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15 March 2022, Volume 17 Issue 3 Previous Issue   

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Therapeutic potential of glial cell line-derived neurotrophic factor and cell reprogramming for hippocampal-related neurological disorders Priscila Chiavellini, Martina Canatelli-Mallat, Marianne Lehmann, Rodolfo G. Goya, Gustavo R. Morel 2022, 17 (3):  469-476.  doi: 10.4103/1673-5374.320966 Abstract ( 175 )   PDF (520KB) ( 105 )   Save Hippocampus serves as a pivotal role in cognitive and emotional processes, as well as in the regulation of the hypothalamus-pituitary axis. It is known to undergo mild neurodegenerative changes during normal aging and severe atrophy in Alzheimer’s disease. Furthermore, dysregulation in the hippocampal function leads to epilepsy and mood disorders. In the first section, we summarized the most salient knowledge on the role of glial cell-line-derived neurotrophic factor and its receptors focused on aging, cognition and neurodegenerative and hippocampal-related neurological diseases mentioned above. In the second section, we reviewed the therapeutic approaches, particularly gene therapy, using glial cell-line-derived neurotrophic factor or its gene, as a key molecule in the development of neurological disorders. In the third section, we pointed at the potential of regenerative medicine, as an emerging and less explored strategy for the treatment of hippocampal disorders. We briefly reviewed the use of partial reprogramming to restore brain functions, non-neuronal cell reprogramming to generate neural stem cells, and neural progenitor cells as source-specific neuronal types to be implanted in animal models of specific neurodegenerative disorders.  Related Articles | Metrics

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Influence of Sox protein SUMOylation on neural development and regeneration Kun-Che Chang 2022, 17 (3):  477-481.  doi: 10.4103/1673-5374.320968 Abstract ( 259 )   PDF (797KB) ( 127 )   Save SRY-related HMG-box (Sox) transcription factors are known to regulate central nervous system development and are involved in several neurological diseases. Post-translational modification of Sox proteins is known to alter their functions in the central nervous system. Among the different types of post-translational modification, small ubiquitin-like modifier (SUMO) modification of Sox proteins has been shown to modify their transcriptional activity. Here, we review the mechanisms of three Sox proteins in neuronal development and disease, along with their transcriptional changes under SUMOylation. Across three species, lysine is the conserved residue for SUMOylation. In Drosophila, SUMOylation of SoxN plays a repressive role in transcriptional activity, which impairs central nervous system development. However, deSUMOylation of SoxE and Sox11 plays neuroprotective roles, which promote neural crest precursor formation in Xenopus and retinal ganglion cell differentiation as well as axon regeneration in the rodent. We further discuss a potential translational therapy by SUMO site modification using AAV gene transduction and Clustered regularly interspaced short palindromic repeats-Cas9 technology. Understanding the underlying mechanisms of Sox SUMOylation, especially in the rodent system, may provide a therapeutic strategy to address issues associated with neuronal development and neurodegeneration.      Related Articles | Metrics

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Pentadecapeptide BPC 157 and the central nervous system Jakša Vukojević, Marija Milavić, Darko Perović, Spomenko Ilić, Andrea Zemba Čilić, Nataša Đuran, Sanja Štrbe, Zoran Zoričić, Igor Filipčić, Petrana Brečić, Sven Seiverth, Predrag Sikirić 2022, 17 (3):  482-487.  doi: 10.4103/1673-5374.320969 Abstract ( 448 )   PDF (344KB) ( 93 )   Save We reviewed the pleiotropic beneficial effects of the stable gastric pentadecapeptide BPC 157, three very recent demonstrations that may be essential in the gut-brain and brain-gut axis operation, and therapy application in the central nervous system disorders, in particular. Firstly, given in the reperfusion, BPC 157 counteracted bilateral clamping of the common carotid arteries-induced stroke, sustained brain neuronal damages were resolved in rats as well as disturbed memory, locomotion, and coordination. This therapy effect supports particular gene expression in hippocampal tissues that appeared in BPC 157-treated rats. Secondly, there are L-NG-nitro arginine methyl ester (L-NAME)- and haloperidol-induced catalepsy as well as the rat acute and chronic models of ‘positive-like’ schizophrenia symptoms, that BPC 157 counteracted, and resolved the complex relationship of the nitric oxide-system with amphetamine and apomorphine (dopamine agents application), MK-801 (non-competitive antagonist of the N-methyl-D-aspartate receptor) and chronic methamphetamine administration (to induce sensitivity). Thirdly, after rat spinal cord compression, there were advanced healing and functional recovery (counteracted tail paralysis).  Likewise, in BPC 157 therapy, there is specific support for each of these topics: counteracted encephalopathies; alleviated vascular occlusion disturbances (stroke); counteracted dopamine disturbances (dopamine receptors blockade, receptors super sensitivity development, or receptor activation,  over-release, nigrostriatal damage, vesicles depletion), and  nitric oxide-system disturbances (“L-NAME non-responsive, L-arginine responsive,” and “L-NAME responsive, L-arginine responsive”) (schizophrenia therapy); inflammation reduction, nerve recovery in addition to alleviated hemostasis and vessels function after compression (spinal cord injury therapy). Thus, these disturbances may be all resolved within the same agent’s beneficial activity, i.e., the stable gastric pentadecapeptide BPC 157. Related Articles | Metrics

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The short form of the SUR1 and its functional implications in the damaged brain Iván Alquisiras-Burgos, Javier Franco-Pérez, Moisés Rubio-Osornio, Penélope Aguilera 2022, 17 (3):  488-496.  doi: 10.4103/1673-5374.320967 Abstract ( 756 )   PDF (1445KB) ( 384 )   Save Sulfonylurea receptor (SUR) belongs to the adenosine 5′-triphosphate (ATP)-binding cassette (ABC) transporter family; however, SUR is associated with ion channels and acts as a regulatory subunit determining the opening or closing of the pore. Abcc8 and Abcc9 genes code for the proteins SUR1 and SUR2, respectively. The SUR1 transcript encodes a protein of 1582 amino acids with a mass around 140–177 kDa expressed in the pancreas, brain, heart, and other tissues. It is well known that SUR1 assembles with Kir6.2 and TRPM4 to establish KATP channels and non-selective cation channels, respectively. Abbc8 and 9 are alternatively spliced, and the resulting transcripts encode different isoforms of SUR1 and SUR2, which have been detected by different experimental strategies. Interestingly, the use of binding assays to sulfonylureas and Western blotting has allowed the detection of shorter forms of SUR (~65 kDa). Identity of the SUR1 variants has not been clarified, and some authors have suggested that the shorter forms are unspecific. However, immunoprecipitation assays have shown that SUR2 short forms are part of a functional channel even coexisting with the typical forms of the receptor in the heart. This evidence confirms that the structure of the short forms of the SURs is fully functional and does not lose the ability to interact with the channels. Since structural changes in short forms of SUR modify its affinity to ATP, regulation of its expression might represent an advantage in pathologies where ATP concentrations decrease and a therapeutic target to induce neuroprotection. Remarkably, the expression of SUR1 variants might be induced by conditions associated to the decrease of energetic substrates in the brain (e.g. during stroke and epilepsy). In this review, we want to contribute to the knowledge of SUR1 complexity by analyzing evidence that shows the existence of short SUR1 variants and its possible implications in brain function. Related Articles | Metrics

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Oligodendrocyte pathology in fetal alcohol spectrum disorders Nune Darbinian, Michael E. Selzer 2022, 17 (3):  497-502.  doi: 10.4103/1673-5374.314294 Abstract ( 198 )   PDF (382KB) ( 129 )   Save The pathology of fetal alcohol syndrome and the less severe fetal alcohol spectrum disorders includes brain dysmyelination. Recent studies have shed light on the molecular mechanisms underlying these white matter abnormalities. Rodent models of fetal alcohol syndrome and human studies have shown suppressed oligodendrocyte differentiation and apoptosis of oligodendrocyte precursor cells. Ethanol exposure led to reduced expression of myelin basic protein and delayed myelin basic protein expression in rat and mouse models of fetal alcohol syndrome and in human histopathological specimens. Several studies have reported increased expression of many chemokines in dysmyelinating disorders in central nervous system, including multiple sclerosis and fetal alcohol syndrome. Acute ethanol exposure reduced levels of the neuroprotective insulin-like growth factor-1 in fetal and maternal sheep and in human fetal brain tissues, while ethanol increased the expression of tumor necrosis factor α in mouse and human neurons. White matter lesions have been induced in the developing sheep brain by alcohol exposure in early gestation. Rat fetal alcohol syndrome models have shown reduced axon diameters, with thinner myelin sheaths, as well as reduced numbers of oligodendrocytes, which were also morphologically aberrant oligodendrocytes. Expressions of markers for mature myelination, including myelin basic protein, also were reduced. The accumulating knowledge concerning the mechanisms of ethanol-induced dysmyelination could lead to the development of strategies to prevent dysmyelination in children exposed to ethanol during fetal development. Future studies using fetal oligodendrocyte- and oligodendrocyte precursor cell-derived exosomes isolated from the mother’s blood may identify biomarkers for fetal alcohol syndrome and even implicate epigenetic changes in early development that affect oligodendrocyte precursor cell and oligodendrocyte function in adulthood. By combining various imaging modalities with molecular studies, it may be possible to determine which fetuses are at risk and to intervene therapeutically early in the pregnancy.  Related Articles | Metrics

