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15 February 2020, Volume 15 Issue 2 Previous Issue    Next Issue

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Peripheral nerve injury induced changes in the spinal cord and strategies to counteract/enhance the changes to promote nerve regeneration Yan Liu, Huan Wang 2020, 15 (2):  189-198.  doi: 10.4103/1673-5374.265540 Abstract ( 123 )   PDF (320KB) ( 1080 )   Save Peripheral nerve injury leads to morphological, molecular and gene expression changes in the spinal cord and dorsal root ganglia, some of which have positive impact on the survival of neurons and nerve regeneration, while the effect of others is the opposite. It is crucial to take prompt measures to capitalize on the positive effects of these reactions and counteract the negative impact after peripheral nerve injury at the level of spinal cord, especially for peripheral nerve injuries that are severe, located close to the cell body, involve long distance for axons to regrow and happen in immature individuals. Early nerve repair, exogenous supply of neurotrophic factors and Schwann cells can sustain the regeneration inductive environment and enhance the positive changes in neurons. Administration of neurotrophic factors, acetyl-L-carnitine, N-acetyl-cysteine, and N-methyl-D-aspartate receptor antagonist MK-801 can help counteract axotomy-induced neuronal loss and promote regeneration, which are all time-dependent. Sustaining and reactivation of Schwann cells after denervation provides another effective strategy. FK506 can be used to accelerate axonal regeneration of neurons, especially after chronic axotomy. Exploring the axotomy-induced changes after peripheral nerve injury and applying protective and promotional measures in the spinal cord which help to retain a positive functional status for neuron cell bodies will inevitably benefit regeneration of the peripheral nerve and improve functional outcomes. Related Articles | Metrics

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Genetic targeting of astrocytes to combat neurodegenerative disease Rachel Kéry, Allen P. F. Chen, Gregory W. Kirschen 2020, 15 (2):  199-211.  doi: 10.4103/1673-5374.265541 Abstract ( 135 )   PDF (770KB) ( 309 )   Save orcid: 0000-0003-1371-8137 (Gregory W. Kirschen) Related Articles | Metrics

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Pathological significance of tRNA-derived small RNAs in neurological disorders Chuan Qin, Pei-Pei Xu, Xin Zhang, Chao Zhang, Chang-Bin Liu, De-Gang Yang, Feng Gao, Ming-Liang Yang, Liang-Jie Du, Jian-Jun Li 2020, 15 (2):  212-221.  doi: 10.4103/1673-5374.265560 Abstract ( 184 )   PDF (1430KB) ( 234 )   Save Non-coding RNAs (ncRNAs) are a type of RNA that is not translated into proteins. Transfer RNAs (tRNAs), a type of ncRNA, are the second most abundant type of RNA in cells. Recent studies have shown that tRNAs can be cleaved into a heterogeneous population of ncRNAs with lengths of 18–40 nucleotides, known as tRNA-derived small RNAs (tsRNAs). There are two main types of tsRNA, based on their length and the number of cleavage sites that they contain: tRNA-derived fragments and tRNA-derived stress-induced RNAs. These RNA species were first considered to be byproducts of tRNA random cleavage. However, mounting evidence has demonstrated their critical functional roles as regulatory factors in the pathophysiological processes of various diseases, including neurological diseases. However, the underlying mechanisms by which tsRNAs affect specific cellular processes are largely unknown. Therefore, this study comprehensively summarizes the following points: (1) The biogenetics of tsRNA, including their discovery, classification, formation, and the roles of key enzymes. (2) The main biological functions of tsRNA, including its miRNA-like roles in gene expression regulation, protein translation regulation, regulation of various cellular activities, immune mediation, and response to stress. (3) The potential mechanisms of pathophysiological changes in neurological diseases that are regulated by tsRNA, including neurodegeneration and neurotrauma. (4) The identification of the functional diversity of tsRNA may provide valuable information regarding the physiological and pathophysiological mechanisms of neurological disorders, thus providing a new reference for the clinical treatment of neurological diseases. Research into tsRNAs in neurological diseases also has the following challenges: potential function and mechanism studies, how to accurately quantify expression, and the exact relationship between tsRNA and miRNA. These challenges require future research efforts. Related Articles | Metrics

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Applications of advanced signal processing and machine learning in the neonatal hypoxic-ischemic electroencephalography Hamid Abbasi, Charles P. Unsworth 2020, 15 (2):  222-231.  doi: 10.4103/1673-5374.265542 Abstract ( 152 )   PDF (232KB) ( 294 )   Save Perinatal hypoxic-ischemic-encephalopathy significantly contributes to neonatal death and life-long disability such as cerebral palsy. Advances in signal processing and machine learning have provided the research community with an opportunity to develop automated real-time identification techniques to detect the signs of hypoxic-ischemic-encephalopathy in larger electroencephalography/amplitude-integrated electroencephalography data sets more easily. This review details the recent achievements, performed by a number of prominent research groups across the world, in the automatic identification and classification of hypoxic-ischemic epileptiform neonatal seizures using advanced signal processing and machine learning techniques. This review also addresses the clinical challenges that current automated techniques face in order to be fully utilized by clinicians, and highlights the importance of upgrading the current clinical bedside sampling frequencies to higher sampling rates in order to provide better hypoxic-ischemic biomarker detection frameworks. Additionally, the article highlights that current clinical automated epileptiform detection strategies for human neonates have been only concerned with seizure detection after the therapeutic latent phase of injury. Whereas recent animal studies have demonstrated that the latent phase of opportunity is critically important for early diagnosis of hypoxic-ischemic-encephalopathy electroencephalography biomarkers and although difficult, detection strategies could utilize biomarkers in the latent phase to also predict the onset of future seizures. Related Articles | Metrics

