Mohammad Javan
Tarbiat Modares University, Physiology, Faculty Member
- Active in the field of Neural regeneration and Repair with focus on Myelin repair in Multiple Sclerosis and neural re... moreActive in the field of Neural regeneration and Repair with focus on Myelin repair in Multiple Sclerosis and neural replacement in Parkinson's disease as well as targeted drug delivery in this context.edit
Research Interests: Biology, Asthma, Medicine, Multidisciplinary, Lung, and 3 morePLoS one, Respiratory System, and Ovalbumin
Multiple sclerosis (MS) is a chronic inflammatory disease, which leads to focal demyelination in the brain and spinal cord. Studies showed that iron released during the course of myelin breakdown exacerbates tissue damage, which is in... more
Multiple sclerosis (MS) is a chronic inflammatory disease, which leads to focal demyelination in the brain and spinal cord. Studies showed that iron released during the course of myelin breakdown exacerbates tissue damage, which is in agreement with the features of iron-dependent cell death, ferroptosis. Here, we aimed to investigate the possible contribution of ferroptosis in the demyelinated optic nerve, and to explore the effectiveness of ferroptosis inhibitor, deferiprone (DFP), on the extent of demyelination, inflammation and axonal damage. For this purpose, focal demyelination was induced by injection of lysolecithin (LPC), into the optic nerve of male C57BL/6J mice. Afterward, optic nerves were harvested at different time points from as early as 6 h up to 7 days post-LPC injection. Next, to evaluate the effectiveness of DFP two groups of animals received daily intraperitoneal injection of DFP for 3 or 7 continuous days. Vehicle groups received saline. Iron deposition was obse...
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<p>Double labeling of BrdU (red) with Olig2, GFAP or PSA-NCAM (green) was done in coronal sections of third ventricle area in different groups. (A–C) BrdU+/GFAP+ cells in the rims of third ventricle of LPC group at 3 (A), 7 (B) and... more
<p>Double labeling of BrdU (red) with Olig2, GFAP or PSA-NCAM (green) was done in coronal sections of third ventricle area in different groups. (A–C) BrdU+/GFAP+ cells in the rims of third ventricle of LPC group at 3 (A), 7 (B) and 14 dpi (C). (D–F) BrdU+/GFAP+ cells in the rims of third ventricle of LPC+siNgR treated animals at 3 (D), 7 (E) and 14 dpi (F). (G–I) BrdU/Olig2 double staining in third ventricle of LPC+siNgR treated animals at 3 (G), 7 (H) and 14 (I) dpi (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106378#pone.0106378.s001" target="_blank">fig. S1D</a>–F for BrdU+/Olig2+ cells in LPC group). (J–L) BrdU/PSA-NCAM positive cells in the third ventricle of LPC+siNgR treated animals at 3 (J), 7 (K) and 14 dpi (L) (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106378#pone.0106378.s001" target="_blank">fig. S1G</a>-I for BrdU+/PSA-NCAM+ cells in LPC group). Square shows the cells magnified in inset. Arrows show double marker positive cells. (M–O) Histograms show quantification of double marker positive cells, BrdU+/GAFP+ (M), BrdU+/Olig2+ (N) and BrdU+/PSA-NCAM+ (O) in different groups. Double marker positive cells per area/mm<sup>2</sup> are averaged from the counts of nine sections of each brain, n = 3. Statistical analysis used two-way ANOVA with Bonferroni's post-test. Differences between groups were significant (p<0.001). The number of BrdU+/GFAP+ cells in third ventricle of LPC 3, 7 and 14 dpi was increased but changes were not significant compared to Control 7dpi (mice received saline inside chiasm), but this type of cells in LPC+siNgR treated animals at 3, 7 and 14 dpi were considerably increased compared to Control (<sup>*</sup>p<0.05, <sup>***</sup>p<0.001, <sup>**</sup>p<0.01, respectively) (M). The number of BrdU+/Olig2+ cells was considerably increased in siNgR-LPC group at 3, 7 and 14 dpi compared to Control (<sup>**</sup>p<0.01, <sup>***</sup>p<0.001; respectively) (N). Additionally in these animals, at 7 dpi the number of BrdU+/Olig2+ was considerably increased compared to LPC 7 dpi (<sup>∧∧∧</sup>p<0.001) (N). The number of BrdU/PSA-NCAM positive cells in the third ventricle of LPC+siNgR treated animals was significantly increased at 3 and 7 dpi (both, p<0.01), while it was significantly increases in LPC treated animals at 7 and 14 dpi (p<0.05, p<0.01; respectively). Data are expressed as Mean ±SEM, Bars: 50 µm.</p
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<p>(A) Real-time PCR shows changes in the expression a set of neural progenitor (NP) gene markers. Data shows increased expression of <i>NESTIN</i>, <i>SOX1,</i> and <i>PAX6</i> relative to hiPSCs... more