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Promise of metformin for preventing age-related cognitive dysfunction Leelavathi N. Madhu, Maheedhar Kodali, Ashok K. Shetty 2022, 17 (3):  503-507.  doi: 10.4103/1673-5374.320971 Abstract ( 312 )   PDF (1117KB) ( 121 )   Save The expanded lifespan of people, while a positive advance, has also amplified the prevalence of age-related disorders, which include mild cognitive impairment, dementia, and Alzheimer’s disease. Therefore, competent therapies that could improve the healthspan of people have great significance. Some of the dietary and pharmacological approaches that augment the lifespan could also preserve improved cognitive function in old age. Metformin, a drug widely used for treating diabetes, is one such candidate that could alleviate age-related cognitive dysfunction. However, the possible use of metformin to alleviate age-related cognitive dysfunction has met with conflicting results in human and animal studies. While most clinical studies have suggested the promise of metformin to maintain better cognitive function and reduce the risk for developing dementia and Alzheimer’s disease in aged diabetic people, its efficacy in the nondiabetic population is still unclear. Moreover, a previous animal model study implied that metformin could adversely affect cognitive function in the aged. However, a recent animal study using multiple behavioral tests has reported that metformin treatment in late middle age improved cognitive function in old age. The study also revealed that cognition-enhancing effects of metformin in aged animals were associated with the activation of the energy regulator adenosine monophosphate-activated protein kinase, diminished neuroinflammation, inhibition of the mammalian target of rapamycin signaling, and augmented autophagy in the hippocampus. The proficiency of metformin to facilitate these favorable modifications in the aged hippocampus likely underlies its positive effect on cognitive function. Nonetheless, additional studies probing the outcomes of different doses and durations of metformin treatment at specific windows in the middle and old age across sex in nondiabetic and non-obese prototypes are required to substantiate the promise of metformin to maintain better cognitive function in old age.   Related Articles | Metrics

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One ring is sufficient to inhibit α-synuclein aggregation Samuel Peña-Díaz, Salvador Ventura 2022, 17 (3):  508-511.  doi: 10.4103/1673-5374.320973 Abstract ( 330 )   PDF (497KB) ( 138 )   Save Parkinson’s disease, the second most prevalent neurodegenerative disorder worldwide, is characterized by a progressive loss of dopaminergic neurons in substantia nigra pars compacta, causing motor symptoms. This disorder’s main hallmark is the formation of intraneuronal protein inclusions, named Lewy bodies and neurites. The major component of these arrangements is α-synuclein, an intrinsically disordered and soluble protein that, in pathological conditions, can form toxic and cell-to-cell transmissible amyloid structures. Preventing α-synuclein aggregation has attracted significant effort in the search for a disease-modifying therapy for Parkinson’s disease. Small molecules like SynuClean-D, epigallocatechin gallate, trodusquemine, or anle138b exemplify this therapeutic potential. Here, we describe a subset of compounds containing a single aromatic ring, like dopamine, ZPDm, gallic acid, or entacapone, which act as molecular chaperones against α-synuclein aggregation. The simplicity of their structures contrasts with the complexity of the aggregation process, yet the block efficiently α-synuclein assembly into amyloid fibrils, in many cases, redirecting the reaction towards the formation of non-toxic off-pathway oligomers. Moreover, some of these compounds can disentangle mature α-synuclein amyloid fibrils. Their simple structures allow structure-activity relationship analysis to elucidate the role of different functional groups in the inhibition of α-synuclein aggregation and fibril dismantling, making them informative lead scaffolds for the rational development of efficient drugs. Related Articles | Metrics

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Neural functions of small heat shock proteins Teresa de los Reyes, Sergio Casas-Tintó 2022, 17 (3):  512-515.  doi: 10.4103/1673-5374.320975 Abstract ( 222 )   PDF (487KB) ( 103 )   Save Stress response is a cellular widespread mechanism encoded by a common protein program composed by multiple cellular factors that converge in a defense reaction to protect the cell against damage. Among many mechanisms described, heat shock proteins were proposed as universally conserved protective factors in the stress core proteome, coping with different stress stimuli through its canonical role in protein homeostasis. However, emerging evidences reveal non-canonical roles of heat shock proteins relevant for physiological and pathological conditions. Here, we review the implications of inducible heat shock proteins in the central nervous system physiology. In particular, we discuss the relevance of heat shock proteins in the maintenance of synapses, as a balanced protective mechanism in central nervous system development, pathological conditions and aging.  Related Articles | Metrics

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The role of miRNA in retinal ganglion cell health and disease Ben Mead, Stanislav Tomarev 2022, 17 (3):  516-522.  doi: 10.4103/1673-5374.320974 Abstract ( 332 )   PDF (452KB) ( 102 )   Save miRNA are short non-coding RNA responsible for the knockdown of proteins through their targeting and silencing of complimentary mRNA sequences. The miRNA landscape of a cell thus affects the levels of its proteins and has significant consequences to its health. Deviations in this miRNA landscape have been implicated in a variety of neurodegenerative diseases and have also garnered interest as targets for treatment. Retinal ganglion cells are the sole projection neuron of the retina with their axons making up the optic nerve. They are a focus of study not only for their importance in vision and the myriad of blinding diseases characterized by their dysfunction and loss, but also as a model of other central nervous system diseases such as spinal cord injury and traumatic brain injury. This review summarizes current knowledge on the role of miRNA in retinal ganglion cell function, highlighting how perturbations can result in disease, and how modulating their abundance may provide a novel avenue of therapeutic research. Related Articles | Metrics

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Diabetes mellitus and Parkinson’s disease: dangerous liaisons between insulin and dopamine Angela De Iuliis, Ennio Montinaro, Giuseppe Fatati, Mario Plebani, Carlo Colosimo 2022, 17 (3):  523-533.  doi: 10.4103/1673-5374.320965 Abstract ( 308 )   PDF (1885KB) ( 175 )   Save The relationship between diabetes mellitus and Parkinson’s disease has been described in several epidemiological studies over the 1960s to date. Molecular studies have shown the possible functional link between insulin and dopamine, as there is strong evidence demonstrating the action of dopamine in pancreatic islets, as well as the insulin effects on feeding and cognition through central nervous system mechanism, largely independent of glucose utilization. Therapies used for the treatment of type 2 diabetes mellitus appear to be promising candidates for symptomatic and/or disease-modifying action in neurodegenerative diseases including Parkinson’s disease, while an old dopamine agonist, bromocriptine, has been repositioned for the type 2 diabetes mellitus treatment. This review will aim at reappraising the different studies that have highlighted the dangerous liaisons between diabetes mellitus and Parkinson’s disease. Related Articles | Metrics

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Circulating extracellular vesicles: friends and foes in neurodegeneration Anna Picca, Flora Guerra, Riccardo Calvani, Hélio José Coelho-Junior, Cecilia Bucci, Emanuele Marzetti 2022, 17 (3):  534-542.  doi: 10.4103/1673-5374.320972 Abstract ( 430 )   PDF (2556KB) ( 120 )   Save Extracellular vesicles have been identified as pivotal mediators of intercellular communication with critical roles in physiological and pathological conditions. Via this route, several molecules (e.g., nucleic acids, proteins, metabolites) can be transferred to proximal and distant targets to convey specific information. Extracellular vesicle-associated cargo molecules have been proposed as markers of several disease conditions for their potential of tracking down the generating cell. Indeed, circulating extracellular vesicles may represent biomarkers of dysfunctional cellular quality control systems especially in conditions characterized by the accrual of intracellular misfolded proteins. Furthermore, the identification of extracellular vesicles as tools for the delivery of nucleic acids or other cargo molecules to diseased tissues makes these circulating shuttles possible targets for therapeutic development. The increasing interest in the study of extracellular vesicles as biomarkers resides mainly in the fact that the identification of peripheral levels of extracellular vesicle-associated proteins might reflect molecular events occurring in hardly accessible tissues, such as the brain, thereby serving as a “brain liquid biopsy”. The exploitation of extracellular vesicles for diagnostic and therapeutic purposed might offer unprecedented opportunities to develop personalized approaches. Here, we discuss the bright and dark sides of extracellular vesicles in the setting of two main neurodegenerative diseases (i.e., Parkinson’s and Alzheimer’s diseases). A special focus will be placed on the possibility of using extracellular vesicles as biomarkers for the two conditions to enable disease tracking and treatment monitoring. Related Articles | Metrics