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Protective effect of hydrogen sulfide on oxidative stress-induced neurodegenerative diseases Rubaiya Tabassum, Na Young Jeong, Junyang Jung 2020, 15 (2):  232-241.  doi: 10.4103/1673-5374.265543 Abstract ( 311 )   PDF (2051KB) ( 172 )   Save Hydrogen sulfide is an antioxidant molecule that has a wide range of biological effects against oxidative stress. Balanced oxidative stress is also vital for maintaining cellular function in biological system, where reactive oxygen species are the main source of oxidative stress. When the normal redox balance is disturbed, deoxyribonucleic acid, lipid, and protein molecules are oxidized under pathological conditions, like diabetes mellitus that leads to diabetic peripheral neuropathy. In diabetes mellitus-induced diabetic peripheral neuropathy, due to hyperglycemia, pancreatic beta cell (β cell) shows resistance to insulin secretion. As a consequence, glucose metabolism is disturbed in neuronal cells which are distracted from providing proper cell signaling pathway. Not only diabetic peripheral neuropathy but also other central damages occur in brain neuropathy. Neurological studies regarding type 1 diabetes mellitus patients with Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis have shown changes in the central nervous system because high blood glucose levels (HbA1c) appeared with poor cognitive function. Oxidative stress plays a role in inhibiting insulin signaling that is necessary for brain function. Hydrogen sulfide exhibits antioxidant effects against oxidative stress, where cystathionine β synthase, cystathionine γ lyase, and 3-mercaptopyruvate sulfurtransferase are the endogenous sources of hydrogen sulfide. This review is to explore the pathogenesis of diabetes mellitus-induced diabetic peripheral neuropathy and other neurological comorbid disorders under the oxidative stress condition and the anti-oxidative effects of hydrogen sulfide. Related Articles | Metrics

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Current status and future prospects of stem cell therapy in Alzheimer’s disease Fu-Qiang Zhang, Jin-Lan Jiang, Jing-Tian Zhang, Han Niu, Xue-Qi Fu, Lin-Lin Zeng 2020, 15 (2):  242-250.  doi: 10.4103/1673-5374.265544 Abstract ( 258 )   PDF (1051KB) ( 226 )   Save Alzheimer’s disease is a common progressive neurodegenerative disorder, pathologically characterized by the presence of β-amyloid plaques and neurofibrillary tangles. Current treatment approaches using drugs only alleviate the symptoms without curing the disease, which is a serious issue and influences the quality of life of the patients and their caregivers. In recent years, stem cell technology has provided new insights into the treatment of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Currently, the main sources of stem cells include neural stem cells, embryonic stem cells, mesenchymal stem cells, and induced pluripotent stem cells. In this review, we discuss the pathophysiology and general treatment of Alzheimer’s disease, and the current state of stem cell transplantation in the treatment of Alzheimer’s disease. We also assess future challenges in the clinical application and drug development of stem cell transplantation as a treatment for Alzheimer’s disease. Related Articles | Metrics

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Pluripotent stem cell derived inhibitory interneurons – principles and applications in health and disease Francesca Keefe, Meng Li 2020, 15 (2):  251-252.  doi: 10.4103/1673-5374.265547 Abstract ( 128 )   PDF (687KB) ( 148 )   Save Inhibitory interneurons are gamma-aminobutyric acid-ergic (GABAergic) nerve cells that act to maintain the appropriate excitation-inhibition balance, and synchronise the output of principle cells to generate rhythmic patterns of firing (Kessaris et al., 2014). This critical role, along with their brain-wide distribution, has led to the implication of interneurons in many neuropathologies, including schizophrenia, autism, dystonia and epilepsies (Marín, 2012). This has in turn fuelled a growing interest into their investigation. The molecular and functional heterogeneities within this class of neurons have resulted in a complex multifactorial classification system to assign interneurons into multiple subtypes (Figure 1A). Our journey towards understanding the interneuron diversity behind the classification system has brought to light the following principles. First, the subtype reflects the birthplace of the interneuron. Within the developing brain, inhibitory interneurons are born within focal regions, including the caudal and medial ganglionic eminences (CGE and MGE, respectively). Fate-mapping experiments in rodents demonstrated that calretinin (CR), vasoactive intestinal peptide and reelin positive interneurons are predominantly derived from CGE progenitors. Whereas, somatostatin (SST) and parvalbumin (PV) subtypes are MGE-derived, with an apparent SST: PV ratio shift along the MGE dorsoventral gradient (Kessaris et al., 2014). Second, interneuron subtypes exhibit differential vulnerability in neurological diseases (Marín, 2012). Third, there are brain region-specific differences in interneuron subtype composition, which are also species-dependent (Wu and Parent, 2000). The significance of these findings is unclear, as the manner to which interneuron lineages are determined by intrinsic and extrinsic cues remains under investigation (Kessaris et al., 2014). Related Articles | Metrics

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Regulation of apoptosis in the ischemic penumbra in the first day post-stroke Anatoly B. Uzdensky 2020, 15 (2):  253-254.  doi: 10.4103/1673-5374.265546 Abstract ( 176 )   PDF (138KB) ( 175 )   Save Stroke is one of leading causes of human disability and death. More than 17 million stroke incidences occur in the world each year. In ischemic stroke (70–80% of all strokes) cerebral vessel occlusion quickly, for few minutes causes oxygen and glucose depletion, ATP deficit, and tissue infarction. It is impossible to rescue neurons in the infarction core. However, the injury propagates to neighboring tissues and forms the transition zone (ischemic penumbra) where cells are damaged slower, for several hours. Protection of penumbra cells and restriction of infarction volume are the main goals of neurologists (Nakka et al., 2008; Chen et al., 2011; Puyal et al., 2013). Despite testing of numerous pro-survival drugs such as glutamate antagonists, blockers of Ca2+ channels, antioxidants, and apoptosis inhibitors, an effective anti-stroke neuroprotector that can rescue neurons within first post-stroke hours is not found yet. Even drugs that protect the ischemic animal brain or cultured neurons in the experiments were either ineffective or caused unacceptable adverse effects in humans (Nakka et al., 2008; Puyal et al., 2013). Therefore, further studies of neurodegeneration and neuroprotection mechanisms in the ischemic penumbra are needed. Unlike ischemic core, where cells die mostly through necrosis, apoptosis prevails in the penumbra (Ferrer, 2006; Radak et al., 2017; Uzdensky, 2019). The dichotomy between necrosis in the infarction core and apoptosis in the penumbra is not strict. Sometimes the signs of apoptotic cell death are revealed in the infarction core. Related Articles | Metrics