<p>(A) Real-time PCR shows changes in the expression a set of neural progenitor (NP) gene markers. Data shows increased expression of <i>NESTIN</i>, <i>SOX1,</i> and <i>PAX6</i> relative to hiPSCs as averaged from three independent experiments. (B) The number of positive cells for NP markers was determined by flowcytometric analysis, which revealed a high percentage of NPs that expressed NESTIN, OTX 2, and SOX1. Sample FACS histograms are presented as <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071855#pone.0071855.s001" target="_blank">Fig. S1</a>. (C) Immunofluorescence staining of hiPSC-NPs showed high expression levels of NESTIN, SOX1, PAX6, and OTX2. The blue stain represents nuclear counterstaining with DAPI. (D) Immunofluorescence staining following spontaneous differentiation of hiPSC-NPs. The representative micrographs of MAPII, TUJ1 as neural markers, and GFAP as a glial marker show a high percentage of neural differentiation. (E) Quantitative data for the percent of positive cells following spontaneous differentiation.</p
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In addition to its antioxidant effect, Vitamin E or α–tocopherol is suggested to enhance remyelination in the animal model of non-inflammatory demyelination. In this study, the possible proliferative effect of vitamin E on human- induced... more
In addition to its antioxidant effect, Vitamin E or α–tocopherol is suggested to enhance remyelination in the animal model of non-inflammatory demyelination. In this study, the possible proliferative effect of vitamin E on human- induced pluripotent stem cell-derived neural progenitors (hiPS-NPs) and the underlying mechanisms were investigated in vitro. NPs were induced from iPS cells via 3 steps within 18 days and then characterized for NPs markers NESTIN, SOX1 and OTX2. MTT assay was used to compare cell populations. LY294002, U0126 and PP2 were used for selective inhibition of enzymes PI3K, MEK and Src-kinase, respectively. Vitamin E increased hiPS-NPs proliferation after 24 and 48 h exposure. The inhibition of both PI3K/Akt and Src-kinase signaling pathways counteracted the effect of vitamin E of NPs. Our data suggest that vitamin E may enhance NPs proliferation via activating PI 3K and Src-kinase and may enhance myelin repair following demyelinating Injuries.
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Objective Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. The autoimmune pathology and long-term inflammation lead to substantial demyelination. These events lead to a substantial loss of oligodendrocytes... more
Objective Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. The autoimmune pathology and long-term inflammation lead to substantial demyelination. These events lead to a substantial loss of oligodendrocytes (OLs), which in a longer period, results in axonal loss and long-term disabilities. Neural cells protection approaches decelerate or inhibit the disease progress to avoid further disability. Previous studies showed that metformin has beneficial effects against neurodegenerative conditions. In this experimental study, we examined possible protective effects of metformin on toxin-induced myelin destruction in adult mice brains. Materials and Methods Lysophosphatidylcholine (LPC) was used to induce demyelination in mice optic chiasm. We examined the extent of demyelination at different time points post LPC injection using myelin staining and evaluated the severity of inflammation. Functional state of optic pathway was evaluated by visual evoked potent...
Research Interests: Multiple sclerosis, Inflammation, Medicine, Metformin, Optic Nerve, and 3 moreCell, Demyelination, and Myelin
Alzheimer’s disease (AD) is one of the most devastating brain disorders. Currently, there are no effective treatments to stop the disease progression and it is becoming a major public health concern. Several risk factors are involved in... more
Alzheimer’s disease (AD) is one of the most devastating brain disorders. Currently, there are no effective treatments to stop the disease progression and it is becoming a major public health concern. Several risk factors are involved in the progression of AD, modifying neuronal circuits and brain cognition, and eventually leading to neuronal death. Among them, obesity and type 2 diabetes mellitus (T2DM) have attracted increasing attention, since brain insulin resistance can contribute to neurodegeneration. Consequently, AD has been referred to “type 3 diabetes” and antidiabetic medications such as intranasal insulin, glitazones, metformin or liraglutide are being tested as possible alternatives. Metformin, a first line antihyperglycemic medication, is a 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activator hypothesized to act as a geroprotective agent. However, studies on its association with age-related cognitive decline have shown controversial results with po...
