Publications by authors named "Leila Dargahi"

81 Publications

Enhancement of angiogenesis and neurogenesis by intracerebroventricular injection of secretome from human embryonic stem cell-derived mesenchymal stem cells in ischemic stroke model.

Biomed Pharmacother 2021 May 18;140:111709. Epub 2021 May 18.

Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

It is well accepted that the success of mesenchymal stem cells (MSCs) therapy against experimental stroke is mainly due to cellular paracrine manners rather than to replace lost tissue per se. Given such "bystander" effects, cell-free therapeutics manifest as a promising approach in regenerative medicine. Here we aimed at evaluating the effect of conditioned medium (CM) derived from human embryonic MSCs (hESC-MSC) on the neurological deficit, neurogenesis, and angiogenesis in experimental stroke. Adult male Wistar rats subjected to middle cerebral artery occlusion (MCAO), were treated with intracerebroventricular CM either one time (1 h post MCAO) or three times (1, 24, and 48 h post MCAO). Motor performance was assessed by the cylinder test on days 3 and 7. Cerebral samples were obtained for infarct size and molecular analysis on day 7 post-injury. Neurogenesis was evaluated by probing Nestin, Ki67, DCX, and Reelin transcripts and protein levels in the striatum, cortex, subventricular zone, and corpus callosum. The mRNA and protein expression of CD31 were also assessed in the striatum and cortical region to estimate angiogenesis post MCAO. Our findings demonstrate that CM treatment could significantly ameliorate neurological deficits and infarct volume in MCAO rats. Furthermore, ischemic stroke was associated with higher levels of neurogenesis and angiogenesis markers. Following treatment with CM, these markers were further potentiated in the brain regions. This study suggests that the therapeutic benefits of CM obtained from hESC-MSCs at least partly are mediated through improved neurogenesis and angiogenesis to accelerate the recovery of cerebral ischemia insult.
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http://dx.doi.org/10.1016/j.biopha.2021.111709DOI Listing
May 2021

Optogenetic stimulation of entorhinal cortex reveals the implication of insulin signaling in adult rat's hippocampal neurogenesis.

Prog Neuropsychopharmacol Biol Psychiatry 2021 May 6;111:110344. Epub 2021 May 6.

Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Adult neurogenesis in the hippocampal dentate gyrus plays a critical role in learning and memory. Projections originating from entorhinal cortex, known as the perforant pathway, provide the main input to the dentate gyrus and promote neurogenesis. However, neuromodulators and molecular changes mediating neurogenic effects of this pathway are not yet fully understood. Here, by means of an optogenetic approach, we investigated neurogenesis and synaptic plasticity in the hippocampus of adult rats induced by stimulation of the perforant pathway. The lentiviruses carrying hChR2 (H134R)-mCherry gene under the control of the CaMKII promoter were injected into the medial entorhinal cortex region of adult rats. After 21 days, the entorhinal cortex region was exposed to the blue laser (473 nm) for five consecutive days (30 min/day). The expression of synaptic plasticity and neurogenesis markers in the hippocampus were evaluated using molecular and histological approaches. In parallel, the changes in the gene expression of insulin and its signaling pathway, trophic factors, and components of mitochondrial biogenesis were assessed. Our results showed that optogenetic stimulation of the entorhinal cortex promotes hippocampal neurogenesis and synaptic plasticity concomitant with the increased levels of insulin mRNA and its signaling markers, neurotrophic factors, and activation of mitochondrial biogenesis. These findings suggest that effects of perforant pathway stimulation on the hippocampus, at least in part, are mediated by insulin increase in the dentate gyrus and subsequently activation of its downstream signaling pathway.
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http://dx.doi.org/10.1016/j.pnpbp.2021.110344DOI Listing
May 2021

Imipramine alleviates memory impairment and hippocampal apoptosis in STZ-induced sporadic Alzheimer's rat model: Possible contribution of MAPKs and insulin signaling.

Behav Brain Res 2021 Jun 26;408:113260. Epub 2021 Mar 26.

Department of Physiology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, associated with several pathophysiological complaints. Impaired insulin signaling in the brain, is one of the important characteristic features of AD which is accompanied by cognitive deficits. According to the multifactorial and complicated pathology of AD, no modifying therapy has been approved yet. Imipramine is a kind of tricyclic antidepressant with reported anti-inflammatory and anti-oxidant effects in the brain. There are controversial studies about the effect of this drug on spatial memory. This study investigates the effect of imipramine on streptozotocin (STZ) induced memory impairment in rats. Pursuing this objective, rats were treated with imipramine 10 or 20 mg/kg i.p. once a day for 14 days. 24 h after the last injection, memory function was evaluated by the Morris water maze (MWM) test in 4 consecutive days. Then, hippocampi were removed and the activity of caspase-3, mitogen activated protein kinases (MAPKs) family and inhibitory phosphorylation of insulin receptor substrate-1 (IRS-1) were analyzed using Western blotting. Results showed that imipramine prevents memory impairment in STZ induced rats and this improvement was accompanied with an increase in ERK activity, reduction of caspase-3 and JNK activity, as well as partial restoration of P38 and IRS-1 activity. In conclusion, our study demonstrated that at least some members of the MAPK family are involved in the neuroprotective effect of imipramine.
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http://dx.doi.org/10.1016/j.bbr.2021.113260DOI Listing
June 2021

Intranasal insulin improves mitochondrial function and attenuates motor deficits in a rat 6-OHDA model of Parkinson's disease.

CNS Neurosci Ther 2021 Mar 26;27(3):308-319. Epub 2021 Jan 26.

Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Aims: Experimental and clinical evidences demonstrate that common dysregulated pathways are involved in Parkinson's disease (PD) and type 2 diabetes. Recently, insulin treatment through intranasal (IN) approach has gained attention in PD, although the underlying mechanism of its potential therapeutic effects is still unclear. In this study, we investigated the effects of insulin treatment in a rat model of PD with emphasis on mitochondrial function indices in striatum.

Methods: Rats were treated with a daily low dose (4IU/day) of IN insulin, starting 72 h after 6-OHDA-induced lesion and continued for 14 days. Motor performance, dopaminergic cell survival, mitochondrial dehydrogenases activity, mitochondrial swelling, mitochondria permeability transition pore (mPTP), mitochondrial membrane potential (Δψ ), reactive oxygen species (ROS) formation, and glutathione (GSH) content in mitochondria, mitochondrial adenosine triphosphate (ATP), and the gene expression of PGC-1α, TFAM, Drp-1, GFAP, and Iba-1 were assessed.