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Novel pluripotent stem cell lines for enriched grafting in Parkinson’s disease Agustin Cota-Coronado, Lachlan H. Thompson, N. Emmanuel Diaz-Martinez 2020, 15 (2):  255-256.  doi: 10.4103/1673-5374.265548 Abstract ( 104 )   PDF (240KB) ( 164 )   Save Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting 1% of the population over 55 years of age and up to 4% of the population over 80 years of age (Blesa et al., 2012). This progressive and neurodegenerative condition results from an excessive loss of dopaminergic neurons (50–70%) of the substantia nigra pars compacta, leading to a significant decrease in dopamine (DA) levels in the striatum and consequently a functional deterioration of motor circuity (Blesa et al., 2012; Nielsen et al., 2016). The direct relationship between the loss of motor function and the degeneration of a single cell type makes PD an attractive prospect for cellular replacement therapy (Lindvall et al., 1990) and we are now on the verge of seeing the first clinical trials using human induced pluripotent stem cells (hiPSCs) as a source of transplantable dopamine neurons in clinical trials (Barker et al., 2017). The application of hiPSCs as a donor source for neural transplantation has progressed rapidly and may offer advantages over embryonic stem cells by avoiding ethical issues and potentially also complications related to immune response. Related Articles | Metrics

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Complement pathway in Alzheimer’s pathology and retinal neurodegenerative disorders – the road ahead. Mehdi Mirzaei, Liting Deng, Veer Bala Gupta, Stuart Graham, Vivek Gupta 2020, 15 (2):  257-258.  doi: 10.4103/1673-5374.265550 Abstract ( 95 )   PDF (112KB) ( 167 )   Save Chronic inflammation has increasingly been acknowledged as a hallmark feature of several progressive neurodegenerative disorders. Accruing evidence indicates that sustained inflammation compromises the core neuroprotective mechanisms underlying neural injury in Alzheimer’s disease (AD) and retinal neurodegenerative disorders. Innate immunity and activation of the classical complement pathways are suggested to play important roles in normal central nervous system physiology and complex tissue remodeling during the disease process (Gasque et al., 2000). The pathway is implicated in normal brain development and is also involved in the inflammatory response in a wide range of neurodegenerative conditions either directly or indirectly through recruitment and activation of immune cells. The classical, alternative and lectin complement pathways, together encompass about 30 plasma and membrane-bound proteins. The classical pathway is comprised of about 20 proteins including several serine proteinases and proteinase inhibitors connected as part of an amplifying cascade. Activation of the classical pathway is triggered once C1q is attached to the immune complexes containing IgG or IgM leading to production of the C3 convertase Related Articles | Metrics

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Increased intron retention is linked to Alzheimer’s disease Chin-Tong Ong, Swarnaseetha Adusumalli 2020, 15 (2):  259-260.  doi: 10.4103/1673-5374.265549 Abstract ( 100 )   PDF (494KB) ( 194 )   Save AD is an age-related neurodegenerative disorder with pathological accumulation of amyloid plaque (Masters et al., 2015), which can be classified into familial and sporadic form. In familial AD, mutations in genes encoding either amyloid precursor protein or presenilin (PS1 and PS2) cause overproduction of amyloid-42 molecules and early onset of dementia. Late-onset sporadic AD, which accounts for majority of the cases (> 95%), is characterized by high degree of genetic and pathological heterogeneity. Although aging and genetic variants are two risks factors for sporadic AD, it remains unclear how epigenetic alterations during aging may contribute to its etiology. To determine the transcriptional changes that are associated with aging, we analyzed the transcriptome of head or brain tissues isolated at different ages from adult Drosophila, mice and human (Adusumalli et al., 2019). We observed an increase in the level of intron retention (IR) in the mRNA transcripts during aging across different species. These retained introns share highly conserved features and surprisingly, do not affect the expression level of their mRNA transcripts. As many age-dependent IR mRNA transcripts overlapped with curated AD genes, we further compared the IR patterns in the frontal cortex and cerebellum isolated from large AD cohorts with their age-matched controls. Consistent with reports of aberrant splicing in AD (Tollervey et al., 2011; Bai et al., 2013; Raj et al., 2018), we found a significant increase in the rate of IR at genes that are involved in RNA processing and protein homeostasis in AD samples. Furthermore, many of these IR genes showed significant changes in their protein levels when compared to age-matched controls. Taken together, our findings suggest that increased IR is a transcriptional signature that is conserved across species during aging and may be linked to AD progression. Related Articles | Metrics

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Determining the mechanism behind yoga’s effects on preventing the symptoms of Alzheimer’s disease Adithy Hassan, Meghan Robinson, Stephanie M. Willerth 2020, 15 (2):  261-262.  doi: 10.4103/1673-5374.265553 Abstract ( 95 )   PDF (264KB) ( 183 )   Save Dementia refers to a variety of conditions that affect the normal function of the brain, leading to symptoms like memory loss, issues with problem solving, difficulty in processing thoughts and disordered language (McKhann et al., 2011). AD serves as one of the major causes of dementia as it is responsible for ~80% of its cases according to the Alzheimer’s Association. AD affects the ability of neurons, the major information transmitting cells of both the peripheral and central nervous system, to send and receive signals through the body, leading to the aforementioned symptoms associated with dementia. The biological hallmarks of AD include the presence of amyloid beta (Aβ) plaques as well as neurofibrillary tangles containing a protein called tau (Lane et al., 2018). These proteins disrupt the normal function of neurons through a variety of mechanisms. In particular, AD first results in a loss of a specific neuronal subtype – the cholinergic neurons found in the basal forebrain - by reducing the expression levels of choline acetyltransferase. This enzyme breaks down acetylcholine, a neurotransmitter expressed in the neuromuscular junction, resulting in the loss of normal brain function. This loss of acetylcholine in AD patients was first noted in the late 1970s, and is now known to correlate with reduced cortical choline acetyltransferase, the enzyme responsible for synthesizing acetycholine from choline, which in turn correlates with neuritic plaque numbers and reduced Mini-Mental State Exam scores (Gauthier, 2002). Currently available pharmacological treatments for AD focus on inhibiting the loss of choline acetyltransferase, but do not represent a longterm cure. Related Articles | Metrics