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Due to recent progress in production of human embryonic stem cell-derived oligodendrocyte progenitor cells (hESC-OPCs) for ameliorating myelin disease such as multiple sclerosis (MS) and the role of purinergic signaling in OPCs... more
Due to recent progress in production of human embryonic stem cell-derived oligodendrocyte progenitor cells (hESC-OPCs) for ameliorating myelin disease such as multiple sclerosis (MS) and the role of purinergic signaling in OPCs development, we avaluated the profile of purinergic receptors expression during development of OPCs from hESC. In this experimental study, we used reverse transcription and quantitative polymerase chain reaction (RT-qPCR) to obtain more information about potential roles of purinergic receptors during in vitro production of hESC-OPCs. We first determined the expression level of different subtypes of purinergic receptors in hESCs, embryoid bodies (EBs), and hESC-OPCs. The effects of A1 adenosine receptor (A1AR) activation on hESC-OPCs development were subsequently examined. hESCs and OPCs had different mRNA expression levels of the AR subtypes. ARs mRNA were expressed in the EB stage, except for A2AAR. We observed expressions of several P2X (P2X1, 2, 3, 4, 5, 7...
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Despite the progress in safety and efficacy of cell replacement therapy with pluripotent stem cells (PSCs), the presence of residual undifferentiated stem cells or proliferating neural progenitor cells (NPCs) with rostral identity remains... more
Despite the progress in safety and efficacy of cell replacement therapy with pluripotent stem cells (PSCs), the presence of residual undifferentiated stem cells or proliferating neural progenitor cells (NPCs) with rostral identity remains a major challenge. Here we report the generation of a LIM homeobox transcription factor 1 alpha (LMX1A) knock-in GFP reporter human embryonic stem cell (hESC) line that marks the early dopaminergic progenitors during neural differentiation to find reliable membrane protein markers for isolation of midbrain dopaminergic neurons. Purified GFP positive cells in vitro exhibited expression of mRNA and proteins that characterized and matched the midbrain dopaminergic identity. Further quantitative proteomics analysis of enriched LMX1A+ cells identified several membrane-associated proteins including polysialylated embryonic form of neural cell adhesion molecule (PSA-NCAM) and contactin 2 (CNTN2), enabling prospective isolation of LMX1A+ progenitor cells. ...
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This study was conducted to evaluate the antinociceptive and anti-inflammatory activities of the essential oil of Nepeta crispa. The study was done using the tail-flick and formalin test pain models and the paw oedema model of... more
This study was conducted to evaluate the antinociceptive and anti-inflammatory activities of the essential oil of Nepeta crispa. The study was done using the tail-flick and formalin test pain models and the paw oedema model of inflammation. Male Wistar rats were used as the animal model. The essential oil dose-dependently produced analgesia in the acute pain models, including the tail-flick (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) and the first phase of the formalin test (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). In the late phase of the formalin test, as a model of chronic pain, the essential oil significantly reduced the pain-induced behaviour (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). Nepeta crispa essential oil caused potent anti-inflammatory effects in the formalin-induced paw inflammation model and significantly reduced the paw oedema in all applied doses (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). Its effects on pain in both the acute and chronic pain models and its anti-inflammatory effect suggest both central and peripheral mechanisms of action for the essential oil obtained from N. crispa.