Results: Intranasal insulin significantly reduces 6-OHDA-induced motor dysfunction and dopaminergic cell death. In parallel, it improves mitochondrial function indices and modulates mitochondria biogenesis and fission as well as activation of astrocytes and microglia.

Conclusion: Considering the prominent role of mitochondrial dysfunction in PD pathology, IN insulin as a disease-modifying therapy for PD should be considered for extensive research.
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http://dx.doi.org/10.1111/cns.13609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871791PMC
March 2021

The role of ERα36 in cell type-specific functions of estrogen and cancer development.

Pharmacol Res 2021 01 25;163:105307. Epub 2020 Nov 25.

Department of Medical Physiology, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran. Electronic address:

Exploring the regulatory effects of estrogen on different body organs via its receptors is largely of interest. Recently, the expression, signaling and the clinical significance of ERα36, the newly identified isoform of ERα, mediating non-genomic signaling of estrogen, have been studied in a wide range of organs and tumors. ERα36 is expressed highly in the CNS and actively involved in neuroprotection. It is also suggested to be an important estrogen receptor involved in preserving bone in postmenopausal women. On the oncological side, although ERα36 has usually been considered to be an oncogenic molecule, results from some studies paradoxically imply its protective role in certain tumors. Collectively, it seems that ERα36 is highly involved in cell type-specific functions of estrogen through its MAPK/ERK signaling, which is dependent on ERα36 expression levels, ligand concentrations and disease stage. The response is also dependent on the levels of ERα66 and ERβ. These factors influence the ERK kinetic and determine the ultimate mitogenic or antimitogenic signaling of estrogen, leading to cell survival or cell death. In this review, we summarize the recent organ-specific, cellular and molecular events and the mechanisms involved in estrogen effects mediated through the ERα36/ ERα66 with a particular focus on carcinomas where more clinical information has recently emerged.
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http://dx.doi.org/10.1016/j.phrs.2020.105307DOI Listing
January 2021

Extracellular Vesicles as a Neprilysin Delivery System Memory Improvement in Alzheimer's Disease.

Iran J Pharm Res 2020 ;19(2):45-60

Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Alzheimer's disease (AD) is a neurodegenerative brain disorder which has no effective treatment yet due to the blood barrier in the brain that limits the drugs with the potential of disease improvement. Extracellular vesicles (EVs) are biocompatible nanoparticles with a lipid membrane. These vesicles are secreted from various cells such as mesenchymal stem cells (MSCs) and can pass through biological barriers for transfer of information such as signals or be used as carriers for various proteins like Neprilysin (NEP). NEP is an active enzyme in the clearance of abnormal aggregated beta-amyloid sheets in the brain. In the present study, we used EVs to carry NEP for memory improvement in Alzheimer's disease. For this purpose, bone marrow MSCs were isolated from rat femur. Stemness evaluation of established cells was characterized by differentiation potency and specific markers with flowcytometry. EVs were isolated from MSCs supernatant by ultracentrifugation and analyzed by scanning electron microscopy (SEM), dynamic light scattering (DLS) and western blotting. EVs were loaded with NEP by freeze-thaw cycle and then administrated intranasally in a rat model of the AD for 14 days. Our findings showed EV-loaded NEP caused a decrease in IL-1beta and also BAX but an increase in BCL2 expression level in the rat brain. Altogether, these data showed that EV-loaded NEP can improve brain-related behavioural function which may be mediated through the regulation of inflammation and apoptosis. These findings suggest that EV-loaded NEP can be considered as a potential drug delivery system for the improvement of AD.
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http://dx.doi.org/10.22037/ijpr.2020.112062.13508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667544PMC
January 2020

Fingolimod increases oligodendrocytes markers expression in epidermal neural crest stem cells.

Eur J Pharmacol 2020 Oct 26;885:173502. Epub 2020 Aug 26.

Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Epidermal neural crest stem cells (EPI-NCSCs) are propitious candidates for cell replacement therapy and supplying neurotrophic factors in the neurological disorders. Considering the potential remyelinating and regenerative effects of fingolimod, in this study, we evaluated its effects on EPI-NCSCs viability and the expression of neurotrophic and oligodendrocyte differentiation factors. EPI-NCSCs, extracted from the bulge of rat hair follicles, were characterized and treated with fingolimod (0, 50, 100, 200, 400, 600, 1000, and 5000 nM). The cell viability was evaluated by MTT assay at 6, 24 and 72 h. The expression of neurotrophic and differentiation factors in the cells treated with 100 and 400 nM fingolimod were measured at 24 and 120 h. Fingolimod at 50-600 nM increased the cells viability after 6 h, with no change at the higher concentrations. The highest concentration (5000nM) induced toxicity at 24 and 72 h. NGF and GDNF genes expression were decreased at 120 h, but on the contrary, brain derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) were increased by both concentrations at both time points. Oligodendrocyte markers including platelet-derived growth factor receptor A (PDGFRα), neuron-glial antigen 2 (NG2) and growth associated protein 43 (GAP43) were elevated at 120 h, which was accompanied with reduce in stemness markers (Nestin and early growth response 1 (EGR1)). Fingolimod increased the expression of neurotrophic factors in EPI-NCSCs, and guided them to oligodendrocyte fate. Therefore, fingolimod in combination with EPI-NCSCs, can be considered as a promising approach for demyelinating neurological disorders.
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http://dx.doi.org/10.1016/j.ejphar.2020.173502DOI Listing
October 2020

Individual Subnuclei of the Rat Anterior Thalamic Nuclei Differently affect Spatial Memory and Passive Avoidance Tasks.

Neuroscience 2020 09 31;444:19-32. Epub 2020 Jul 31.

Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, P.O. Box 19615-1178, Tehran, Iran. Electronic address:

The role of the anterior thalamic nuclei (ATN) has been proven in different learning and memory tasks. The ATN consist of three main subnuclei, the anterodorsal (AD), anteroventral (AV) and anteromedial (AM), which have different biological characteristics such as distinct circuitry, cell population and neurotransmitter content. The role of ATN subnuclei in learning and memory has been shown in several studies. However, their probable role in different phases of memory including acquisition, consolidation and retrieval are not still well-known. For this purpose, the effect of reversible inactivation of each ATN subnucleus on different memory phases in two behavioral tasks including passive avoidance (PA) and Morris water maze (MWM) was studied. Wister male rats were bilaterally implanted with cannulas above the AD, AV or AM subnucleus in separate experimental groups in order to inject lidocaine (4%) for their temporal inactivation or, equal volume of saline. Animals were trained in the behavioral tasks and different phases of memory were investigated. Our findings indicated that the AV inactivation strongly disrupts all memory phases in the MWM, and consolidation and retrieval phases in the PA tasks. The AM inactivation had no effect on acquisition of both tasks while it impaired the PA consolidation and MWM retrieval. However, the AD inactivation could not disrupt memory phases in the PA task but impaired the MWM retrieval. In conclusion, it seems that the ATN distinct subnuclei differently affect different phases of memory in these two tasks.
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http://dx.doi.org/10.1016/j.neuroscience.2020.07.046DOI Listing
September 2020

The conditioned medium of human embryonic stem cell-derived mesenchymal stem cells alleviates neurological deficits and improves synaptic recovery in experimental stroke.

J Cell Physiol 2021 Mar 30;236(3):1967-1979. Epub 2020 Jul 30.

Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.

The transplantation of mesenchymal stem cells (MSCs) is of main approaches in regenerative therapy for stroke. Due to the potential tumorigenicity and low survival rate of transplanted cells, focuses have been shifted from cell replacement to their paracrine effects. Therefore, stem cell-conditioned medium (CM) therapy has emerged as an alternative candidate. Here, we investigated the effect of CM derived from human embryonic MSCs on experimental ischemic stroke. Wistar rats underwent ischemic stroke by the right middle cerebral artery occlusion (MCAO). CM was infused either one time (1 hr post-MCAO) or three times (1, 24, and 48 hr post-MCAO) through guide cannula into the left lateral ventricle. Neurological functions were evaluated using Bederson's test and modified Neurological Severity Score on Days 1, 3, and 7 following MCAO. Infarction volumes and cerebral edema were measured on Days 3 and 7. growth-associated protein-43, synaptophysin, cAMP response element-binding protein, and phosphorylated-cAMP response element-binding protein levels were also assessed in peri-ischemic cortical tissue on Day 7 postsurgery. Our results indicated that three times injections of CM could significantly reduce body weight loss, mortality rate, infarct volumes, cerebral edema, and improve neurological deficits in MCAO rats. Moreover, three injections of CM could restore decreased levels of synaptic markers in MCAO rats up to its normal levels observed in the sham group. Our data suggest that using the CM obtained from embryonic stem cells-MSCs could be a potent therapeutic approach to attenuate cerebral ischemia insults which may be partly mediated through modulation of synaptic plasticity.
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http://dx.doi.org/10.1002/jcp.29981DOI Listing
March 2021

Mitochondrial Complex I Is an Essential Player in LPS-Induced Preconditioning in Differentiated PC12 Cells.

Iran J Pharm Res 2019 ;18(3):1445-1455

Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Preconditioning (PC) as a protective strategy against noxious insults can decline cell death and apoptosis. It has been approved that mitochondria play a key role in PC mechanism. The critical role of complex I (CI) in oxidative phosphorylation machinery and intracellular ROS production, particularly in the brain, accentuates its possible role in PC-induced neuroprotection. Here, differentiated PC12 cells were preconditioned with ultra-low dose LPS (ULD, 3 μg/mL) prior to exposure to high concentration of LPS (HD, 750 μg/mL). Our results showed that HD LPS treatment reduces cell viability and CI activity, and intensifies expression of cleaved caspase 3 compared to the control group. Intriguingly, PC induction resulted in enhancement of cell viability and CI activity and reduction of caspase3 cleavage compared to HD LPS group. In order to explore the role of CI in PC, we combined the ULD LPS with rotenone, a CI inhibitor. Following rotenone administration, cell viability significantly reduced while caspase3 cleavage increased compared to PC induction group. Taken together, cell survival and reduction of apoptosis followed by PC can be at least partially attributed to the preservation of mitochondrial CI function.
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http://dx.doi.org/10.22037/ijpr.2019.1100711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934967PMC
January 2019

Neurogenic differentiation of human dental pulp stem cells by optogenetics stimulation.

J Chem Neuroanat 2020 11 5;109:101821. Epub 2020 Jun 5.

Laser and Plasma Research Institute-Shahid Beheshti University, Tehran, Iran.

Introduction: Human dental pulp stem cells (hDPSCs), a promising source for autologous transplantation in regenerative medicine, have been shown to be able to differentiate into neural precursors. Optogenetics is considered as an advanced biological technique in neuroscience which is able to control the activity of genetically modified stem cells by light. The purpose of this study is to investigate the neurogenic differentiation of hDPSCs following optogenetic stimulation.

Methods: The hDPSCs were isolated by mechanical enzymatic digestion from an impacted third molar and cultured in DMEM/F12. The cells were infected with lentiviruses carrying CaMKIIa-hChR2 (H134R). Opsin-expressing hDPSCs were plated at the density of 5 × 10 cells/well in 6-well plates and optical stimulation was conducted with blue light (470 nm) pulsing at 15 Hz, 90 % Duty Cycle and 10 mW power for 10 s every 90 minutes, 6 times a day for 5 days. Two control groups including non-opsin-expressing hDPSCs and opsin-expressing hDPSCs with no optical stimulation were also included in the study. A day after last light stimulation, the viability of cells was analyzed by the MTT assay and the morphological changes were examined by phase contrast microscopy. The expression of Nestin, Microtubule-Associated protein 2 (MAP2) and Doublecortin (DCX) were examined by immunocytochemistry.

Results: Human DPSCs expressed the reporter gene, mCherry, 72 hours after lentiviral infection. The result of MTT assay revealed a significant more viability in optical stimulated opsin-expressing hDPSCs as compared with two control groups. Moreover, optical stimulation increased the expression of Nestin, Doublecortin and MAP2 along with morphological changes from spindle shape to neuron-like shape.

Conclusion: Optogenetics stimulation through depolarizing the hDPSCs can increase the cells viability and/or proliferation and also promote the differentiation toward neuron-like cells.
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http://dx.doi.org/10.1016/j.jchemneu.2020.101821DOI Listing
November 2020

Epidermal neural crest stem cell transplantation as a promising therapeutic strategy for ischemic stroke.

CNS Neurosci Ther 2020 07 12;26(7):670-681. Epub 2020 Apr 12.

Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Introduction: Cell-based therapy is considered as promising strategy to cure stroke. However, employing appropriate type of stem cell to fulfill many therapeutic needs of cerebral ischemia is still challenging. In this regard, the current study was designed to elucidate therapeutic potential of epidermal neural crest stem cells (EPI-NCSCs) compared to bone marrow mesenchymal stem cells (BM-MSCs) in rat model of ischemic stroke.