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Ependymal cells and multiple sclerosis: proposing a relationship Dale Hatrock, Nina Caporicci-Dinucci, Jo Anne Stratton 2020, 15 (2):  263-264.  doi: 10.4103/1673-5374.265551 Abstract ( 86 )   PDF (468KB) ( 257 )   Save Multiple sclerosis (MS) currently affects ~2.5 million people worldwide. MS is typically diagnosed in young adults and is usually not fatal, meaning people live long lives with MS. Affected individuals usually suffer from progressive physical and/or cognitive disability, often including fatigue (89.6%), depression (53.9%), memory loss (49.0%), motor or sensory dysfunction (76.4%, 70.4%) and urinary incontinence (50.8%). This disability weighs on patients, loved ones and caretakers, and costs the economy billions of dollars each year. Related Articles | Metrics

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Genetic testing in neurology exploiting next generation sequencing: state of art. Chiara Di Resta, Maurizio Ferrari 2020, 15 (2):  265-266.  doi: 10.4103/1673-5374.265554 Abstract ( 108 )   PDF (228KB) ( 156 )   Save Next generations sequencing (NGS) is definitely one of the most revolutionary technology of the last years in genetic and medical field (Kricka and Di Resta, 2013). It brought important changes in genetic testing of inherited human disorders, in particular in neurological Mendelian forms, such as inherited neuropathies, ataxias or monogenic form of epilepsy, where “diagnostic odyssey” is quite common. This term refers to the single-gene test approach where patients are evaluated by multiple providers, sometimes for years, without a genetic diagnosis (Di Resta et al., 2018). Indeed, in the Sanger sequencing era, neurologists were quite frustrated by the low diagnostic yield obtained by testing selected candidate genes, also due to the difficulties in differentiating genetic forms from acquired one, having the same clinical manifestations. In this context, clinicians had to pick a candidate gene to analyze and the gene-by-gene sequencing approach was not economical or efficient (Di Resta et al., 2018). Related Articles | Metrics

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Metabolic checkpoints in neurodegenerative T helper 17 (TH17) and neuroregenerative regulatory T (Treg) cells as new therapeutic targets for multiple sclerosis Hongxing Shen, James A. Bonner, Lewis Zhichang Shi 2020, 15 (2):  267-269.  doi: 10.4103/1673-5374.265552 Abstract ( 117 )   PDF (772KB) ( 181 )   Save The central nervous system (CNS) is an immune-privileged site with tightly-regulated immune responses, a concept proposed by Nobel Laureate Sir Peter Medawar in 1960. Under physiological conditions, only a few T lymphocytes conducting immunosurveillance can infiltrate the CNS. However, in neurodegenerative pathology such as multiple sclerosis (MS), a devastating inflammatory demyelinating disease, transmigration of encephalitogenic T cells from the periphery to the CNS is evident, contributing to the etiology of MS. Among the encephalitogenic T cells, in recent years, interleukin-17-producing T helper 17 (TH17) cells have attracted intensive research interests because of their superior ability to induce MS, as compared to the interferon-γ-producing T helper 1 (TH1) cells that had long been regarded as the primary culprit in the pathogenesis of MS, prior to the discovery of TH17 cells in 2005. An early study showed that C-C chemokine receptor 6 (CCR6)+ TH17 cells are the first encephalitogenic T cells to infiltrate the CNS, which leads to the second wave of infiltration by other neuroinflammatory immune cells including TH1 cells (Reboldi et al., 2009). These T cells drive the development of clinical signs of MS. Conversely, forkhead box P3 (Foxp3)+ regulatory T (Treg) cells suppress TH17 and TH1 cells, mitigating neuroinflammation in MS. Intriguingly, a recent study showed that Treg cells can actually promote remyelination, a key event in neural regeneration (Dombrowski et al., 2017). Analogous to the well-established dichotomy of TH1 and interleukin-4-producing T helper 2 cells, TH17 and Treg cells are considered dichotomous cell fates of activated CD4+ T cells, because of the intimate physical and functional interactions of their master transcriptional factors (retineic-acid-receptor-related orphan nuclear receptor-γ (RORγt) and Foxp3) and the dynamic two-way transdifferentiation between them in various pathogenic conditions. While immune signals (TCR ligation, CD28-mediated co-stimulation, and cytokine) seemingly orchestrate the differentiation of these T cell subsets, an emerging frontier in immunology research is the realization that at a fundamental level, it is the cellular metabolism that dictates the T cell fate decisions including TH17 vs. Treg. To this end, TH17 cells primarily engage glycolysis and fatty acid synthesis (FAS), while Treg cells mainly use oxidative phosphorylation and fatty acid oxidation (FAO) to satisfy their bioenergetic and biosynthetic demands. This suggests that targeting these metabolic pathways may offer a legitimate approach to cure MS by suppressing neurodegenerative TH17 and concomitantly promoting neuroregenerative Treg cells. Thus, in this perspective, we focus on metabolic checkpoints capable of tipping the TH17/Treg balance in favor of Treg formation. Related Articles | Metrics