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Pathological mechanisms and therapeutic strategies for Alzheimer’s disease Yaojun Ju, Kin Yip Tam 2022, 17 (3):  543-549.  doi: 10.4103/1673-5374.320970 Abstract ( 607 )   PDF (407KB) ( 280 )   Save Alzheimer’s disease is a rather complex neurodegenerative disease, which is attributed to a combination of multiple factors. Among the many pathological pathways, synaptic dysfunctions, such as synapses loss and deficits in synaptic plasticity, were thought to be strongly associated with cognitive decline. The deficiencies in various sorts of neurotransmissions are responsible for the multifarious neurodegenerative symptoms in Alzheimer’s disease, for example, the cholinergic and glutamatergic deficits for cognitive decline, the excitatory and inhibitory neurotransmission dyshomeostasis for synaptic plasticity deficits and epileptiform symptoms, and the monoamine neurotransmission for neuropsychiatric symptoms. Amyloid cascade hypothesis is the most popular pathological theory to explain Alzheimer’s disease pathogenesis and attracts considerable attention. Multiple lines of genetic and pathological evidence support the predominant role of amyloid beta in Alzheimer’s disease pathology. Neurofibrillary tangles assembled by microtubule-associated protein tau are other important histopathological characteristics in Alzheimer’s disease brains. Cascade of tau toxicity was proved to lead to neuron damage, neuroinflammation and oxidative stress in brain. Ageing is the main risk factor of neurodegenerative diseases, and is associated with inflammation, oxidative stress, reduced metabolism, endocrine insufficiencies and organ failures. These aging related risk factors were also proved to be some of the risk factors contributing to Alzheimer’s disease. In Alzheimer’s disease drug development, many good therapeutic strategies have been investigated in clinical evaluations. However, complex mechanism of Alzheimer’s disease and the interplay among different pathological factors call for the come out of all-powerful therapies with multiple curing functions. This review seeks to summarize some of the representative treatments targeting different pathological pathways currently under clinical evaluations. Multi-target therapies as an emerging strategy for Alzheimer’s disease treatment will be highlighted. Related Articles | Metrics

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Female sex in experimental traumatic brain injury research: forging a path forward Theresa Currier Thomas, Caitlin E. Bromberg, Gokul Krishna 2022, 17 (3):  550-552.  doi: 10.4103/1673-5374.316602 Abstract ( 226 )   PDF (437KB) ( 66 )   Save Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, with estimates indicating that ~50% of the world’s population will acquire a head injury at some point in their lifetime (Maas et al., 2017). Mild TBIs account for ~80% of all reported cases, with up to 43% of all TBI patients reporting symptoms beyond 2 weeks post-injury. As of 2016, only 7% of preclinical TBI experiments included both male and female sexes, and fewer studies analyzed the data using sex as a biological variable (Spani et al., 2018). Since 2016, there has been a bigger push for TBI research to include both sexes, due to reports of sex disparities in symptom presentation, recovery, and vulnerability to other neurological disorders; emphasizing how little we know about the pathophysiology of TBI in females. In this Perspective, we discuss some preclinical and clinical sex differences, challenges addressing female inclusion in preclinical TBI research, and potential solutions towards finding a balance between female sex inclusion and sex as an independent biological variable; forging a path towards improving scientific rigor, reproducibility and inclusivity for evaluating pathophysiological sex-differences after TBI. Related Articles | Metrics

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Locomotor recovery after spinal cord injury: intimate dependence between axonal regeneration and re-connection Hector Ramiro Quintá 2022, 17 (3):  553-554.  doi: 10.4103/1673-5374.320977 Abstract ( 287 )   PDF (463KB) ( 133 )   Save Traumatic spinal cord injuries (SCI) are characterized by damage in the integrity of the spinal cord, which results in either temporary or permanent alterations in the locomotor, sensory and/or autonomic functions (Yezierski, 2009). The traumatic event leads to impairments in voluntary control of movement below the injury by affecting the connection between the brain and the neurons localized in the spinal cord. Therefore, the recovery of locomotor activity is considered one of the main goals in the search of new therapies by the scientists around the world. For many years, axon regeneration has been considered the Holy Grail in SCI research, however, now we know that the regeneration of sectioned axons is necessary but not enough to promote locomotor recovery (Raineteau and Schwab, 2001). The disruption of long motor and sensory axonal tracts as a consequence of the lesion prevents their specific interactions with their cellular targets. For this reason the goal of ongoing investigations is to promote the re-growth of axonal tracts across the lesion site and their re-connection with propiospinal neurons at different segments of the spinal cord (Figure 1A). In particular, regeneration and re-connection of corticospinal tract (CST) axons is of vital significance to regain voluntary locomotor activity after a complete spinal cord injury (Oudega and Perez, 2012). This is because the axons that integrate the CST transmit voluntary motor information to the forelimbs and hindlimbs, and the damage of this structure in humans affects directly the locomotion (Nathan, 1994). Related Articles | Metrics

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The Hsp90-binding immunophilin FKBP52 enhances neurodifferentiation and neuroregeneration in murine models Cristina Daneri-Becerra, Mario D. Galigniana 2022, 17 (3):  555-556.  doi: 10.4103/1673-5374.320976 Abstract ( 181 )   PDF (804KB) ( 92 )   Save The term immunophilin involves a family of proteins whose domain shows peptidyl-prolyl-(cis/trans)-isomerase (PPIase) enzymatic activity, i.e., the reversible cis/trans interconversion of Xaa-Pro bonds (Annett et al., 2020). The PPIase domain of these proteins usually binds to immunosuppressive drugs, such as the macrolide FK506 (referred to as the FKBP subfamily) or the cyclic undecapeptide cyclosporine A (called CyP subfamily). The binding of the drug implies the inhibition of the PPIase enzymatic activity. Those members of each subfamily that show the smallest molecular weight (i.e., FKBP12 and CyP17/CyPA) are the only proteins responsible for the immunosuppressive action of the cognate drug due to the abrogation of calcineurin (or protein-phosphatase 2B) biological action. This prevents the nuclear translocation of phospho-NFAT, a transcription factor that induces the expression of interleukins and interferon-γ, both factors being critical components of the cell-mediated immune response. In contrast to those two low molecular weight immunophilins, larger members of the family such as the heat-shock protein of 90 kDa (HSP90)-binding immunophilins are not related to immunosuppression and are characterized by the additional presence of degenerate sequences of 34 amino acids repeated in tandem arrays, the TPR domains, through which they interact with dimers of the molecular chaperone HSP90 and the associated cochaperone p23 (Figure 1A).  Among them, FKBP51 and FKBP52 are studied well since they were first described associated with the HSP90-based chaperone heterocomplex of steroid receptors (Storer et al., 2011). Both immunophilins share 75% of amino acid similitude and bind FK506 with equivalent Ki. They play regulatory roles in the steroid-dependent retrotransport of corticosteroid receptors, the translocation of the receptor through the nuclear pore complex, and the hormone-dependent transcriptional regulation (Zgajnar et al., 2019; Mazaira et al., 2020). Usually, both immunophilins show antagonistic action. Thus, FKBP52 favors glucocorticoid binding to the glucocorticoid receptor as well as the active transport of glucocorticoid receptor and other factors (NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; hTERT, human telomerase reverse transcriptase; p53, tumor protein of 53-kDa) throughout the cytoplasm to the nucleus using dynein/dynactin motors to power that movement. The motor complex interacts with the PPIase domain of FKBP52, but not with that of FKBP51 (Storer et al., 2011). In addition to its role in protein trafficking, FKBP52 also enhances the steroid-dependent transcriptional activity of steroid receptors and NF-kB, whereas its partner FKBP51 shows inhibitory effects (Lagadari et al., 2016; Daneri-Becerra et al., 2019). In the nervous system, the expression of FKBP51 and FKBP52 is noteworthy in both neurons and glial cells.  Related Articles | Metrics