Methods: Ischemic stroke was induced by middle cerebral artery occlusion (MCAO) for 45 minutes. Immediately after reperfusion, EPI-NCSCs or BM-MSCs were transplanted via intra-arterial or intravenous route. A test for neurological function was performed before ischemia and 1, 3, and 7 days after MCAO. Also, infarct volume ratio and relative expression of 15 selected target genes were evaluated 7 days after transplantation.

Results: EPI-NCSCs transplantation (both intra-arterial and intravenous) and BM-MSCs transplantation (only intra-arterial) tended to result in a better functional outcome, compared to the MCAO group; however, this difference was not statistically significant. The infarct volume ratio significantly decreased in NCSC-intra-arterial, NCSC-intravenous and MSC-intra-arterial groups compared to the control. EPI-NCSCs interventions led to higher expression levels of Bdnf, nestin, Sox10, doublecortin, β-III tubulin, Gfap, and interleukin-6, whereas neurotrophin-3 and interleukin-10 were decreased. On the other hand, BM-MSCs therapy resulted in upregulation of Gdnf, β-III tubulin, and Gfap and down-regulation of neurotrophin-3, interleukin-1, and interleukin-10.

Conclusion: These findings highlight the therapeutic effects of EPI-NCSCs transplantation, probably through simultaneous induction of neuronal and glial formation, as well as Bdnf over-expression in a rat model of ischemic stroke.
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http://dx.doi.org/10.1111/cns.13370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298983PMC
July 2020

Combination therapy with astaxanthin and epidermal neural crest stem cells improves motor impairments and activates mitochondrial biogenesis in a rat model of spinal cord injury.

Mitochondrion 2020 05 6;52:125-134. Epub 2020 Mar 6.

Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Spinal cord injury (SCI), a multifactorial disease, can lead to irreversible motor and sensory disabilities. Cell therapy in combination with pharmacological agents can be a promising approach to attenuate SCI damages. Epidermal neural crest stem cells (EPI-NCSCs) extracted from bulge hair follicle in adults are attractive candidates due to the possibility of autologous transplantation. This study evaluated the effect of EPI-NCSCs combined with astaxanthin (Ast), a potent antioxidant, on damages induced by SCI. Male rats were treated with Ast (0.2 mM) and EPI-NCSCs (10/10 μl PBS) alone and combined together after SCI contusion. Motor function was assessed by Basso, Beattie and Bresnahan (BBB) test on days 1, 3, 7, 14, 21, 28, 35 and 42 post-injury. Motor neurons number and myelin level were evaluated on days 14 and 42 using Nissl and Luxol Fast Blue staining. The gene expression of mitochondrial biogenesis involved factors (PGC1α, NRF1 and TFAM) was measured by qPCR. All treatments improved motor function, with the highest BBB score in Ast + Cell compared to Ast and Cell. Decreased motor neurons number and myelin level following SCI, were increased by Ast, Cell and Ast + Cell, but combination therapy significantly had a better effect. We observed reduction in PGC1α, NRF1, and TFAM expression in spinal tissue after SCI, and treatment with Cell and Ast + Cell significantly restored NRF1 and TFAM mRNA levels. These results suggested that Ast in combination with EPI-NCSCs has better effects on behavioral dysfunction, motor neuron loss and demyelination after SCI. These protective effects may be attributed to mitochondrial biogenesis activation.
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http://dx.doi.org/10.1016/j.mito.2020.03.002DOI Listing
May 2020

Expression patterns of ERα66 and its novel variant isoform ERα36 in lactotroph pituitary adenomas and associations with clinicopathological characteristics.

Pituitary 2020 Jun;23(3):232-245

Department of Pharmacology and Neurobiology Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Velenjak, Tehran, Iran.

Purpose: The regulatory effects of estradiol on pituitary homeostasis have been well documented. However, the expression patterns of ERα66 and ERα36 and their correlations with the clinical course of postoperative prolactinoma tumors remain unclear.

Methods: The expression of ERα36, ERα66, Ki67, p53, and CD31 were determined by immunohistochemistry in 62 prolactinoma patients. Snap-frozen tumors and normal pituitaries were also examined by western blotting for estrogen receptor detection.

Results: A broad expression of ERα36 was identified in normal pituitaries. The median scores of ERα36 and ERα66 expression were 8 and 6 in normal pituitaries and 4 and 0 in tumors, respectively. Four phenotypes of ERα36 and ERα66 expression were explored in tumors with regard to sex, invasiveness, dopamine resistance, and recurrence. Low ERα36 expression was associated with tumor invasion and increased Ki67. Low ERα66 expression was associated with tumor invasion, dopamine-agonist resistance, and enhanced tumor size. Multivariable logistic regression analysis showed that low ERα36 expression is an independent risk factor for invasiveness. The significant inverse association of ERα66 with invasiveness, dopamine resistance, and tumor size remained significant after adjustment for sex as a potential confounder. After controlling for sex, the low ERα66/low ERα36 phenotype was 6.24 times more prevalent in invasive tumors than in noninvasive tumors. Although the decreasing trend of CD31 expression from surrounding nontumoral lactotroph adenomas to tumors was similar to that of the estrogen receptors, a significant correlation was not observed here.

Conclusion: The decreasing trends of ERα36 and ERα66 expression from normal pituitaries to tumors are associated with aggressive clinical behavior.
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http://dx.doi.org/10.1007/s11102-020-01029-zDOI Listing
June 2020

Substrate stiffness affects the morphology and gene expression of epidermal neural crest stem cells in a short term culture.

Biotechnol Bioeng 2020 02 20;117(2):305-317. Epub 2019 Nov 20.

NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

According to the intrinsic plasticity of stem cells, controlling their fate is a critical issue in cell-based therapies. Recently, a growing body of evidence has suggested that substrate stiffness can affect the fate decisions of various stem cells. Epidermal neural crest stem cells as one of the main neural crest cell derivatives hold great promise for cell therapies due to presenting a high level of plasticity. This study was conducted to define the influence of substrate stiffness on the lineage commitment of these cells. Here, four different polyacrylamide hydrogels with elastic modulus in the range of 0.7-30 kPa were synthesized and coated with collagen and stem cells were seeded on them for 24 hr. The obtained data showed that cells can attach faster to hydrogels compared with culture plate and cells on <1 kPa stiffness show more neuronal-like morphology as they presented several branches and extended longer neurites over time. Moreover, the transcription of actin downregulated on all hydrogels, while the expression of Nestin, Tubulin, and PDGFR-α increased on all of them and SOX-10 and doublecortin gene expression were higher only on <1 kPa. Also, it was revealed that soft hydrogels can enhance the expression of glial cell line-derived neurotrophic factor, neurotrophin-3, and vascular endothelial growth factor in these stem cells. On the basis of the results, these cells can respond to the substrate stiffness in the short term culture and soft hydrogels can alter their morphology and gene expression. These findings suggested that employing proper substrate stiffness might result in cells with more natural profiles similar to the nervous system and superior usefulness in therapeutic applications.
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http://dx.doi.org/10.1002/bit.27208DOI Listing
February 2020

Intranasal interferon beta improves memory and modulates inflammatory responses in a mutant APP-overexpressing rat model of Alzheimer's disease.

Brain Res Bull 2019 08 21;150:297-306. Epub 2019 Jun 21.

NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by progressive cognitive decline. According to the critical role of inflammation in pathogenesis of AD and memory deficits, a cytokine with anti-inflammatory properties like interferon beta (IFNβ), currently used to slow down disease progression and protect against cognitive disturbance in multiple sclerosis, might be also an effective treatment in AD condition. This study aimed to answer if the intranasal (IN) administration of IFNβ with high CNS accessibility can alleviate memory impairments in a mutant APP-overexpressing rat model of AD through modulating inflammatory responses. To address this question, the lentiviruses carrying human amyloid protein precursor (APP) with the Swedish and Indiana mutations (LV-APP) were bilaterally injected in the hippocampus of adult rats. Memory performance was assessed using passive avoidance task on days 49 and 50 after injection. Moreover, the expression of glial markers (GFAP and Iba1) and pro-inflammatory (TNF-α, IL-1β and IL-6) and anti-inflammatory cytokines (IL-10) were evaluated in the hippocampus. Therapeutic effects of IN-administered IFNβ (0.5 μg/kg and 1 μg/kg doses, every other day from day 23 to 50 after lentivirus injection) were examined in the LV-APP-injected rats. Our results showed that over-expression of mutant human APP gene in the hippocampus led to learning and memory deficits concomitant with gliosis and pro-inflammatory responses. Interestingly, treatment of AD-modeled rats with IFNβ ameliorated memory impairments possibly through suppressing gliosis and shifting from pro-inflammatory toward anti-inflammatory status, suggesting that IFNβ may be a promising therapeutic agent to improve cognitive functions and modulate inflammatory responses in an AD-like neurodegenerative context.
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http://dx.doi.org/10.1016/j.brainresbull.2019.06.015DOI Listing
August 2019

Corrigendum to "Effect of Methamphetamine on Rat Primary Midbrain Cells; Mitochondrial Biogenesis as a Compensatory Response" [Neuroscience 406C (2019) 278-289].

Neuroscience 2019 Aug 8;413:317-318. Epub 2019 Jun 8.

Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

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http://dx.doi.org/10.1016/j.neuroscience.2019.05.057DOI Listing
August 2019

Interferon beta ameliorates cognitive dysfunction in a rat model of Alzheimer's disease: Modulation of hippocampal neurogenesis and apoptosis as underlying mechanism.

Prog Neuropsychopharmacol Biol Psychiatry 2019 08 29;94:109661. Epub 2019 May 29.

Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Neuronal apoptosis and impaired hippocampal neurogenesis are major players in cognitive/memory dysfunctions including Alzheimer's disease (AD). Interferon beta (IFNβ) is a cytokine with anti-apoptotic and neuroprotective properties on the central nervous system (CNS) cells which specifically affects neural progenitor cells (NPCs) even in the adult brain. In this study, we examined the effect of IFNβ on memory impairment as well as hippocampal neurogenesis and apoptosis in a rat model of AD. AD model was induced by lentiviral-mediated overexpression of mutant APP in the hippocampus of adult rats. Intranasal (IN) administration of IFNβ (0.5 μg/kg and 1 μg/kg doses) was started from day 23 after virus injection and continued every other day to the final day of experiments. The expression levels of APP, neurogenesis (Nestin, Ki67, DCX, and Reelin) and apoptosis (Bax/Bcl-2 ratio, cleaved-caspase-3 and seladin-1) markers were evaluated by immunohistochemistry, real-time PCR, immunofluorescence and western blotting. Moreover, thioflavin T and Nissl stainings were used to assess Aβ plaque levels and neuronal degeneration in the hippocampus, respectively. Our results showed that IFNβ treatment reduced APP expression and Aβ plaque formation, and concomitantly ameliorated spatial learning and memory deficits examined in Y-maze and Morris water maze tests. Moreover, in parallel with reducing apoptosis and neural loss in the hippocampal subfields, IFNβ decreased ectopic neurogenesis in the CA1 and CA3 regions of the AD rat hippocampus. However, IFNβ increased neurogenesis in the dentate gyrus neurogenic niche. Our findings suggest that IFNβ exerts neuroprotective effects at least partly by inhibition of apoptosis and modulation of neurogenesis. Taken together, IFNβ can be a promising therapeutic approach to improve cognitive performance in AD-like neurodegenerative context.
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http://dx.doi.org/10.1016/j.pnpbp.2019.109661DOI Listing
August 2019

Thyroid hormone treatment alleviates the impairments of neurogenesis, mitochondrial biogenesis and memory performance induced by methamphetamine.

Neurotoxicology 2019 09 7;74:7-18. Epub 2019 May 7.

Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Chronic use of methamphetamine (MA), a neurotoxic psychostimulant, leads to long-lasting cognitive dysfunctions in humans and animal models. Thyroid hormones (THs) have several physiological actions and are crucial for normal behavioral, intellectual and neurological development. Considering the importance of THs in the cognitive processes, the present study was designed to evaluate the therapeutic effects of THs on cognitive and neurological impairments induced by MA. Escalating doses of MA (1-10 mg/kg, IP) were injected twice daily for 10 consecutive days in rats and cognitive functions were evaluated using behavioral tests. The expression of factors involved in neurogenesis (NES and DCX), mitochondrial biogenesis (PGC-1α, NRF-1, and TFAM), neuroinflammation (GFAP, Iba-1, and COX-2) as well as Reelin and NT-3 (synaptic plasticity and neurotrophic factor, respectively) was measured in the hippocampus of MA-treated animals. The effects of three different doses of T4 (20, 40 or 80 μg/kg; intraperitoneally) or T3 (20, 40 or 80 μg/rat; 2.5 μl/nostril; intranasal) treatment, once a day for one week after MA cessation, were assessed in MA-treated rats. After the last behavioral test, serum T4 and T3 levels were measured using radioimmunoassay. The results revealed that repeated escalating regimen of MA impaired cognitive functions concomitant with neurogenesis and synaptic plasticity impairments, mitochondrial dysfunction, and neuroinflammation. T4 or T3 treatment partially decreased the alterations induced by MA. These findings suggest that THs can be considered as potential candidates for the reduction of MA abuse related neurocognitive disturbances.
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http://dx.doi.org/10.1016/j.neuro.2019.05.003DOI Listing
September 2019

Enhancing the expression of neurotrophic factors in epidermal neural crest stem cells by valproic acid: A potential candidate for combinatorial treatment.