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Differential expression of glial cell line-derived neurotrophic factor splice variants in the mouse brain Xiao-He Gu, Heng Li, Lin Zhang, Tao He, Xiang Chai, He Wei, Dian-Shuai Gao 2020, 15 (2):  270-276.  doi: 10.4103/1673-5374.265561 Abstract ( 111 )   PDF (1177KB) ( 176 )   Save Glial cell line-derived neurotrophic factor (GDNF) plays a critical role in neuronal survival and function. GDNF has two major splice variants in the brain, α-pro-GDNF and β-pro-GDNF, and both isoforms have strong neuroprotective effects on dopamine neurons. However, the expression of the GDNF splice variants in dopaminergic neurons in the brain remains unclear. Therefore, in this study, we investigated the mRNA and protein expression of α- and β-pro-GDNF in the mouse brain by real-time quantitative polymerase chain reaction, using splice variant-specific primers, and western blot analysis. At the mRNA level, β-pro-GDNF expression was significantly greater than that of α-pro-GDNF in the mouse brain. In contrast, at the protein level, α-pro-GDNF expression was markedly greater than that of β-pro-GDNF. To clarify the mechanism underlying this inverse relationship in mRNA and protein expression levels of the GDNF splice variants, we analyzed the expression of sorting protein-related receptor with A-type repeats (SorLA) by real-time quantitative polymerase chain reaction. At the mRNA level, SorLA was positively associated with β-pro-GDNF expression, but not with α-pro-GDNF expression. This suggests that the differential expression of α- and β-pro-GDNF in the mouse brain is related to SorLA expression. As a sorting protein, SorLA could contribute to the inverse relationship among the mRNA and protein levels of the GDNF isoforms. This study was approved by the Animal Ethics Committee of Xuzhou Medical University, China on July 14, 2016. Related Articles | Metrics

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Neuroprotective mechanism of TMP269, a selective class IIA histone deacetylase inhibitor, after cerebral ischemia/reperfusion injury Lu Su, Dan Liang, Shen-Yi Kuang, Qiang Dong, Xiang Han, Zheng Wang 2020, 15 (2):  277-284.  doi: 10.4103/1673-5374.265562 Abstract ( 137 )   PDF (3868KB) ( 169 )   Save TMP269 is a selective class IIA histone deacetylase inhibitor that has a protective effect on the central nervous system, whose specific mechanism of action is unclear. We aimed to reveal the optimal concentration of TMP269 for protecting against cerebral ischemia/reperfusion injury and its neuroprotective mechanism. Male Sprague-Dawley rats were randomly divided into sham, ischemia/reperfusion, and 1, 4, 10 and 16 mg/kg TMP269 groups. Cerebral ischemia/reperfusion injury was induced by middle cerebral artery occlusion. TMP269 was intraperitoneally administered at different doses 0.5 hours before ischemia induction. Western blot assay and immunohistochemistry were used to detect effects of TMP269 on histone 2 acetylation. The results showed that the level of histone 2 acetylation was increased 24 hours after TMP269 injection. 2,3,5-Triphenyltetrazolium chloride staining was utilized to examine effect of TMP269 on infarct volume. The results found that different doses of TMP269 could reduce the infarct volume. Western blot assay, immunohistochemistry and Evans blue staining were employed to measure the effect of TMP269 on blood-brain barrier. The results showed that TMP269 counteracted the abnormal endothelial cell permeability changes caused by cerebral ischemia/reperfusion. Western blot assay and immunohistochemistry were used to determine the effect of TMP269 on tissue kallikrein. The results found that TMP269 up-regulated the expression of tissue kallikrein. Western blot assay further determined the optimal concentration to be 4 mg/kg. In conclusion, TMP269 plays a neuroprotective role by up-regulating the level of histone 2 acetylation, alleviating endothelial cell injury after cerebral ischemia/reperfusion, and up-regulating the expression of tissue kallikrein. The experimental protocol was approved in 2014 by the Department of Laboratory Animal Science, Fudan University, China (approval No. 20140143C001). Related Articles | Metrics

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Alteration of functional connectivity in patients with Alzheimer’s disease revealed by resting-state functional magnetic resonance imaging Jie Zhao, Yu-Hang Du, Xue-Tong Ding, Xue-Hu Wang, Guo-Zun Men 2020, 15 (2):  285-292.  doi: 10.4103/1673-5374.265566 Abstract ( 147 )   PDF (2783KB) ( 190 )   Save The main symptom of patients with Alzheimer’s disease is cognitive dysfunction. Alzheimer’s disease is mainly diagnosed based on changes in brain structure. Functional connectivity reflects the synchrony of functional activities between non-adjacent brain regions, and changes in functional connectivity appear earlier than those in brain structure. In this study, we detected resting-state functional connectivity changes in patients with Alzheimer’s disease to provide reference evidence for disease prediction. Functional magnetic resonance imaging data from patients with Alzheimer’s disease were used to show whether particular white and gray matter areas had certain functional connectivity patterns and if these patterns changed with disease severity. In nine white and corresponding gray matter regions, correlations of normal cognition, early mild cognitive impairment, and late mild cognitive impairment with blood oxygen level-dependent signal time series were detected. Average correlation coefficient analysis indicated functional connectivity patterns between white and gray matter in the resting state of patients with Alzheimer’s disease. Functional connectivity pattern variation correlated with disease severity, with some regions having relatively strong or weak correlations. We found that the correlation coefficients of five regions were 0.3–0.5 in patients with normal cognition and 0–0.2 in those developing Alzheimer’s disease. Moreover, in the other four regions, the range increased to 0.45–0.7 with increasing cognitive impairment. In some white and gray matter areas, there were specific connectivity patterns. Changes in regional white and gray matter connectivity patterns may be used to predict Alzheimer’s disease; however, detailed information on specific connectivity patterns is needed. All study data were obtained from the Alzheimer’s Disease Neuroimaging Initiative Library of the Image and Data Archive Database. Related Articles | Metrics