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Toward future adaptive deep brain stimulation for Parkinson’s disease: the novel biomarker — narrowband gamma oscillation Hao Ding, Sergiu Groppa, Muthuraman Muthuraman 2022, 17 (3):  557-558.  doi: 10.4103/1673-5374.320984 Abstract ( 189 )   PDF (510KB) ( 123 )   Save Parkinson’s disease (PD) is one of the most common neurodegenerative diseases, affecting individuals especially over 60 years of age. In the next three decades, more than 12 million people will suffer from PD worldwide (Rocca, 2018). The characteristic symptoms of PD begin as a movement disorder including bradykinesia, resting tremor, rigidity, and postural instability. Among these symptoms, bradykinesia is considered to be the major feature in diagnosing PD. At early stages, the motor symptoms of PD can be traced back to the loss of dopaminergic neurons of the substantia nigra (Armstrong and Okun, 2020). The other known neuropathological hallmark of PD is the intracellular inclusions containing the aggregates of a-synuclein (Armstrong and Okun, 2020). Nevertheless, consensus exists that the dysfunction of the interconnected neural networks plays a fundamental role in the presence of clinical symptoms given the anatomical and functional interactions within the brain. The current most prevalent clinical treatment involves substituting dopamine with medication and suppressing pathological neural activity via deep brain stimulation (DBS).  Related Articles | Metrics

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Heat shock factor 1 is a direct anti-amyloid factor: connecting neurodegeneration and uncontrolled growth Zijian Tang, Chengkai Dai 2022, 17 (3):  559-560.  doi: 10.4103/1673-5374.320983 Abstract ( 178 )   PDF (725KB) ( 76 )   Save Worldwide, more than 40 million people are afflicted with Alzheimer’s disease (AD) (Esquerda-Canals et al., 2017). AD is a devastating neurodegenerative disroder characterized by progressive decline in cognitive abilities. A hallmark of AD and other neurodegenerative disorders in humans is the aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions (Iadanza et al., 2018). In AD, following a series of proteolytic cleavage events amyloid precursor proteins give rise to Aβ monomers, which, in turn, assemble into soluble amyloid oligomers (AOs) that ultimately become insoluble mature amyloid fibrils enriched with highly ordered cross β-sheet structures. This entire process is termed as amyloidogenesis (Chen et al., 2017).  Related Articles | Metrics

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Novel insights into the pathogenesis of DYT1 dystonia from induced patient-derived neurons Baojin Ding 2022, 17 (3):  561-562.  doi: 10.4103/1673-5374.320978 Abstract ( 210 )   PDF (1234KB) ( 122 )   Save Dystonia is a common movement disorder characterized by sustained or intermittent muscle contractions causing abnormal movements and/or postures (Keller Sarmiento and Mencacci, 2021). The dystonic syndromes are classified as primary dystonia (dystonia is the only motor feature without tremor) and the secondary dystonia (dystonia is combined with other movement disorders, such as Parkinsonism). Based on the age of onset, dystonias are also dichotomously classified as childhood onset or adulthood onset. The distribution of affected body parts may change over time and progressively spread of dystonia to previously uninvolved sites. Because the clinical characteristics and underlying causes of dystonia are very heterogeneous, the pathological mechanisms of dystonia remain largely unknown. The diagnosis and etiological definition of this disorder remain challenges. The current therapies, such as anticholinergics, intramuscular botulinum toxin injection and deep brain stimulation, are largely symptom-based and only partially satisfactory (Balint et al., 2018). The childhood-onset torsin dystonia, also called DYT1 dystonia, represents the most frequent and severe form of hereditary primary dystonia, providing an excellent example to understand the pathogenesis of this disease (Gonzalez-Alegre, 2019; Keller Sarmiento and Mencacci, 2021).  Related Articles | Metrics

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Noise-induced hippocampal damage: potential mechanisms Sonia Jazmín Molina, Laura Ruth Guelman 2022, 17 (3):  563-564.  doi: 10.4103/1673-5374.320982 Abstract ( 243 )   PDF (578KB) ( 125 )   Save Exposure to noise of high intensities (> 80 dB) is considered a stressful event and might produce both auditory and extra-auditory damage, including different central nervous system (CNS) injuries. Within the CNS, the hippocampus (HC), a structure related to several cognitive functions, has shown to be particularly susceptible to the effects of noise. Human and animal studies have demonstrated that exposure to noise can generate different HC-related alterations, including morphological, functional and behavioral changes (Molina et al., 2016b, 2019; Nadhimi and Llano, 2020). Unfortunately, little is known about the mechanisms involved in noise-induced hippocampal damage and more research is needed to understand how the different alterations are caused. In addition, considering that noise exposure constitutes a public health problem that is increasing in urbanized societies, accurate knowledge of these mechanisms has clinical relevance as it can lead to develop preventive strategies. In this perspective, the possible mechanisms involved in noise-induced hippocampal cell damage will be discussed, as well as the pathways through which these mechanisms could be triggered by noise exposure. Related Articles | Metrics

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Glial decline and loss of homeostatic support rather than inflammation defines cognitive aging Alexei Verkhratsky, Natalia Lazareva, Alexey Semyanov 2022, 17 (3):  565-566.  doi: 10.4103/1673-5374.320979 Abstract ( 236 )   PDF (2093KB) ( 191 )   Save The preservation of cognitive longevity and arresting the pandemic of senile dementia engulfing the modern world is arguably the major challenge faced by biomedical research in the 21st century. Age is the leading risk factor for neurodegenerative diseases and vascular dementia, and yet there is a clear distinction between physiological and pathological brain aging; the former proceeds with cognitive abilities mainly preserved, whereas the latter is manifested with rapid cognitive decline. The cellular and molecular mechanisms of brain aging remain disputed, with numerous indications for metabolic and signaling alterations (Mattson and Arumugam, 2018). Chronic neuroinflammation in particular, is frequently considered as a universal attribute of aging (Di Benedetto et al., 2017), with brain aging being but a part of “inflammageing” (Franceschi et al., 2007) embracing the whole organism. This view, however, needs to be corroborated, particularly considering that the concept of neuroinflammation is not clearly defined. Reactive gliosis (astrogliosis or microgliosis, and possibly reactivity of oligodendrocyte precursor cells also known as NG-2 glia) is frequently regarded as the ultimate sign of neuroinflammation and aging is generally believed to be associated with progressive increase in glial reactivity. Experimental evidence for the predominance of reactive glia in the old brain is however controversial; instead, the age-dependent glial morphofunctional decline may present more accurate description of brain aging.  Related Articles | Metrics

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Injectable versus oral first-line multiple sclerosis therapies: knows and unknowns from observational studies Emanuele D’Amico, Aurora Zanghì, Carlo Avolio 2022, 17 (3):  567-568.  doi: 10.4103/1673-5374.320985 Abstract ( 241 )   PDF (449KB) ( 83 )   Save The approval of oral disease modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) has changed considerably the therapeutic scenario and they often represent the first therapeutic choice for patients with RRMS, since their safety and efficacy profile has been extensively validated (D’Amico et al., 2015).  Related Articles | Metrics

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Serial block face scanning electron microscopy reveals novel organizational details of the retinal pigment epithelium J. Arjuna Ratnayaka, Eloise Keeling 2022, 17 (3):  569-571.  doi: 10.4103/1673-5374.321002 Abstract ( 181 )   PDF (17386KB) ( 33 )   Save Advances in imaging have led to the development of several new types of microscopes such as serial block face scanning electron microscopy (SBF-SEM), lightsheet microscopy, as well as X-ray micro-computed tomography (micro-CT), which enables the study of samples in fundamentally different ways. Significantly, these are now commercially available, which facilitates their widespread use in research. With SBF-SEM, fixed and resin-embedded specimens can be serially sectioned and imaged to construct a 3D dataset of the ultrastructure of cells and tissues at high resolution. We used this technique on perfusion-fixed C57BL/6 mouse eyes to image the outer retina. Our findings revealed novel organizational details of the retinal pigment epithelium (RPE) (Keeling et al., 2020b); a specialized cell monolayer that maintains the overlying photoreceptors and also forms the outer blood-retinal-barrier. RPE cells were found to look after far more photoreceptors than was widely assumed. 3D-data enabled measurements of the RPE cytoplasmic and nuclear volumes, the length and angle of microvilli on the apical RPE surface, as well as sub-RPE spaces under the basolateral membrane. The study also compared between mono-nucleate vs. bi-nucleate RPE cells, whilst the use of computing microinstructions (macros) provided information on interactions between adjacent cells in the RPE monolayer. Analysis of SBF-SEM stacks showed several hundred mitochondria which were rendered in 3D, providing information on their volume and spatial distribution in healthy RPE. Mitochondria were found in varying shapes and sizes, and predominantly localized to the mid and basal-zones of cells. The capabilities of SBF-SEM alongside other imaging techniques are being increasingly harnessed by investigators to gain novel insights into the organization of cells and tissues in the eye. These findings also help improve the current understanding of pathology linked with common blinding conditions such as age-related macular degeneration (AMD), as well as rare forms of retinopathy which leads to irreversible sight-loss.    Related Articles | Metrics

