy: a bibliometric and visual analysis Xiang-Jun Li, Chun-Yan Li, Dan Bai, Ying Leng 2021, 16 (1):  172-178.  doi: 10.4103/1673-5374.286974 Abstract ( 232 )   PDF (1950KB) ( 248 )   Save Stem cells have been confirmed to be involved in the occurrence and development of diabetic retinopathy; however, the underlying mechanisms remain unclear. In this study, we used Citespace software to visually analyze 552 articles exploring the stem cell-based treatment of diabetic retinopathy over the past 20 years, which were included in the Web of Science Core Collection. We found the following: (1) a co-citation analysis of the references cited by all 552 articles indicated 15 clusters. In cluster #0, representing the stem cell field, some highly cited landmark studies emerged between 2009–2013. For example, endothelial progenitor cells and diabetic retinopathy gradually received the full attention of scholars, in terms of their relationship and therapeutic prospects. Some researchers also verified the potential of adipose-derived stem cells to differentiate into stable retinal perivascular cells, using a variety of animal models of retinal vascular disease. All of these achievements provided references for the subsequent stem cell research. (2) An analysis of popular keywords among the 552 articles revealed that, during the past 20 years, a relative increase in basic research articles examining stem cells and endothelial progenitor cells for the treatment of diabetic retinopathy was observed. The contents of these articles primarily involved the expression of vascular endothelial growth factor, vascular regeneration, oxidative stress, and inflammatory response. (3) A burst analysis of keywords used in the 552 articles indicated that genetic and cytological research regarding the promotion of angiogenesis was an issue of concern from 2001 to 2012, including several studies addressing the expression of various growth factor genes; from 2014 to 2020, mouse models of diabetic retinopathy were recognized as mature animal models, and the most recent research has focused on macular degeneration, macular edema, neurodegeneration, and inflammatory changes in diabetic animal models. (4) Globally, the current authoritative studies have focused on basic research towards the stem cell treatment of diabetic retinopathy. Existing clinical studies are of low quality and have insufficient evidence levels, and their findings have not yet been widely accepted in clinical practice. Major challenges during stem cell transplantation remain, including stem cell heterogeneity, cell delivery, and the effective homing of stem cells to damaged tissue. However, clinical trials examining potential stem cell-based treatments of diabetic retinopathy, including the use of pluripotent stem cells, retinal pigment epithelial cells, bone marrow mesenchymal stem cells, and endothelial progenitor cells, are currently ongoing, and high-quality clinical evidence is likely to appear in the future, to promote clinical transformation. Related Articles | Metrics

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Nogo-A aggravates oxidative damage in oligodendrocytes Yang-Yang Wang, Na Han, Dao-Jun Hong, Jun Zhang 2021, 16 (1):  179-185.  doi: 10.4103/1673-5374.286979 Abstract ( 122 )   PDF (4506KB) ( 161 )   Save Nogo-A is considered one of the most important inhibitors of myelin-associated axonal regeneration in the central nervous system. It is mainly expressed by oligodendrocytes. Although previous studies have found regulatory roles for Nogo-A in neurite outgrowth inhibition, neuronal homeostasis, precursor migration, plasticity, and neurodegeneration, its functions in the process of oxidative injury are largely uncharacterized. In this study, oligodendrocytes were extracted from the cerebral cortex of newborn Sprague-Dawley rats. We used hydrogen peroxide (H2O2) to induce an in vitro oligodendrocyte oxidative damage model and found that endogenously expressed Nogo-A is significantly upregulated in oligodendrocytes. After recombinant virus Ad-ZsGreen-rat Nogo-A infection of oligodendrocytes, Nogo-A expression was increased, and the infected oligodendrocytes were more susceptible to acute oxidative insults and exhibited a markedly elevated rate of cell death. Furthermore, knockdown of Nogo-A expression in oligodendrocytes by Ad-ZsGreen-shRNA-Nogo-A almost completely protected against oxidative stress induced by exogenous H2O2. Intervention with a Nogo-66 antibody, a LINGO1 blocker, or Y27632, an inhibitor in the Nogo-66-NgR/p75/LINGO-1-RhoA-ROCK pathway, did not affect the death of oligodendrocytes. Ad-ZsGreen-shRNA-Nogo-A also increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 and inhibited BCL2 expression in oligodendrocytes. In conclusion, Nogo-A aggravated reactive oxygen species damage in oligodendrocytes, and phosphorylated extracellular signal-regulated kinase 1/2 and BCL2 might be involved in this process. This study was approved by the Ethics Committee of Peking University People’s Hospital, China (approval No. 2018PHC081) on December 18, 2018. Related Articles | Metrics