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Action of trichostatin A on Alzheimer’s disease-like pathological changes in SH-SY5Y neuroblastoma cells Li-Hua Li, Wen-Na Peng, Yu Deng, Jing-Jing Li, Xiang-Rong Tian 2020, 15 (2):  293-301.  doi: 10.4103/1673-5374.265564 Abstract ( 187 )   PDF (2932KB) ( 210 )   Save The histone deacetylase inhibitor, trichostatin A, is used to treat Alzheimer’s disease and can improve learning and memory but its underlying mechanism of action is unknown. To determine whether the therapeutic effect of trichostatin A on Alzheimer’s disease is associated with the nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like epichlorohydrin-related protein-1 (Keap1) signaling pathway, amyloid β-peptide 25–35 (Aβ25–35) was used to induce Alzheimer’s disease-like pathological changes in SH-SY5Y neuroblastoma cells. Cells were then treated with trichostatin A. The effects of trichostatin A on the expression of Keap1 and Nrf2 were detected by real-time quantitative polymerase chain reaction, western blot assays and immunofluorescence. Total antioxidant capacity and autophagy activity were evaluated by total antioxidant capacity assay kit and light chain 3-I/II levels, respectively. We found that trichostatin A increased cell viability and Nrf2 expression, and decreased Keap1 expression in SH-SY5Y cells. Furthermore, trichostatin A increased the expression of Nrf2-related target genes, such as superoxide dismutase, NAD(P)H quinone dehydrogenase 1 and glutathione S-transferase, thereby increasing the total antioxidant capacity of SH-SY5Y cells and inhibiting amyloid β-peptide-induced autophagy. Knockdown of Keap1 in SH-SY5Y cells further increased trichostatin A-induced Nrf2 expression. These results indicate that the therapeutic effect of trichostatin A on Alzheimer’s disease is associated with the Keap1-Nrf2 pathway. The mechanism for this action may be that trichostatin A increases cell viability and the antioxidant capacity of SH-SY5Y cells by alleviating Keap1-mediated inhibition Nrf2 signaling, thereby alleviating amyloid β-peptide-induced cell damage. Related Articles | Metrics

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Identification of protein targets for the antidepressant effects of Kai-Xin-San in Chinese medicine using isobaric tags for relative and absolute quantitation Xian-Zhe Dong, Dong-Xiao Wang, Tian-Yi Zhang, Xu Liu, Ping Liu, Yuan Hu 2020, 15 (2):  302-310.  doi: 10.4103/1673-5374.265555 Abstract ( 125 )   PDF (2311KB) ( 230 )   Save Kai-Xin-San consists of Ginseng Radix, Polygalae Radix, Acori Tatarinowii Rhizoma, and Poria at a ratio of 3:3:2:2. Kai-Xin-San has been widely used for the treatment of emotional disorders in China. However, no studies have identified the key proteins implicated in response to Kai-Xin-San treatment. In this study, rat models of chronic mild stress were established using different stress methods over 28 days. After 14 days of stress stimulation, rats received daily intragastric administrations of 600 mg/kg Kai-Xin-San. The sucrose preference test was used to determine depression-like behavior in rats, while isobaric tags were used for relative and absolute quantitation-based proteomics to identify altered proteins following Kai-Xin-San treatment. Kai-Xin-San treatment for 2 weeks noticeably improved depression-like behaviors in rats with chronic mild stress. We identified 33 differentially expressed proteins: 7 were upregulated and 26 were downregulated. Functional analysis showed that these differentially expressed proteins participate in synaptic plasticity, neurodevelopment, and neurogenesis. Our results indicate that Kai-Xin-San has an important role in regulating the key node proteins in the synaptic signaling network, and are helpful to better understand the mechanism of the antidepressive effects of Kai-Xin-San and to provide objective theoretical support for its clinical application. The study was approved by the Ethics Committee for Animal Research from the Chinese PLA General Hospital (approval No. X5-2016-07) on March 5, 2016. Related Articles | Metrics

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Is there a relationship between dopamine and rhegmatogenous retinal detachment? Alessio Martucci , Massimo Cesareo, Maria Dolores Pinazo-Durán, Michela Di Pierro, Matteo Di Marino, Carlo Nucci, Massimiliano Coletta, Raffaele Mancino 2020, 15 (2):  311-314.  doi: 10.4103/1673-5374.265559 Abstract ( 176 )   PDF (281KB) ( 167 )   Save Dopamine and its receptors have been widely studied in the neurological conditions and in the retina. In this study, we evaluated the possible role of dopamine in rhegmatogenous retinal detachment (RRD) by comparing the amount of 3,4-dihydroxyphenylacetic acid (DOPAC), a surrogate index of retinal dopamine levels, in the vitreous sample of patients affected by RRD with those affected by macular pucker and vitreous hemorrhage. Our results showed that significantly higher levels of DOPAC were found in the vitreous sample of patients affected by RRD compared with those affected by vitreous hemorrhage and macular pucker (P = 0.002). Specifically, no trace of the substance was found in vitreous hemorrhage and macular pucker samples. A slightly significant positive correlation was found among DOPAC and post-operative best corrected visual acuity (r = 0.470, P = 0.049). No correlation was found between DOPAC and the days elapsed between diagnosis and surgery (P = 0.317). For the first time our findings suggest that DOPAC is released in RRD, but not in other retinal diseases such as vitreous hemorrhage and macular pucker. Moreover, we showed a correlation between visual acuity outcome and the amount of DOPAC in the vitreous. This might have a potential, although still unknown, implication in the pathogenesis of the disease and/or in the associated photoreceptors loss. This study was approved by the Ethics Committee of Rome Tor Vergata University Hospital (R.S.92.10) on September 24, 2010. Related Articles | Metrics

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Different protein expression patterns in rat spinal nerves during Wallerian degeneration assessed using isobaric tags for relative and absolute quantitation proteomics profiling Shuai Wei, Xue-Zhen Liang, Qian Hu, Wei-Shan Wang, Wen-Jing Xu, Xiao-Qing Cheng, Jiang Peng, Quan-Yi Guo, Shu-Yun Liu, Wen Jiang, Xiao Ding, Gong-Hai Han, Ping Liu, Chen-Hui Shi, Yu Wang 2020, 15 (2):  315-323.  doi: 10.4103/1673-5374.265556 Abstract ( 151 )   PDF (2381KB) ( 213 )   Save Sensory and motor nerve fibers of peripheral nerves have different anatomies and regeneration functions after injury. To gain a clear understanding of the biological processes behind these differences, we used a labeling technique termed isobaric tags for relative and absolute quantitation to investigate the protein profiles of spinal nerve tissues from Sprague-Dawley rats. In response to Wallerian degeneration, a total of 626 proteins were screened in sensory nerves, of which 368 were upregulated and 258 were downregulated. In addition, 637 proteins were screened in motor nerves, of which 372 were upregulated and 265 were downregulated. All identified proteins were analyzed using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of bioinformatics, and the presence of several key proteins closely related to Wallerian degeneration were tested and verified using quantitative real-time polymerase chain reaction analyses. The differentially expressed proteins only identified in the sensory nerves were mainly relevant to various biological processes that included cell-cell adhesion, carbohydrate metabolic processes and cell adhesion, whereas differentially expressed proteins only identified in the motor nerves were mainly relevant to biological processes associated with the glycolytic process, cell redox homeostasis, and protein folding. In the aspect of the cellular component, the differentially expressed proteins in the sensory and motor nerves were commonly related to extracellular exosomes, the myelin sheath, and focal adhesion. According to the Kyoto Encyclopedia of Genes and Genomes, the differentially expressed proteins identified are primarily related to various types of metabolic pathways. In conclusion, the present study screened differentially expressed proteins to reveal more about the differences and similarities between sensory and motor nerves during Wallerian degeneration. The present findings could provide a reference point for a future investigation into the differences between sensory and motor nerves in Wallerian degeneration and the characteristics of peripheral nerve regeneration. The study was approved by the Ethics Committee of the Chinese PLA General Hospital, China (approval No. 2016-x9-07) in September 2016. Related Articles | Metrics