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Glaucoma-like damage induced by S100B injection is accompanied by microglial response Teresa Tsai, Stephanie C. Joachim 2022, 17 (3):  572-574.  doi: 10.4103/1673-5374.320980 Abstract ( 144 )   PDF (1365KB) ( 95 )   Save Glaucoma is currently the second leading cause of blindness worldwide. Due to aging societies the number of patients suffering from this disease will further increase in the next years. Unfortunately, glaucoma can remain asymptomatic until it is rather far progressed, hence about 10–50% of patients are unaware they suffer from this disease. Glaucoma is a progressive optic neuropathy associated with changes at the optic nerve head, gradual retinal ganglion cell (RGC) death, and visual field loss. High intraocular pressure (IOP) is the main risk factor, but the exact pathomechanism of glaucoma remains unexplained to date. In addition to mechanical damage due to increased IOP, which can injure axons and disrupt the ocular blood flow, numerous other factors have been recorded that contribute to the development of glaucoma. In recent years, the role of the immune system has come into focus as a possible contributor to glaucoma pathology. The involvement of immunological changes in glaucoma disease is based on the detection of altered antibody titer in serum samples of primary open-angle or normal-tension glaucoma patients and tear film samples of primary open-angle glaucoma patients. Affected patients showed antibodies against proteins such as heat shock protein (HSP)60, HSP27, or S100B (Grus et al., 2010; Bell et al., 2013).  Related Articles | Metrics

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Matrin-3 dysfunction in myopathy and motor neuron degeneration Caroline Ward, Udai Bhan Pandey 2022, 17 (3):  575-576.  doi: 10.4103/1673-5374.320986 Abstract ( 254 )   PDF (1480KB) ( 177 )   Save The MATR3 protein was first identified comprising the nuclear matrix, an essential part of preserving the skeletal framework of the nucleus, amongst other nuclear matrins. Composed mainly of intrinsically disordered regions, the protein is made up of 847 amino acids, creating 4 distinct functional domains: two zinc-finger domains (ZF1 and ZF2) and two RNA-recognition motifs (RRM1 and RRM2,) as well as a highly acidic carboxy-terminal with histone-binding ability. This structural design allows MATR3 protein to interact with DNA and/or DNA/RNA-binding proteins, aiding in chromosomal and genomic integrity regulation, RNA-binding mediated post-transcriptional mRNA regulation, and nuclear lamina association to maintain nuclear framework. An autosomal dominant Ser85Cys (S85C) mutation in MATR3 was identified in a multigenerational family displaying vocal cord and pharyngeal weakness as well as distal and asymmetrical myopathy (Senderek et al., 2009). Intriguingly, a neurogenic or myopathic pattern was indicated by these patients neurophysiological and muscle biopsy-based examinations. They displayed several signs emblematic of upper motor neuron lesions such as a “split-hand” pattern, tongue fasciculations, brunt jaw-jerk, upper limb reflexes, and brisk knee. Due to this, S85C patients in three independent families were reassessed and found to suffer progressive respiratory failure leading to death 15 years after onset (Johnson et al., 2014), in contrast to the typical 2–5 years. This led to a recategorization of S85C-associated disorder to “slow progressive amytrophic lateral sclerosis (ALS) with distal myopathy,” and is approximated at 0.5% frequency of all mutations. Initially, 3 cohorts containing unique missense MATR3 mutations associated with ALS were characterized; Phe115Cys (F115C) and Thr622Ala (T622A) were found in familial ALS patients, and Pro154Ser (P154S) in a sporadic ALS patient (Johnson et al., 2014). Subsequently, 3 additional MATR3 mutations including p.Ser610Phe (Xu et al., 2016), a missense mutation found in ALS patients from Chinese origin with 3 variants (p.Ala313Gly, p.Arg147Lys, and p.Gln347Lys). Secondly, a duplication of exon 15 referred to as MATR3 Variant 5 (Castro et al., 2020) was found in a patient presenting symptoms of frontotemporal dementia, lastly, a heterozygous missense mutation called Ala72Thr was found in a Taiwanese ALS patient (Lin et al., 2015).   Related Articles | Metrics

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Downregulation of miR-491-5p promotes neovascularization after traumatic brain injury Wei Tang, Zong-Duo Guo, Wei-Na Chai, Dong-Lin Du, Xiao-Min Yang, Lang Cao, Hong Chen, Chao Zhou, Chong-Jie Cheng, Xiao-Chuan Sun, Zhi-Jian Huang, Jian-Jun Zhong 2022, 17 (3):  577-586.  doi: 10.4103/1673-5374.314326 Abstract ( 181 )   PDF (9556KB) ( 37 )   Save MicroRNA-491-5p (miR-491-5p) plays an important role in regulating cell proliferation and migration; however, the effect of miR-491-5p on neovascularization after traumatic brain injury remains poorly understood. In this study, a controlled cortical injury model in C57BL/6 mice and an oxygen-glucose deprivation model in microvascular endothelial cells derived from mouse brain were established to simulate traumatic brain injury in vivo and in vitro, respectively. In the in vivo model, quantitative real-time-polymerase chain reaction results showed that the expression of miR-491-5p increased or decreased following the intracerebroventricular injection of an miR-491-5p agomir or antagomir, respectively, and the expression of miR-491-5p decreased slightly after traumatic brain injury. To detect the neuroprotective effects of miR-491-p, neurological severity scores, Morris water maze test, laser speckle techniques, and immunofluorescence staining were assessed, and the results revealed that miR-491-5p downregulation alleviated neurological dysfunction, promoted the recovery of regional cerebral blood flow, increased the number of lectin-stained microvessels, and increased the survival of neurons after traumatic brain injury. During the in vitro experiments, the potential mechanism of miR-491-5p on neovascularization was explored through quantitative real-time-polymerase chain reaction, which showed that miR-491-5p expression increased or decreased in brain microvascular endothelial cells after transfection with an miR-491-5p mimic or inhibitor, respectively. Dual-luciferase reporter and western blot assays verified that metallothionein-2 was a target gene for miR-491-5p. Cell counting kit 8 (CCK-8) assay, flow cytometry, and 2ʹ,7ʹ-dichlorofluorescein diacetate (DCFH-DA) assay results confirmed that the downregulation of miR-491-5p increased brain microvascular endothelial cell viability, reduced cell apoptosis, and alleviated oxidative stress under oxygen-glucose deprivation conditions. Cell scratch assay, Transwell assay, tube formation assay, and western blot assay results demonstrated that miR-491-5p downregulation promoted the migration, proliferation, and tube formation of brain microvascular endothelial cells through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor pathway. These findings confirmed that miR-491-5p downregulation promotes neovascularization, restores cerebral blood flow, and improves the recovery of neurological function after traumatic brain injury. The mechanism may be mediated through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor signaling pathway and the alleviation of oxidative stress. All procedures were approved by Ethics Committee of the First Affiliated Hospital of Chongqing Medical University, China (approval No. 2020-304) on June 22, 2020.  Related Articles | Metrics

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Morphometric changes in the cortex following acute mild traumatic brain injury Meng-Jun Li, Si-Hong Huang, Chu-Xin Huang, Jun Liu 2022, 17 (3):  587-593.  doi: 10.4103/1673-5374.320995 Abstract ( 186 )   PDF (802KB) ( 169 )   Save Morphometric changes in cortical thickness (CT), cortical surface area (CSA), and cortical volume (CV) can reflect pathological changes after acute mild traumatic brain injury (mTBI). Most previous studies focused on changes in CT, CSA, and CV in subacute or chronic mTBI, and few studies have examined changes in CT, CSA, and CV in acute mTBI. Furthermore, acute mTBI patients typically show transient cognitive impairment, and few studies have reported on the relationship between cerebral morphological changes and cognitive function in patients with mTBI. This prospective cohort study included 30 patients with acute mTBI (15 males, 15 females, mean age 33.7 years) and 27 matched healthy controls (12 males, 15 females, mean age 37.7 years) who were recruited from the Second Xiangya Hospital of Central South University between September and December 2019. High-resolution T1-weighted images were acquired within 7 days after the onset of mTBI. The results of analyses using FreeSurfer software revealed significantly increased CSA and CV in the right lateral occipital gyrus of acute-stage mTBI patients compared with healthy controls, but no significant changes in CT. The acute-stage mTBI patients also showed reduced executive function and processing speed indicated by a lower score in the Digital Symbol Substitution Test, and reduced cognitive ability indicated by a longer time to complete the Trail Making Test-B. Both increased CSA and CV in the right lateral occipital gyrus were negatively correlated with performance in the Trail Making Test part A. These findings suggest that cognitive deficits and cortical alterations in CSA and CV can be detected in the acute stage of mTBI, and that increased CSA and CV in the right lateral occipital gyrus may be a compensatory mechanism for cognitive dysfunction in acute-stage mTBI patients. This study was approved by the Ethics Committee of the Second Xiangya Hospital of Central South University, China (approval No. 086) on February 9, 2019. Related Articles | Metrics