Neurosci Lett 2019 06 20;704:8-14. Epub 2019 Mar 20.

NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, 19615-1178, Velenjak, Iran. Electronic address:

Effective delivery of trophic factors to cure neurological disorders and traumatic injuries is a major challenge. With promising therapeutic effects of epidermal neural crest stem cells (EPI-NCSCs) in preclinical spinal cord injury, there is an implication that these stem cells might provide supportive role through releasing various trophic agents. Hence, the present study was designed to assess the influence of valproic acid (VPA), a well-known histone deacetylases inhibitor, on mRNA expression of selected trophic factors. In this study, following stem cell migration from explanted hair bulges, immunostaining against Nestin, SOX-10, DCX, β-III tubulin and GFAP was carried out. Then, cells were treated with various clinically relevant concentrations of VPA and the survival rate was defined by MTT assay. Finally, stem cells were treated with 0.1 and 1 mM VPA and the drug impact on the transcription level of BDNF, GDNF, VEGF, NGF and NT3 at 6, 24, 72, 168 h was assessed by quantitative real-time PCR. The examined proteins expressions in the population of migrated cells confirmed the identity of stem cells as EPI-NCSCs. In addition, MTT assay showed that all three tested concentrations of VPA were suitable to treat these cells. Trophic factors assessment, following treatment revealed the mRNA expression level of BDNF, GDNF and VEGF could be significantly up- regulated at various time points, mainly by 1 mM VPA. However, NGF and NT3 transcripts were enhanced at few limited time points. Our findings showed that EPI-NCSCs due to secretion of various trophic factors are potential candidate to deliver the required trophic agents and their potential can be enhanced by 1 mM VPA, predominantly following 168 h treatment. Hence, these cells can be utilized to modulate destructive context of neurological disorders and injuries.
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http://dx.doi.org/10.1016/j.neulet.2019.03.033DOI Listing
June 2019

Effect of methamphetamine on rat primary midbrain cells; mitochondrial biogenesis as a compensatory response.

Neuroscience 2019 05 15;406:278-289. Epub 2019 Mar 15.

Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Methamphetamine (MA), neurotoxic drug of abuse, causes cell death in vitro and in vivo via several mechanisms such as mitochondrial dysfunction. In this study we evaluated the effect of MA on cell viability and mitochondrial biogenesis in primary midbrain culture. Primary mesencephalon cells prepared from E14.5 rat embryo were treated with 0.2-5 mM MA concentrations for 24, 48, and 72 h. Morphological changes of the cells were observed under light microscope. Cell viability and cell death following MA were assessed using MTT assay and immunocytochemistry. Gene expressions of mitochondrial biogenesis-involved factors (PGC1α, NRF1 and TFAM), and neuronal and glial markers were measured by qPCR. Low to moderate MA concentrations elevated cell viability in all time points, while higher concentrations and longer incubation times (48 and 72 h) decreased it. Sphered cell bodies and neurites degeneration were observed following exposure to high MA concentrations. MA at 5 mM concentration decreased the number of β3-tubulin-, TH-, GFAP- and Iba1-positive cells, and their corresponding mRNA levels; however, 1 mM MA reduced α-synuclein mRNA. Unexpectedly, gene expression of PGC1α, NRF1 and TFAM was increased in response to 5 mM MA, with no changes following 1 mM MA. The results indicated that MA effect on cell viability occurs in a dose-dependent manner. While moderate concentrations increased cell viability, the higher ones reduced it and caused cell death. Mitochondrial biogenesis activation, as a compensatory mechanism, did not prevent neuronal and glial cell death following high MA concentration.
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http://dx.doi.org/10.1016/j.neuroscience.2019.03.016DOI Listing
May 2019

To be or not to be: PP2A as a dual player in CNS functions, its role in neurodegeneration, and its interaction with brain insulin signaling.

Cell Mol Life Sci 2019 Jun 14;76(12):2277-2297. Epub 2019 Mar 14.

Department of Physiology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Accumulating evidence has reached the consensus that the balance of phosphorylation state of signaling molecules is a pivotal point in the regulation of cell signaling. Therefore, characterizing elements (kinases-phosphatases) in the phosphorylation balance are at great importance. However, the role of phosphatase enzymes is less investigated than kinase enzymes. PP2A is a member of serine/threonine protein phosphatase that its imbalance has been reported in neurodegenerative diseases. Therefore, we reviewed the superfamily of phosphatases and more specifically PP2A, its regulation, and physiological functions participate in CNS. Thereafter, we discussed the latest findings about PP2A dysregulation in Alzheimer and Parkinson diseases and possible interplay between this phosphatase and insulin signaling pathways. Finally, activating/inhibitory modulators for PP2A activity as well as experimental methods for PP2A study have been reviewed.
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http://dx.doi.org/10.1007/s00018-019-03063-yDOI Listing
June 2019

Probiotic mixture of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 attenuates hippocampal apoptosis induced by lipopolysaccharide in rats.

Int Microbiol 2019 Sep 11;22(3):317-323. Epub 2018 Dec 11.

Cellular and Molecular Research Center, Department of Pharmacology, Qazvin University of Medical Sciences, P.O. Box 341197-5981, Qazvin, Iran.