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Multiple Sclerosis (MS) is an inflammatory demyelinating disorder of central nervous system (CNS). Polyphenol curcumin has been used in traditional medicine as an effective drug for a variety of diseases. Different formulations of... more
Multiple Sclerosis (MS) is an inflammatory demyelinating disorder of central nervous system (CNS). Polyphenol curcumin has been used in traditional medicine as an effective drug for a variety of diseases. Different formulations of curcumin are introduced to increase its stability and effectiveness. Here we have examined the effect of polymerized form of nano-curcumin (PNC) on experimental autoimmune encephalomyelitis (EAE) as an animal model of MS. EAE was induced in female Lewis rats and PNC or curcumin was daily administrated intraperitonealy from day 12-29 post immunization. When the prophylactic effect of PNC was under investigation, rats received PNC from the first day of immunization. Treatment with PNC resulted in decreased scores of disease in therapeutic and prophylactic administration when compared with control group. Staining by luxol fast blue and H&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;E and immuno-staining of lumbar spinal cord cross sections, confirmed a significant decrease in the amounts of demyelination, inflammation and BBB breaking down. Gene expression studies in lumbar spinal cord showed a corrected balance of pro-inflammatory and anti-inflammatory genes expression, decreased oxidative stress, improved remyelination and increased progenitor cell markers after treatment with PNC. Our results demonstrated an efficient therapeutic effect of PNC as an anti-inflammatory and anti-oxidative stress agent, with significant effects on the EAE scores and myelin repair mechanisms.
Research Interests: Pharmacology, Multiple sclerosis, Neuropharmacology, Inflammation, Oxidative Stress, and 15 moreMedicine, Neuroprotection, Curcumin, Blood brain barrier, Female, Animals, Nanostructures, Central Nervous System, Myelin, Experimental Autoimmune Encephalomyelitis, Neurosciences, Neuroprotective Agents, Myelin Sheath, Pharmacology and pharmaceutical sciences, and myelin basic protein
Research Interests: Developmental Biology, Biology, Cellular Neuroscience, Medicine, Multidisciplinary, and 15 moreBiological Sciences, Cell Differentiation, Humans, Anatomy and Physiology, Animals, Male, Cytoprotection, Nerve Regeneration, Cell physiology, Neural, Neural Stem Cells, Induced Pluripotent Stem Cells, Cell Survival, Ciliary Neurotrophic Factor, and Induced
In this study the effect of adenosine A1 receptors of the entorhinal cortex (EC) and amygdala on kindled seizures was investigated. Animals were kindled by daily electrical stimulation of amygdala (group 1) or EC (group 2). In the fully... more
In this study the effect of adenosine A1 receptors of the entorhinal cortex (EC) and amygdala on kindled seizures was investigated. Animals were kindled by daily electrical stimulation of amygdala (group 1) or EC (group 2). In the fully kindled animals, N6-cyclohexyladenosine (CHA), a selective A1 receptor agonist, and 1, 3-dimethyl-8-cyclopenthylxanthine (CPT), a selective A1 receptor antagonist, were microinjected bilaterally into the EC (group 1) or amygdala (group 2). The seizure parameters were measured at 5, 15, 60 and 120min post ...
Research Interests: Biophysics, Chemistry, Long Term Potentiation, Epilepsy, Medicine, and 15 moreAnimals, Male, Clinical Sciences, Dentate Gyrus, Rats, Analysis of Variance, Kindling, Perforant Path, Neurosciences, Gtp Binding Proteins, Gene Expression Regulation, Rolipram, Epileptogenesis, Antidepressive agents, and Electric stimulation
Introduction: Stress inhibits the development of tolerance to morphine analgesia via activating HypothalamicPituitary-Adrenal (HPA) axis. Modified catecholamine systems have been reported following morphine tolerance development. In the... more
Introduction: Stress inhibits the development of tolerance to morphine analgesia via activating HypothalamicPituitary-Adrenal (HPA) axis. Modified catecholamine systems have been reported following morphine tolerance development. In the current study we tried to evaluate changes in the gene expression levels for MAO-A, MAO-B, COMT and thyrosine hydroxylase (TyH) enzymes following chronic pain, development of morphine tolerance and their combined administration. Methods: Analgesic tolerance was induced by intrapritoneal injections of morphine 20 mg/kg twice a day for 4 days. To study the effect of pain on morphine tolerance, 50 µl of formalin 5% was injected into the animal paws prior to morphine injections. Semi-quantitative RT-PCR was used to evaluate the gene expression level in lumbar spinal cord on day 5. Three separate control groups received saline or morphine injections or pain induction. Results: Chronic administration of morphine increased the expression level of MAO-B, dec...