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The mechanisms through which auricular vagus nerve stimulation protects against cerebral ischemia/reperfusion injury Jing-Jun Zhao, Zheng-Hui Wang, Ying-Jie Zhang, Wen-Jing Wang, Ai-Fang Cheng, Pei-Jing Rong, Chun-Lei Shan 2022, 17 (3):  594-600.  doi: 10.4103/1673-5374.320992 Abstract ( 217 )   PDF (4435KB) ( 139 )   Save Previous studies have shown that vagus nerve stimulation can improve patients’ locomotor function. The stimulation of the auricular vagus nerve, which is the only superficial branch of the vagus nerve, may have similar effects to vagus nerve stimulation. However, the precise mechanisms remain poorly understood. In this study, rat models of cerebral ischemia/reperfusion injury were established by modified Longa ligation. Twenty-four hours later, 7-day auricular vagus nerve stimulation was performed. The results showed that auricular vagus nerve stimulation promoted the secretion of acetylcholine, inhibited the secretion of interleukin-1β, interleukin-6, and tumor necrosis factor-α, and reduced connexin 43 phosphorylation in the ischemic penumbra and motor cortex, promoting locomotor function recovery in rats with cerebral ischemia/reperfusion injury. These findings suggested that auricular vagus nerve stimulation promotes the recovery of locomotor function in rats with cerebral ischemia/reperfusion injury by altering the secretion of acetylcholine and inflammatory factors and the phosphorylation of connexin 43. This study was approved by the Animal Use and Management Committee of Shanghai University of Traditional Chinese Medicine on November 8, 2019 (approval No. PZSHUTCM191108014). Related Articles | Metrics

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A flexible electrode array for determining regions of motor function activated by epidural spinal cord stimulation in rats with spinal cord injury Guang-Wei Mao, Jian-Jun Zhang, Hao Su, Zhi-Jun Zhou, Lin-Sen Zhu, Xiao-Ying Lü, Zhi-Gong Wang 2022, 17 (3):  601-607.  doi: 10.4103/1673-5374.320987 Abstract ( 231 )   PDF (7214KB) ( 94 )   Save Epidural stimulation of the spinal cord is a promising technique for the recovery of motor function after spinal cord injury. The key challenges within the reconstruction of motor function for paralyzed limbs are the precise control of sites and parameters of stimulation. To activate lower-limb muscles precisely by epidural spinal cord stimulation, we proposed a high-density, flexible electrode array. We determined the regions of motor function that were activated upon epidural stimulation of the spinal cord in a rat model with complete spinal cord, which was established by a transection method. For evaluating the effect of stimulation, the evoked potentials were recorded from bilateral lower-limb muscles, including the vastus lateralis, semitendinosus, tibialis anterior, and medial gastrocnemius. To determine the appropriate stimulation sites and parameters of the lower muscles, the stimulation characteristics were studied within the regions in which motor function was activated upon spinal cord stimulation. In the vastus lateralis and medial gastrocnemius, these regions were symmetrically located at the lateral site of L1 and the medial site of L2 vertebrae segment, respectively. The tibialis anterior and semitendinosus only responded to stimulation simultaneously with other muscles. The minimum and maximum stimulation threshold currents of the vastus lateralis were higher than those of the medial gastrocnemius. Our results demonstrate the ability to identify specific stimulation sites of lower muscles using a high-density and flexible array. They also provide a reference for selecting the appropriate conditions for implantable stimulation for animal models of spinal cord injury. This study was approved by the Animal Research Committee of Southeast University, China (approval No. 20190720001) on July 20, 2019.  Related Articles | Metrics

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Profile of the RNA in exosomes from astrocytes and microglia using deep sequencing: implications for neurodegeneration mechanisms Hui-Min Xie, Xing Su, Feng-Yuan Zhang, Chao-Lun Dai, Rong-Hua Wu, Yan Li, Xiao-Xiao Han, Xing-Mei Feng, Bin Yu, Shun-Xing Zhu, Song-Lin Zhou 2022, 17 (3):  608-617.  doi: 10.4103/1673-5374.320999 Abstract ( 260 )   PDF (5142KB) ( 227 )   Save Glial cells play an important role in signal transduction, energy metabolism, extracellular ion homeostasis and neuroprotection of the central nervous system. However, few studies have explained the potential effects of exosomes from glial cells on central nervous system health and disease. In this study, the genes expressed in exosomes from astrocytes and microglia were identified by deep RNA sequencing. Kyoto Encyclopedia of Genes and Genomes analysis indicated that several pathways in these exosomes are responsible for promoting neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Gene ontology analysis showed that extracellular exosome, mitochondrion and growth factor activity were enriched in exosomes from the unique astrocyte group, while extracellular exosome and mitochondrion were enriched in exosomes from the unique microglia group. Next, combined with the screening of hub genes, the protein-protein interaction network analysis showed that exosomes from astrocytes influence neurodegenerative diseases through metabolic balance and ubiquitin-dependent protein balance, whereas exosomes from microglia influence neurodegenerative diseases through immune inflammation and oxidative stress. Although there were differences in RNA expression between exosomes from astrocytes and microglia, the groups were related by the hub genes, ubiquitin B and heat shock protein family A (Hsp70) member 8. Ubiquitin B appeared to be involved in pleiotropic regulatory functions, including immune regulation, inflammation inhibition, protein catabolism, intracellular protein transport, exosomes and oxidative stress. The results revealed the clinical significance of exosomes from glia in neurodegenerative diseases. This study was approved by the Animal Ethics Committee of Nantong University, China (approval No. S20180102-152) on January 2, 2018. Related Articles | Metrics

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Assessment of structural brain changes in patients with type 2 diabetes mellitus using the MRI-based brain atrophy and lesion index Heng Zhao, Fang Wang, Guang-Hua Luo, Hao Lei, Fei Peng, Qiu-Ping Ren, Wei Chen, Yan-Fang Wu, Li-Chun Yin, Jin-Cai Liu, Shi-Nong Pan 2022, 17 (3):  618-624.  doi: 10.4103/1673-5374.320996 Abstract ( 252 )   PDF (917KB) ( 170 )   Save Patients with type 2 diabetes mellitus (T2DM) often have cognitive impairment and structural brain abnormalities. The magnetic resonance imaging (MRI)-based brain atrophy and lesion index can be used to evaluate common brain changes and their correlation with cognitive function, and can therefore also be used to reflect whole-brain structural changes related to T2DM. A total of 136 participants (64 men and 72 women, aged 55–86 years) were recruited for our study between January 2014 and December 2016. All participants underwent MRI and Mini-Mental State Examination assessment (including 42 healthy control, 38 T2DM without cognitive impairment, 26 with cognitive impairment but without T2DM, and 30 T2DM with cognitive impairment participants). The total and sub-category brain atrophy and lesion index scores in patients with T2DM with cognitive impairment were higher than those in healthy controls. Differences in the brain atrophy and lesion index of gray matter lesions and subcortical dilated perivascular spaces were found between non-T2DM patients with cognitive impairment and patients with T2DM and cognitive impairment. After adjusting for age, the brain atrophy and lesion index retained its capacity to identify patients with T2DM with cognitive impairment. These findings suggest that the brain atrophy and lesion index, based on T1-weighted and T2-weighted imaging, is of clinical value for identifying patients with T2DM and cognitive impairment. Gray matter lesions and subcortical dilated perivascular spaces may be potential diagnostic markers of T2DM that is complicated by cognitive impairment. This study was approved by the Medical Ethics Committee of University of South China (approval No. USC20131109003) on November 9, 2013, and was retrospectively registered with the Chinese Clinical Trial Registry (registration No. ChiCTR1900024150) on June 27, 2019. Related Articles | Metrics