In recent years, the beneficial impact of targeted gut microbiota manipulation in various neurological disorders has become more evident. Therefore, probiotics have been considered as a promising approach to modulate brain gene expression and neuronal pathways even in some neurodegenerative diseases. The purpose of this study was to determine the effect of probiotic biotherapy with combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 on the expression levels of proteins critical to neuronal apoptosis in hippocampus of lipopolysaccharide (LPS)-exposed rats. Four groups of animals (Control, LPS, Probiotic + LPS, and Probiotic) were treated with maltodextrin (placebo) or probiotic (10 CFU/ml/rat) for 2 weeks by gavage. On the 15th day, a single intraperitoneal dose of saline or LPS (1 mg/kg) was injected and 4 h later, protein assessment was performed by western blotting in hippocampal tissues. LPS significantly increased the Bax, Bax/Bcl-2 ratio, and cleaved caspase-3 expression along with decreased the Bcl-2 and procaspase-3 protein levels. However, probiotic pretreatment (L. helveticus R0052 + B. longum R0175) significantly downregulated the Bax and Bax/Bcl-2 ratio accompanied with upregulated Bcl-2 expression. Prophylactic treatment with these bacteria also attenuated LPS-induced caspase-3 activation by remarkably increasing the expression of procaspase-3 while reducing the level of cleaved caspase-3 in target tissues. Our data indicate that probiotic formulation (L. helveticus R0052 + B. longum R0175) alleviated hippocampal apoptosis induced by LPS in rats via the gut-brain axis and suggest that this probiotic could play a beneficial role in some neurodegenerative conditions.
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http://dx.doi.org/10.1007/s10123-018-00051-3DOI Listing
September 2019

Cannabidiol modulates the expression of neuroinflammatory factors in stress- and drug-induced reinstatement of methamphetamine in extinguished rats.

Addict Biol 2020 03 22;25(2):e12740. Epub 2019 Feb 22.

Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Methamphetamine (METH) is a highly potent and addictive psychostimulant that is frequently abused worldwide. Although the biggest challenge to the efficient treatment of drug dependence is relapse, its mechanism is completely unclear. Plenty of evidence suggests that inflammation contributes to drug-induced reward especially in brain regions that are involved in the reward system, but there is no document about relapse. Cannabidiol (CBD) is a nonpsychoactive cannabinoid that has powerful anti-inflammatory and immunosuppressive properties. A previous research in our laboratory has demonstrated that CBD prevents reinstatement of METH even in 24-hour rapid eye movement (REM) sleep-deprived (RSD) rats. The aim of this study was to assess whether CBD prevents reinstatement of METH through change of gene expression of cytokines such as interleukin-1β, interleukin-6, interleukin-10, and tumor necrosis factor α (TNF-α) in extinguished rats. Real-time polymerase chain reaction (PCR) was used in this research to assay gene expression of cytokines. We found that stress- and drug-induced reinstatement of METH enhanced mRNA expression of cytokines in the prefrontal cortex (PFC) and hippocampus. Furthermore, CBD treatment significantly reduced the mRNA expression of cytokines in the PFC and hippocampus, but CBD treatment in RSD rats increased expression of cytokines in the hippocampus. It seems that enhancement of cytokines leads to change in neurotransmission and so triggers reinstatement of METH.
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http://dx.doi.org/10.1111/adb.12740DOI Listing
March 2020

Optogenetic Stimulation of the Anterior Cingulate Cortex Ameliorates Autistic-Like Behaviors in Rats Induced by Neonatal Isolation, Caudate Putamen as a Site for Alteration.

Neuromolecular Med 2019 06 19;21(2):132-142. Epub 2019 Feb 19.

Institute for Cognitive and Brain Science, Shahid Beheshti University, Tehran, Iran.

Epigenetic agents, such as neonatal isolation during neurodevelopmental period of life, can change various regions of the brain. It may further induce psychological disorders such as autistic-like phenomena. This study indicated the role of chronic increased anterior cingulate cortex (ACC) output on alteration of caudate putamen (CPu) as a main behavior regulator region of the brain in adult maternal deprived (MD) rats. For making an animal model, neonates were isolated from their mothers in postnatal days (PND 1-10, 3 h/day). Subsequently, they bilaterally received pLenti-CaMKIIa-hChR2 (H134R)-mCherry-WPRE virus in ACC area via stereotaxic surgery in PND50. After 22 days, these regions were exposed to blue laser (473 nm) for six consecutive days (15 min/day). Then, behavioral deficits were tested and were compared with control group in the following day. Animals were immediately killed and their brains were prepared for tissue processing. Results showed that neonatal isolation induces autistic-like behaviors and leads to overexpression of NMDAR1 and Nox2-gp91 proteins and elevation of catalase activity in the CPu regions of the adult offspring compared with control group. Chronic optogenetic stimulation of ACC neurons containing (ChR2+) led to significant reduction in the appearance of stereotypical behavior and alien-phobia in MD rats. The amount of NMDAR1 and Nox2-gp91 expression and the catalase activity in CPu were reduced after this treatment. Therefore, autistic-like behavior seems to be related with elevation of NMDAR1 and Nox2-gp91 protein levels that enhance the effect of glutamatergic projection on CPu regions. Optogenetic treatment also could ameliorate behavioral deficits by modulating these protein densities.
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http://dx.doi.org/10.1007/s12017-019-08526-wDOI Listing
June 2019

The primary neuronal cells are more resistant than PC12 cells to α-synuclein toxic aggregates.

Neurosci Lett 2019 05 16;701:38-47. Epub 2019 Feb 16.

Department of Industrial and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran. Electronic address:

Background: Alpha-synuclein (αSN) is an abundant presynaptic brain protein that its aggregated species believed to play pivotal roles in the development of neurodegenerative diseases, especially Parkinson's disease (PD). In this study, we compared the response of primary neuronal cells with a well-known cell line model, PC12, against the toxic aggregates of αSN.

Methods: Primary hippocampal neurons (PHNs) were isolated from 17 to 18 days old rat embryos. Fibrillization was induced in recombinant αSN and monitored by standard methods. The toxicity of different aggregates of αSN on the treated cells was then studied. Furthermore, changes in the intracellular reactive oxygen species (ROS) and Ca levels were also compared in two kinds of treated cells. We also studied the gene expression profile of certain Ca channels and carriers using the GEO2 database.

Results: The viability rate was significantly lower in PC12 versus PHNs, in response to αSN. This is while the intracellular ROS and Ca levels were significantly increased in both cell types. Analysis of microarray data indicated that some factors involved in Ca hemostasis may face significant changes in the PD condition.

Conclusion: By putting these data together, it is clear that PHN is more resistant than PC12 toward αSN cytotoxicity even in the presence of rising cytoplasmic ROS and Ca levels. Exploring the supporting mechanisms which PHN uses to be more resistant to αSN cytotoxicity can help to open a roadmap toward therapeutic plans in PD and other synucleinopathy disorders.
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http://dx.doi.org/10.1016/j.neulet.2019.01.055DOI Listing
May 2019

Modeling traumatic injury in organotypic spinal cord slice culture obtained from adult rat.