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Multiple sclerosis (MS) is an autoimmune disease which affects myelin in the central nervous system (CNS) and leads to serious disability. Currently available treatments for MS mainly suppress the immune system. Regenerative... more
Multiple sclerosis (MS) is an autoimmune disease which affects myelin in the central nervous system (CNS) and leads to serious disability. Currently available treatments for MS mainly suppress the immune system. Regenerative medicine-based approaches attempt to increase myelin repair by targeting endogenous progenitors or transplanting stem cells or their derivatives. Fingolimod exerts anti-inflammatory effects and directly affects neural cells. In this study we assessed the effect of fingolimod on transplanted human induced pluripotent stem cell derived neural progenitors (hiPSC-NPs). hiPSC-NPs were labeled by green fluorescence protein (GFP) and transplanted into the corpus callosum of mice which were chronically demyelinated after cuprizone (CPZ) feedings for 10 weeks. The animals received fingolimod from 1 day prior to NPs transplantation via gavage as well as daily intraperitoneal cyclosporine A from 2 days before cell transplantation until the time of sampling. At either 7 or ...
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Autoimmune diseases have been described as an interesting and poorly understood group of disorders. There are many challenges in the respective scientific societies concerning the nature, causes and the therapeutic approaches of these... more
Autoimmune diseases have been described as an interesting and poorly understood group of disorders. There are many challenges in the respective scientific societies concerning the nature, causes and the therapeutic approaches of these diseases. In accordance with the evidences the nature and etiology of these disorders is multifactorial and complex but the clearest definition could be expressed as “mosaic of autoimmunity”. Multiple Sclerosis (MS) is an autoimmune disease that affects the Central Nervous System (CNS) resulting in degeneration of the myelin sheaths surrounding the axons of the neurons and death of oligodendrocytes that leads to a wide range of disabilities the in MS patients. The therapy for multiple sclerosis (MS) has changed dramatically over the past decade but overally Treatment of multiple sclerosis (MS) has three aspects: immunomodulatory therapy, therapies to relieve or modify symptoms and cell therapy. Cell Therapy is an emerging form of treatment MS. There ar...
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The generation of oligodendrocyte progenitor cells (OPCs) offers tremendous opportunities for cell replacement therapy in demyelinating diseases such as multiple sclerosis (MS) and spinal cord injury. Recently, the prospect of... more
The generation of oligodendrocyte progenitor cells (OPCs) offers tremendous opportunities for cell replacement therapy in demyelinating diseases such as multiple sclerosis (MS) and spinal cord injury. Recently, the prospect of reprogramming terminally differentiated adult cells towards another mature somatic cell or progenitor cells without an intermediate pluripotent state has been of interest. Trichostatin A is a histone deacetylase inhibitor which opens the chromatin and facilitates the transcription of silence genes. In this study, we have treated human astrocytes line U87 and primary culture of mouse astrocytes with TSA for 12 h, prior their transfer to OPC induction medium. Then we evaluated the morphology and the fate of the treated astrocytes at post-treatment days. Both cell lines acquired OPC morphology and expressed OPC specific markers. Following transfer to differentiation medium, U87-derived iOPCs differentiated to oligodendrocyte like cells and expressed PLP as a matu...
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Introduction: Several researches have reported that stress is able to inhibit the development of morphine tolerance via activating of Hypothalamic-Pituitary-Adrenal (HPA) axis. In the present study we tried to examine the effect of... more
Introduction: Several researches have reported that stress is able to inhibit the development of morphine tolerance via activating of Hypothalamic-Pituitary-Adrenal (HPA) axis. In the present study we tried to examine the effect of epinephrine, the product of adrenal medulla, on the development of morphine tolerance. Methods: Analgesic tolerance was induced by intrathecal (i.t.) injection of morphine 15 μg/kg, twice a day for 5 days. To study the effect of epinephrine on morphine tolerance, epinephrine (2, 5, 10 or 20 μg/kg, i.t.) was administrated 20 minutes before morphine injection. Analgesia was assessed using tail flick test. Results: In animals that received combined treatments of morphine and epinephrine in doses 2, 5, 10 or 20 μg/ kg for 5 days, at 6th day, morphine produced a more potent analgesia comparing with animals that received saline and morphine during days 1-5. Following tolerance induction during first 5 days, co-administration of epinephrine and morphine during d...