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Systemic epigallocatechin gallate protects against retinal degeneration and hepatic oxidative stress in the P23H-1 rat Lorena Perdices, Lorena Fuentes-Broto, Francisco Segura, Ana Cavero, Elvira Orduna-Hospital, Gema Insa-Sánchez, Ana Isabel Sánchez-Cano, Laura Fernández-Sánchez, Nicolás Cuenca, Isabel Pinilla 2022, 17 (3):  625-631.  doi: 10.4103/1673-5374.320990 Abstract ( 153 )   PDF (699KB) ( 159 )   Save Retinitis pigmentosa (RP) is a group of inherited retinal disorders that lead to photoreceptor loss. RP has been reported to be related to oxidative stress, autophagy, and inflammation. (-)-Epigallocatechin gallate (EGCG), the most abundant catechin-based flavonoid in green tea leaves, has significant antioxidant, anti-carcinogenic, antimicrobial, and neuroprotective properties. EGCG, given its low molecular weight and hydrophilic properties, can cross the blood-retinal barrier and is able to reach different ocular tissues such as the lens, cornea, and retina. EGCG has been shown to provide retinal protection against ischemia; sodium nitroprusside-, N-methyl-D-aspartate-, lipopolysaccharide-, light-, sodium iodate-, or H2O2-induced damage and diabetic retinopathy. This suggests that systemic EGCG administration has the potential to protect against retinal degenerative or neurodegenerative diseases such as RP. The aim of this work was to investigate whether EGCG can protect against RP progression in the animal P23H line 1, the model of RP. Albino P23H rats were crossed with pigmented Long Evans rats to produce offspring exhibiting the clinical features of RP. Pigmented P23H rats were treated via intraperitoneal injection with saline or EGCG at a dose of 25 mg/kg every week from P100 to P160 and then compared to wild-type Long Evans rats. Rats treated with EGCG showed better visual and retinal electrical function with increased contrast sensitivity and b-wave values compared with those observed in P23H rats treated with vehicle. EGCG reduced lipid peroxidation and increased total antioxidant capacity and catalase and superoxide dismutase activities. No differences were observed in visual acuity, nitrate levels, nitrite levels or glutathione S-transferase activity. In conclusion, EGCG not only reduced the loss of visual function in P23H rats but also improved the levels of antioxidant enzymes and reduced oxidative damage. This study was approved by the Institutional Animal Care and Use Committee (CEICA) from the University of Zaragoza under project license PI12/14 on July 11, 2014. Related Articles | Metrics

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Exploration of the mechanism by which icariin modulates hippocampal neurogenesis in a rat model of depression Ning-Xi Zeng, Hui-Zhen Li, Han-Zhang Wang, Kai-Ge Liu, Xia-Yu Gong, Wu-Long Luo, Can Yan, Li-Li Wu 2022, 17 (3):  632-642.  doi: 10.4103/1673-5374.320993 Abstract ( 346 )   PDF (12193KB) ( 128 )   Save Icariin (ICA) has a significant capacity to protect against depression and hippocampal injury, but it cannot effectively cross the blood-brain barrier and accumulate in the brain. Therefore, the mechanism by which ICA protects against hippocampal injury in depression remains unclear. In this study, we performed proteomics analysis of cerebrospinal fluid to investigate the mechanism by which ICA prevents dysfunctional hippocampal neurogenesis in depression. A rat model of depression was established through exposure to chronic unpredictable mild stress for 6 weeks, after which 120 mg/kg ICA was administered subcutaneously every day. The results showed that ICA alleviated depressive symptoms, learning and memory dysfunction, dysfunctional neurogenesis, and neuronal loss in the dentate gyrus of rats with depression. Neural stem cells from rat embryonic hippocampi were cultured in media containing 20% cerebrospinal fluid from each group of rats and then treated with 100 μM corticosterone. The addition of cerebrospinal fluid from rats treated with ICA largely prevented the corticosterone-mediated inhibition of neuronal proliferation and differentiation. Fifty-two differentially expressed proteins regulated by chronic unpredictable mild stress and ICA were identified through proteomics analysis of cerebrospinal fluid. These proteins were mainly involved in the ribosome, PI3K-Akt signaling, and interleukin-17 signaling pathways. Parallel reaction monitoring mass spectrometry showed that Rps4x, Rps12, Rps14, Rps19, Hsp90b1, and Hsp90aa1 were up-regulated by chronic unpredictable mild stress and down-regulated by ICA. In contrast, HtrA1 was down-regulated by chronic unpredictable mild stress and up-regulated by ICA. These findings suggest that ICA can prevent depression and dysfunctional hippocampal neurogenesis through regulating the expression of certain proteins found in the cerebrospinal fluid. The study was approved by the Experimental Animal Ethics Committee of Guangzhou University of Chinese Medicine of China in March 2017. Related Articles | Metrics

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Limitations in activities of daily living increase the risk of stroke in older Chinese adults: a population-based longitudinal study Zhuang-Sheng Wei, Yu-Sen Chen, Ying Wu, Chen-Yao Kang, Jia-Yuan Wu, Yu Yang, Hao Wu, Bin Zhao, Zhou Liu 2022, 17 (3):  643-648.  doi: 10.4103/1673-5374.320994 Abstract ( 149 )   PDF (1855KB) ( 116 )   Save It remains unclear whether limitations in activities of daily living (ADL) increase the risk of stroke in older Chinese adults. This longitudinal study used data from the Chinese Longitudinal Healthy Longevity Survey to investigate the effects of limitations in ADL on the incidence of stroke in older adults. Between 2002 and 2011, 46,728 participants from 22 provinces in China were included in this study. Of participants, 11,241 developed limitations in ADL at baseline. A 3-year follow-up was performed to determine the incidence of stroke. During the 3-year follow-up, 929 participants (8.26%) and 2434 participants (6.86%) experienced stroke in the ADL limitations group and non-ADL limitations group, respectively. Logistic regression was used to analyze the effect of ADL limitations on the risk of stroke. The results showed that after adjusting for the confounding factors gender, age, weight, hypertension, diabetes, heart disease, natural teeth, hearing impairment, visual impairment, smoking, alcohol abuse, exercise, ethnicity, literacy, residential area, and poverty, the ADL limitations group had a 77% higher risk of developing stroke than the non-ADL limitations group. After propensity score matching, the ADL limitations group still had a 33% higher risk of developing stroke than the non-ADL limitations group (OR = 1.326, 95% CI: 1.174–1.497). These findings suggest that limitations in ADL are a stroke risk factor. Related Articles | Metrics

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Lesion-induced changes of brevican expression in the perineuronal net of the superior vestibular nucleus Agnes Magyar, Eva Racz, Clara Matesz, Ervin Wolf, Peter Kiss, Botond Gaal 2022, 17 (3):  649-654.  doi: 10.4103/1673-5374.320988 Abstract ( 253 )   PDF (1643KB) ( 156 )   Save Damage to the vestibular sense organs evokes static and dynamic deficits in the eye movements, posture and vegetative functions. After a shorter or longer period of time, the vestibular function is partially or completely restored via a series of processes such as modification in the efficacy of synaptic inputs. As the plasticity of adult central nervous system is associated with the alteration of extracellular matrix, including its condensed form, the perineuronal net, we studied the changes of brevican expression in the perineuronal nets of the superior vestibular nucleus after unilateral labyrinth lesion. Our results demonstrated that the unilateral labyrinth lesion and subsequent compensation are accompanied by the changing of brevican staining pattern in the perineuronal nets of superior vestibular nucleus of the rat. The reduction of brevican in the perineuronal nets of superior vestibular nucleus may contribute to the vestibular plasticity by suspending the non-permissive role of brevican in the restoration of perineuronal net assembly. After a transitory decrease, the brevican expression restored to the control level parallel to the partial restoration of impaired vestibular function. The bilateral changing in the brevican expression supports the involvement of commissural vestibular fibers in the vestibular compensation. All experimental procedures were approved by the ‘University of Debrecen – Committee of Animal Welfare’ (approval No. 6/2017/DEMAB) and the ‘Scientific Ethics Committee of Animal Experimentation’ (approval No. HB/06/ÉLB/2270-10/2017; approved on June 6, 2017). Related Articles | Metrics