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Bone marrow-derived mesenchymal stem cell transplantation attenuates overexpression of inflammatory mediators in rat brain after cardiopulmonary resuscitation Qing-Ming Lin, Xia-Hong Tang, Shi-Rong Lin, Ben-Dun Chen, Feng Chen 2020, 15 (2):  324-331.  doi: 10.4103/1673-5374.265563 Abstract ( 130 )   PDF (1806KB) ( 206 )   Save Emerging evidence suggests that bone marrow-derived mesenchymal stem cell transplantation improves neurological function after cardiac arrest and cardiopulmonary resuscitation; however, the precise mechanisms remain unclear. This study aimed to investigate the effect of bone marrow-derived mesenchymal stem cell treatment on expression profiles of multiple cytokines in the brain after cardiac arrest and cardiopulmonary resuscitation. Cardiac arrest was induced in rats by asphyxia and cardiopulmonary resuscitation was initiated 6 minutes after cardiac arrest. One hour after successful cardiopulmonary resuscitation, rats were injected with either phosphate-buffered saline (control) or 1 × 106 bone marrow-derived mesenchymal stem cells via the tail vein. Serum S100B levels were measured by enzyme-linked immunosorbent assay and neurological deficit scores were evaluated to assess brain damage at 3 days after cardiopulmonary resuscitation. Serum S100B levels were remarkably decreased and neurological deficit scores were obviously improved in the mesenchymal stem cell group compared with the phosphate-buffered saline group. Brains were isolated from the rats and expression levels of 90 proteins were determined using a RayBio Rat Antibody Array, to investigate the cytokine profiles. Brain levels of the inflammatory mediators tumor necrosis factor-α, interferon-γ, macrophage inflammatory protein-1α, macrophage inflammatory protein-2, macrophage inflammatory protein-3α, macrophage-derived chemokine, and matrix metalloproteinase-2 were decreased ≥ 1.5-fold, while levels of the anti-inflammatory factor interleukin-10 were increased ≥ 1.5-fold in the mesenchymal stem cell group compared with the control group. Donor mesenchymal stem cells were detected by immunofluorescence to determine their distribution in the damaged brain, and were primarily observed in the cerebral cortex. These results indicate that bone marrow-derived mesenchymal stem cell transplantation attenuates brain damage induced by cardiac arrest and cardiopulmonary resuscitation, possibly via regulation of inflammatory mediators. This experimental protocol was approved by the Institutional Animal Care and Use Committee of Fujian Medical University, China in January 2016 (approval No. 2016079). Related Articles | Metrics

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Possible mechanisms of lycopene amelioration of learning and memory impairment in rats with vascular dementia Ning-Wei Zhu, Xiao-Lan Yin, Ren Lin, Xiao-Lan Fan, Shi-Jie Chen, Yuan-Ming Zhu, Xiao-Zhen Zhao 2020, 15 (2):  332-341.  doi: 10.4103/1673-5374.265565 Abstract ( 121 )   PDF (8010KB) ( 32 )   Save Oxidative stress is involved in the pathogenesis of vascular dementia. Studies have shown that lycopene can significantly inhibit oxidative stress; therefore, we hypothesized that lycopene can reduce the level of oxidative stress in vascular dementia. A vascular dementia model was established by permanent bilateral ligation of common carotid arteries. The dosage groups were treated with lycopene (50, 100 and 200 mg/kg) every other day for 2 months. Rats without bilateral carotid artery ligation were prepared as a sham group. To test the ability of learning and memory, the Morris water maze was used to detect the average escape latency and the change of search strategy. Hematoxylin- eosin staining was used to observe changes of hippocampal neurons. The levels of oxidative stress factors, superoxide dismutase and malondialdehyde, were measured in the hippocampus by biochemical detection. The levels of reactive oxygen species in the hippocampus were observed by dihydroethidium staining. The distribution and expression of oxidative stress related protein, neuron-restrictive silencer factor, in hippocampal neurons were detected by immunofluorescence histochemistry and western blot assays. After 2 months of drug administration, (1) in the model group, the average escape latency was longer than that of the sham group, and the proportion of straight and tend tactics was lower than that of the sham group, and the hippocampal neurons were irregularly arranged and the cytoplasm was hyperchromatic. (2) The levels of reactive oxygen species and malondialdehyde in the hippocampus of the model group rats were increased, and the activity of superoxide dismutase was decreased. (3) Lycopene (50, 100 and 200 mg/kg) intervention improved the above changes, and the lycopene 100 mg/kg group showed the most significant improvement effect. (4) Neuron-restrictive silencer factor expression in the hippocampus was lower in the sham group and the lycopene 100 mg/kg group than in the model group. (5) The above data indicate that lycopene 100 mg/kg could protect against the learning-memory ability impairment of vascular dementia rats. The protective mechanism was achieved by inhibiting oxidative stress in the hippocampus. The experiment was approved by the Animal Ethics Committee of Fujian Medical University, China (approval No. 2014-025) in June 2014. Related Articles | Metrics