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Laminin-coated multifilament entubulation, combined with Schwann cells and glial cell line-derived neurotrophic factor, promotes unidirectional axonal regeneration in a rat model of thoracic spinal cord hemisection Ling-Xiao Deng, Nai-Kui Liu, Ryan Ning Wen, Shuang-Ni Yang, Xuejun Wen, Xiao-Ming Xu 2021, 16 (1):  186-191.  doi: 10.4103/1673-5374.289436 Abstract ( 117 )   PDF (5302KB) ( 270 )   Save Biomaterial bridging provides physical substrates to guide axonal growth across the lesion. To achieve efficient directional guidance, combinatory strategies using permissive matrix, cells and trophic factors are necessary. In the present study, we evaluated permissive effect of poly (acrylonitrile-co-vinyl chloride) guidance channels filled by different densities of laminin-precoated unidirectional polypropylene filaments combined with Schwann cells, and glial cell line-derived neurotrophic factor for axonal regeneration through a T10 hemisected spinal cord gap in adult rats. We found that channels with filaments significantly reduced the lesion cavity, astrocytic gliosis, and inflammatory responses at the graft-host boundaries. The laminin coated low density filament provided the most favorable directional guidance for axonal regeneration which was enhanced by co-grafting of Schwann cells and glial cell line-derived neurotrophic factor. These results demonstrate that the combinatorial strategy of filament-filled guiding scaffold, adhesive molecular laminin, Schwann cells, and glial cell line-derived neurotrophic factor, provides optimal topographical cues in stimulating directional axonal regeneration following spinal cord injury. This study was approved by Indiana University Institutional Animal Care and Use Committees (IACUC #:11011) on October 29, 2015. Related Articles | Metrics

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Argon reduces microglial activation and inflammatory cytokine expression in retinal ischemia/reperfusion injury Ulrich Goebel, Stefanie Scheid, Sashko Spassov, Nils Schallner, Jakob Wollborn, Hartmut Buerkle, Felix Ulbrich 2021, 16 (1):  192-198.  doi: 10.4103/1673-5374.290098 Abstract ( 132 )   PDF (1955KB) ( 142 )   Save We previously found that argon exerts its neuroprotective effect in part by inhibition of the toll-like receptors (TLR) 2 and 4. The downstream transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-κB) are also affected by argon and may play a role in neuroprotection. It also has been demonstrated that argon treatment could mitigate brain damage, reduce excessive microglial activation, and subsequently attenuate brain inflammation. Despite intensive research, the further exact mechanism remains unclear. In this study, human neuroblastoma cells were damaged in vitro with rotenone over a period of 4 hours (to mimic cerebral ischemia and reperfusion damage), followed by a 2-hour post-conditioning with argon (75%). In a separate in vivo experiment, retinal ischemia/reperfusion injury was induced in rats by increasing intraocular pressure for 1 hour. Upon reperfusion, argon was administered by inhalation for 2 hours. Argon reduced the binding of the transcription factors signal transducer and activator of transcription 3, nuclear factor kappa B, activator protein 1, and nuclear factor erythroid 2-related factor 2, which are involved in regulation of neuronal damage. Flow cytometry analysis showed that argon downregulated the Fas ligand. Some transcription factors were regulated by toll-like receptors; therefore, their effects could be eliminated, at least in part, by the TLR2 and TLR4 inhibitor oxidized phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC). Argon treatment reduced microglial activation after retinal ischemia/reperfusion injury. Subsequent quantitative polymerase chain reaction analysis revealed a reduction in the pro-inflammatory cytokines interleukin (IL-1α), IL-1β, IL-6, tumor necrosis factor α, and inducible nitric oxide synthase. Our results suggest that argon reduced the extent of inflammation in retinal neurons after ischemia/reperfusion injury by suppression of transcription factors crucial for microglial activation. Argon has no known side effects or narcotic properties; therefore, therapeutic use of this noble gas appears ideal for treatment of patients with neuronal damage in retinal ischemia/reperfusion injury. The animal experiments were approved by the Commission for Animal Care of the University of Freiburg (approval No. 35-9185.81/G14-122) on October 19, 2012.  Related Articles | Metrics