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Ultra-early amplitude decrement after repetitive nerve stimulation supports early neuromuscular junction injury in amyotrophic lateral sclerosis: a prospective cross-sectional study Jing-Yue Ma, Xiang-Yi Liu, Shuo Zhang, Dong-Sheng Fan 2022, 17 (3):  655-660.  doi: 10.4103/1673-5374.320998 Abstract ( 219 )   PDF (1045KB) ( 97 )   Save The dying-back hypothesis holds that the damage to neuromuscular junctions and distal axons in amyotrophic lateral sclerosis occurs at the earliest stage of the disease. Previous basic studies have confirmed early damage to neuromuscular junctions, but it is difficult to obtain such evidence directly in clinical practice. In this prospective cross-sectional study, we recruited 22 patients with early amyotrophic lateral sclerosis with disease duration < 12 months and with clinical symptoms limited to the upper limbs. We also recruited 32 healthy controls. Repetitive nerve stimulation was performed, and patients were followed for 12 months. We found a significant change in the response to repetitive nerve stimulation in amyotrophic lateral sclerosis patients without spontaneous electromyographic activity. Patients that were prone to denervation had an increased decrement response of target muscles after repetitive nerve stimulation. These results suggest that changes in response to repetitive nerve stimulation may occur before denervation in amyotrophic lateral sclerosis patients. The damage to lower motor neurons is more obvious in patients with a higher percentage of repetitive never stimulation-related amplitude decrements. This study was approved by the Institutional Ethics Committee of Peking University Third Hospital (approval No. M2017198) on August 24, 2017.  Related Articles | Metrics

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Krüppel-like factor 7 attenuates hippocampal neuronal injury after traumatic brain injury Wen-Yuan Li, Xiu-Mei Fu, Zhen-Dong Wang, Zhi-Gang Li, Duo Ma, Ping Sun, Gui-Bo Liu, Xiao-Feng Zhu, Ying Wang 2022, 17 (3):  661-672.  doi: 10.4103/1673-5374.320991 Abstract ( 166 )   PDF (23334KB) ( 29 )   Save Our previous study has shown that the transcription factor Krüppel-like factor 7 (KLF7) promotes peripheral nerve regeneration and motor function recovery after spinal cord injury. KLF7 also participates in traumatic brain injury, but its regulatory mechanisms remain poorly understood. In the present study, an HT22 cell model of traumatic brain injury was established by stretch injury and oxygen-glucose deprivation. These cells were then transfected with an adeno-associated virus carrying KLF7 (AAV-KLF7). The results revealed that, after stretch injury and oxygen-glucose deprivation, KLF7 greatly reduced apoptosis, activated caspase-3 and lactate dehydrogenase, downregulated the expression of the apoptotic markers B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax) and cleaved caspase-3, and increased the expression of βIII-tubulin and the antiapoptotic marker Bcl-2. Furthermore, KLF7 overexpression upregulated Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) phosphorylation in HT22 cells treated by stretch injury and oxygen-glucose deprivation. Immunoprecipitation assays revealed that KLF7 directly participated in the phosphorylation of STAT3. In addition, treatment with AG490, a selective inhibitor of JAK2/STAT3, weakened the protective effects of KLF7. A mouse controlled cortical impact model of traumatic brain injury was then established. At 30 minutes before modeling, AAV-KLF7 was injected into the ipsilateral lateral ventricle. The protein and mRNA levels of KLF7 in the hippocampus were increased at 1 day after injury and recovered to normal levels at 3 days after injury. KLF7 reduced ipsilateral hippocampal atrophy, decreased the injured cortex volume, downregulated Bax and cleaved caspase-3 expression, and increased the number of 5-bromo-2′-deoxyuridine-positive neurons and Bcl-2 protein expression. Moreover, KLF7 transfection greatly enhanced the phosphorylation of JAK2 and STAT3 in the ipsilateral hippocampus. These results suggest that KLF7 may protect hippocampal neurons after traumatic brain injury through activation of the JAK2/STAT3 signaling pathway. The study was approved by the Institutional Review Board of Mudanjiang Medical University, China (approval No. mdjyxy-2018-0012) on March 6, 2018. Related Articles | Metrics

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Role of microtubule dynamics in Wallerian degeneration and nerve regeneration after peripheral nerve injury Jingmin Liu, Lixia Li, Ying Zou, Lanya Fu, Xinrui Ma, Haowen Zhang, Yizhou Xu, Jiawei Xu, Jiaqi Zhang, Mi Li, Xiaofang Hu, Zhenlin Li, Xianghai Wang, Hao Sun, Hui Zheng, Lixin Zhu, Jiasong Guo 2022, 17 (3):  673-681.  doi: 10.4103/1673-5374.320997 Abstract ( 183 )   PDF (17081KB) ( 59 )   Save Wallerian degeneration, the progressive disintegration of distal axons and myelin that occurs after peripheral nerve injury, is essential for creating a permissive microenvironment for nerve regeneration, and involves cytoskeletal reconstruction. However, it is unclear whether microtubule dynamics play a role in this process. To address this, we treated cultured sciatic nerve explants, an in vitro model of Wallerian degeneration, with the microtubule-targeting agents paclitaxel and nocodazole. We found that paclitaxel-induced microtubule stabilization promoted axon and myelin degeneration and Schwann cell dedifferentiation, whereas nocodazole-induced microtubule destabilization inhibited these processes. Evaluation of an in vivo model of peripheral nerve injury showed that treatment with paclitaxel or nocodazole accelerated or attenuated axonal regeneration, as well as functional recovery of nerve conduction and target muscle and motor behavior, respectively. These results suggest that microtubule dynamics participate in peripheral nerve regeneration after injury by affecting Wallerian degeneration. This study was approved by the Animal Care and Use Committee of Southern Medical University, China (approval No. SMU-L2015081) on October 15, 2015. Related Articles | Metrics

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Mutations in GBA, SNCA, and VPS35 are not associated with Alzheimer’s disease in a Chinese population: a case-control study Ya-Fei Wen, Xue-Wen Xiao, Lu Zhou, Ya-Ling Jiang, Yuan Zhu, Li-Na Guo, Xin Wang, Hui Liu, Ya-Fang Zhou, Jun-Ling Wang, Xin-Xin Liao, Lu Shen, Bin Jiao 2022, 17 (3):  682-689.  doi: 10.4103/1673-5374.321000 Abstract ( 216 )   PDF (600KB) ( 200 )   Save SNCA, GBA, and VPS35 are three common genes associated with Parkinson’s disease. Previous studies have shown that these three genes may be associated with Alzheimer’s disease (AD). However, it is unclear whether these genes increase the risk of AD in Chinese populations. In this study, we used a targeted gene sequencing panel to screen all the exon regions and the nearby sequences of GBA, SNCA, and VPS35 in a cohort including 721 AD patients and 365 healthy controls from China. The results revealed that neither common variants nor rare variants of these three genes were associated with AD in a Chinese population. These findings suggest that the mutations in GBA, SNCA, and VPS35 are not likely to play an important role in the genetic susceptibility to AD in Chinese populations. The study was approved by the Ethics Committee of Xiangya Hospital, Central South University, China on March 9, 2016 (approval No. 201603198). Related Articles | Metrics

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OTX2 stimulates adult retinal ganglion cell regeneration Raoul Torero Ibad, Nicole Quenech’du, Alain Prochiantz, Kenneth L. Moya 2022, 17 (3):  690-696.  doi: 10.4103/1673-5374.320989 Abstract ( 236 )   PDF (6681KB) ( 149 )   Save Retinal ganglion cell (RGC) axons provide the only link between the light sensitive and photon transducing neural retina and visual centers of the brain. RGC axon degeneration occurs in a number of blinding diseases and the ability to stimulate axon regeneration from surviving ganglion cells could provide the anatomic substrate for restoration of vision. OTX2 is a homeoprotein transcription factor expressed in the retina and previous studies showed that, in response to stress, exogenous OTX2 increases the in vitro and in vivo survival of RGCs. Here we examined and quantified the effects of OTX2 on adult RGC axon regeneration in vitro and in vivo. The results show that exogenous OTX2 stimulates the regrowth of axons from RGCs in cultures of dissociated adult retinal cells and from explants of adult retinal tissue and that RGCs respond directly to OTX2 as regrowth is observed in cultures of purified adult rat RGCs. Importantly, after nerve crush in vivo, we observed a positive effect of OTX2 on the number of regenerating axons up to the optic chiasm within 14 days post crush and a very modest level of acuity absent in control mice. The effect of OTX2 on RGC survival and regeneration is of potential interest for degenerative diseases affecting this cell type. All animal procedures were approved by the local “Comié d’éιthique en expérimentation animale n°59” and authorization n° 00702.01 delivered March 28, 2014 by the French “Ministére de l’enseignement supérieur et de la recherche”. Related Articles | Metrics