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Differential neuronal reprogramming induced by NeuroD1 from astrocytes in grey matter versus white matter Min-Hui Liu, Wen Li, Jia-Jun Zheng, Yu-Ge Xu, Qing He, Gong Chen 2020, 15 (2):  342-351.  doi: 10.4103/1673-5374.265185 Abstract ( 190 )   PDF (9047KB) ( 28 )   Save A new technology called in vivo glia-to-neuron conversion has emerged in recent years as a promising next generation therapy for neural regeneration and repair. This is achieved through reprogramming endogenous glial cells into neurons in the central nervous system through ectopically expressing neural transcriptional factors in glial cells. Previous studies have been focusing on glial cells in the grey matter such as the cortex and striatum, but whether glial cells in the white matter can be reprogrammed or not is unknown. To address this fundamental question, we express NeuroD1 in the astrocytes of both grey matter (cortex and striatum) and white matter (corpus callosum) to investigate the conversion efficiency, neuronal subtypes, and electrophysiological features of the converted neurons. We discover that NeuroD1 can efficiently reprogram the astrocytes in the grey matter into functional neurons, but the astrocytes in the white matter are much resistant to neuronal reprogramming. The converted neurons from cortical and striatal astrocytes are composed of both glutamatergic and GABAergic neurons, capable of firing action potentials and having spontaneous synaptic activities. In contrast, the few astrocyte-converted neurons in the white matter are rather immature with rare synaptic events. These results provide novel insights into the differential reprogramming capability between the astrocytes in the grey matter versus the white matter, and highlight the impact of regional astrocytes as well as microenvironment on the outcome of glia-toneuron conversion. Since human brain has large volume of white matter, this study will provide important guidance for future development of in vivo glia-to-neuron conversion technology into potential clinical therapies. Experimental protocols in this study were approved by the Laboratory Animal Ethics Committee of Jinan University (approval No. IACUC-20180321-03) on March 21, 2018. Related Articles | Metrics

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Endothelin increases the proliferation of rat olfactory mucosa cells Bertrand Bryche, Audrey Saint-Albin, Claire Le Poupon Schlegel, Christine Baly, Patrice Congar, Nicolas Meunier 2020, 15 (2):  352-360.  doi: 10.4103/1673-5374.265558 Abstract ( 97 )   PDF (4040KB) ( 170 )   Save The olfactory mucosa holds olfactory sensory neurons directly in contact with an aggressive environment. In order to maintain its integrity, it is one of the few neural zones which are continuously renewed during the whole animal life. Among several factors regulating this renewal, endothelin acts as an anti-apoptotic factor in the rat olfactory epithelium. In the present study, we explored whether endothelin could also act as a proliferative factor. Using primary culture of the olfactory mucosa, we found that an early treatment with endothelin increased its growth. Consistently, a treatment with a mixture of BQ123 and BQ788 (endothelin receptor antagonists) decreased the primary culture growth without affecting the cellular death level. We then used combined approaches of calcium imaging, reverse transcriptase-quantitative polymerase chain reaction and protein level measurements to show that endothelin was locally synthetized by the primary culture until it reached confluency. Furthermore, in vivo intranasal instillation of endothelin receptor antagonists led to a decrease of olfactory mucosa cell expressing proliferating cell nuclear antigen (PCNA), a marker of proliferation. Only short-term treatment reduced the PCNA level in the olfactory mucosa cells. When the treatment was prolonged, the PCNA level was not statistically affected but the expression level of endothelin was increased. Overall, our results show that endothelin plays a proliferative role in the olfactory mucosa and that its level is dynamically regulated. This study was approved by the Comité d’éthique en expérimentation animale COMETHEA (COMETHEA C2EA -45; protocol approval #12-058) on November 28, 2012. Related Articles | Metrics

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Ethanol extract from Gynostemma pentaphyllum ameliorates dopaminergic neuronal cell death in transgenic mice expressing mutant A53T human alpha-synuclein Hyun Jin Park, Ting Ting Zhao, Seung Hwan Kim, Chong Kil Lee, Bang Yeon Hwang, Kyung Eun Lee, Myung Koo Lee 2020, 15 (2):  361-368.  doi: 10.4103/1673-5374.265557 Abstract ( 134 )   PDF (969KB) ( 224 )   Save Gynostemma (G.) pentaphyllum (Cucurbitaceae) contains various bioactive gypenosides. Ethanol extract from G. pentaphyllum (GP-EX) has been shown to have ameliorative effects on the death of dopaminergic neurons in animal models of Parkinson’s disease (PD) induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- and 6-hydroxydopamine. PD patients exhibit multiple symptoms, so PD-related research should combine neurotoxin models with genetic models. In the present study, we investigated the ameliorative effects of GP-EX, including gypenosides, on the cell death of dopaminergic neurons in the midbrain of A53T α-synuclein transgenic mouse models of PD (A53T). Both GP-EX and gypenosides at 50 mg/kg per day were orally administered to the A53T mice for 20 weeks. α-Synuclein-immunopositive cells and α-synuclein phosphorylation were increased in the midbrain of A53T mice, which was reduced following treatment with GP-EX. Treatment with GP-EX modulated the reduced phosphorylation of tyrosine hydroxylase, extracellular signal-regulated kinase (ERK1/2), Bcl-2-associated death promoter (Bad) at Ser112, and c-Jun N-terminal kinase (JNK1/2) due to α-synuclein overexpression. In the A53T group, GP-EX treatment prolonged the latency of the step-through passive avoidance test and shortened the transfer latency of the elevated plus maze test. Gypenosides treatment exhibited the effects and efficacy similar to those of GP-EX. Taken together, GP-EX, including gypenosides, has ameliorative effects on dopaminergic neuronal cell death due to the overexpression of α-synuclein by modulating ERK1/2, Bad at Ser112, and JNK1/2 signaling in the midbrain of A53T mouse model of PD. Further studies are needed to investigate GP-EX as a treatment for neurodegenerative synucleinopathies, including PD. This study was approved by the Animal Ethics Committee of Chungbuk National University (approval No. CBNUA-956-16-01) on September 21, 2016. Related Articles | Metrics