Tissue Cell 2019 Feb 10;56:90-97. Epub 2019 Jan 10.

NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Nowadays there are various models of spinal cord injury (SCI) that recreate mechanisms of human SCI. The ex vivo modeling of injury is a robust approach, confronts with less experimental and ethical challenges. Currently almost all ex vivo models are obtained either from embryonic or postnatal animals, which can hardly mimic features of human SCI. This study was designed to develop SCI in slice culture of adult rats. Here, the lumbar enlargement of an adult rat was sliced and cultured. After seven days in vitro, a weight was dropped to simulate the injury. The result showed that although the rate of cell death in first days of in vitro was high, it reduced after 7 days and dropping a weight at the time caused significant rate of cell death in slices. It was shown that injury can disturb histological features and neuronal integrity in the slices. Treating the injured slices with valproic acid resulted in a significant decrease of TNF-α and increase of BDNF expression. Collected data revealed obtained slices from adult rat were able to adjust to the culture environment after 7 days and dropping a weight at the time point could simulate the injury. Besides mimicking the disturbing features of human SCI, this model can response to VPA pharmacological treatment.
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http://dx.doi.org/10.1016/j.tice.2019.01.002DOI Listing
February 2019

Dimethyl fumarate up-regulates expression of major neurotrophic factors in the epidermal neural crest stem cells.

Tissue Cell 2019 Feb 25;56:114-120. Epub 2019 Jan 25.

Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

There is an agreement that combining treatments can lead to substantial improvement, therefore the present study assessed the effects of different concentrations of dimethyl fumarate (DMF) on viability of epidermal neural crest stem cells (EPI-NCSCs). In addition, this investigation was designed to evaluate the effects of DMF on relative expression of major trophic factors mainly the ones with neurotrophic effects, expressed in EPI-NCSCs in order to enhance their therapeutic potential. To determine the appropriate concentration of DMF for EPI-NCSCs treatment, the MTT assay was employed and based on the obtained data, EPI-NCSCs treated with 10μM DMF for 6, 24, 72 or 168 h. In each time point, quantitative RT-PCR technique was used to evaluate NGF, NT-3, BDNF, GDNF and VEGF transcripts. The acquired data showed that 10μM DMF significantly increased the mRNA expression of NGF, NT-3 and BDNF, 72 h following treatment; however, DMF inhibitory effect on GDNF mRNA expression was observed in various time points. No significant changes were detected for VEGF transcript. Our findings reveled that expression of major neurotrophic factors were up-regulated by dimethyl fumarate treatment. Therefore, combining EPI-NCSCs with DMF treatment might be a valuable strategy to improve their therapeutic functions in vivo.
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http://dx.doi.org/10.1016/j.tice.2019.01.004DOI Listing
February 2019

Entorhinal cortex stimulation induces dentate gyrus neurogenesis through insulin receptor signaling.

Brain Res Bull 2019 01 22;144:75-84. Epub 2018 Nov 22.

Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Deep brain stimulation (DBS) has been established as a therapeutically effective method to treat pharmacological resistant neurological disorders. The molecular and cellular mechanisms underlying the beneficial effects of DBS on the brain are not yet fully understood. Beside numerous suggested mechanisms, regulation of neurogenesis is an attractive mechanism through which DBS can affect the cognitive functions. Considering the high expression of insulin receptors in hippocampus and also impaired neurogenesis in diabetic brain, the present study aimed to examine the role of insulin receptor signaling in DBS induced neurogenesis. High frequency stimulation was applied on the entorhinal cortex of rats and then neurogenesis markers in the dentate gyrus region of the hippocampus were examined using molecular and histological methods in the sham, DBS and insulin receptor antagonist-treated groups. In parallel, the changes in insulin receptor signaling in the hippocampus and spatial learning and memory performance were also assessed. DBS promoted adult hippocampal neurogenesis and facilitated the spatial memory concomitant with changes in insulin receptor signaling parameters including IR, IRS2 and GSK3β. Application of insulin receptor antagonist attenuated the DBS-induced neurogenesis. Our data emphasize that entorhinal cortex stimulation promotes adult hippocampal neurogenesis and facilitates spatial learning and memory at least partly through insulin receptors. Notably, GSK3β inhibition can play a major role in the downstream of insulin receptor signaling in DBS induced neurogenesis.
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http://dx.doi.org/10.1016/j.brainresbull.2018.11.011DOI Listing
January 2019

Effects of astaxanthin on sensory-motor function in a compression model of spinal cord injury: Involvement of ERK and AKT signalling pathway.

Eur J Pain 2019 Apr 10;23(4):750-764. Epub 2018 Dec 10.

Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: Spinal cord injury (SCI) causes continuous neurological deficits and major sensory-motor impairments. There is no effective treatment to enhance sensory-motor function following SCI. Thus, it is crucial to develop novel therapeutics for this particular patient population. Astaxanthin (AST) is a strong antioxidant, anti-inflammatory and anti-apoptotic agent. In the present study, it was tested in a severe compression SCI model with emphasis on sensory-motor outcomes, signalling pathway, along with other complications.

Methods: A severe SCI was induced by compression of the rat thoracic spinal cord with an aneurysm clip and treatment with AST or the vehicle was carried out, 30 min after injury. Behavioural tests including open field, von Frey, hot plate and BBB were performed weekly to 28 days post-injury. Rats were assigned to measure blood glucose, weight and auricle temperature. Western blot and histological analysis also were performed at the same time points.

Results: AST decreased mechanical and thermal pain and also improved motor function performance, reduced blood glucose and auricle temperature increases and attenuated weight loss in SCI rats. Western blot analysis showed decreased activation of ERK1/2 and increased activation of AKT following AST treatment. The histology results revealed that AST considerably preserved myelinated white matter and the number of motor neurons following SCI.

Conclusion: Taken together, the beneficial effects of AST to improve sensory-motor outcomes, attenuate pathological tissue damage and modulate ERK and AKT signalling pathways following SCI, suggest it as a strong therapeutic agent towards clinical applications.

Significance: Spinal cord injury (SCI) impairs sensory-motor function and causes complications, which astaxanthin (AST) has the potential to be used as a treatment for. The present study investigates the effects of AST in a compression model of SCI with emphasis on sensory-motor outcomes alongside other complications, histopathological damage and also related signalling pathways.
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http://dx.doi.org/10.1002/ejp.1342DOI Listing
April 2019