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This paper investigates the problem of age of information (AoI) aware radio resource management for a platooning system. Multiple autonomous platoons exploit the cellular wireless vehicle-to-everything (C-V2X) communication technology to... more
This paper investigates the problem of age of information (AoI) aware radio resource management for a platooning system. Multiple autonomous platoons exploit the cellular wireless vehicle-to-everything (C-V2X) communication technology to disseminate the cooperative awareness messages (CAMs) to their followers while ensuring timely delivery of safety-critical messages to the Road-Side Unit (RSU). Due to the challenges of dynamic channel conditions, centralized resource management schemes that require global information are inefficient and lead to large signaling overheads. Hence, we exploit a distributed resource allocation framework based on multi-agent reinforcement learning (MARL), where each platoon leader (PL) acts as an agent and interacts with the environment to learn its optimal policy. Existing MARL algorithms consider a holistic reward function for the group’s collective success, which often ends up with unsatisfactory results and cannot guarantee an optimal policy for each...
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Neuronal survival in multiple sclerosis (MS) and other demyelinating diseases depends on the preservation of myelin and remyelination of axons. Myelin protection is the main purpose to decrease myelin damage in the central nervous system... more
Neuronal survival in multiple sclerosis (MS) and other demyelinating diseases depends on the preservation of myelin and remyelination of axons. Myelin protection is the main purpose to decrease myelin damage in the central nervous system (CNS). Ursolic acid (UA) as a natural product in apple is suggested to protect neural cells. This study is the first to demonstrate an effect for UA on CNS myelin loss induced by cuprizone toxin. In the current study, we hypothesized that daily treatment with UA in drinking water (1 mg/mL) prevents myelin damage by 6 weeks administration of CPZ in mice pellet which lead to corpus callosum axonal demyelination. We assessed the myelin content and the number of myelinating cells in corpus callosum by FluoroMyelin and luxol fast blue staining as well as by immunostaining against MBP and Olig2. Our finding indicated that UA could decrease the extent of demyelination area and enhanced myelin stain intensity within CC and protected oligodendrocyte lineage ...
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Multiple sclerosis (MS) is an autoimmune disease, associated with central nervous system (CNS) inflammation, demyelination, and axonal loss. Myelin, a multilayer membranous that covers nerve fibers, is essential for rapid impulse... more
Multiple sclerosis (MS) is an autoimmune disease, associated with central nervous system (CNS) inflammation, demyelination, and axonal loss. Myelin, a multilayer membranous that covers nerve fibers, is essential for rapid impulse conduction. Oligodendrocytes that are generated either from CNS‐resident oligodendrocyte progenitor cells (OPCs) or subventricular zone‐derived neural stem cells (NSCs) are the myelinating cells of the CNS. The adult CNS maintains a certain endogenous potential to repair myelin damage. However, this process often fails as MS progresses. The origin of this failure is not fully understood, but it is likely to relate to progenitors/stem cells' arrestment in a quiescent state, incapable of generating new oligodendrocyte. Current treatments for MS are immunomodulatory or immunosuppressive medications, with little to no effect on myelin restoration. Recent studies have provided proof‐of‐principle that CNS remyelination can be promoted either via enhancing endogenous remyelination or by transplanting myelinating cells. Curcumin, a natural polyphenolic compound, has been shown to have therapeutic properties in several neurodegenerative diseases. Here, we investigated the effect of a curcumin nanoformulation, dendrosomal nanoparticles (DNC) on oligodendrogenesis and remyelination, both in vitro and in animal model of demyelination. We indicated that DNC enhanced oligodendrogenesis from NSCs and OPCs, in vitro in dose dependent manner. DNC also induced in vivo remyelination via promotion of oligodendrogenesis. Furthermore, DNC enhanced remyelination capacity of transplanted NSCs through promoting their survival and oligodendrogenesis capacity. Our findings suggest that DNC has significant beneficial effects in demyelinating conditions, either as mono‐therapy or as being paired with transplantation approaches.
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Despite the significant differences in pathological background of neurodegenerative diseases, epileptic seizures are a comorbidity in many disorders such as Huntington disease (HD), Alzheimer’s disease (AD), and multiple sclerosis (MS).... more
Despite the significant differences in pathological background of neurodegenerative diseases, epileptic seizures are a comorbidity in many disorders such as Huntington disease (HD), Alzheimer’s disease (AD), and multiple sclerosis (MS). Regarding the last one, specifically, it has been shown that the risk of developing epilepsy is three to six times higher in patients with MS compared to the general population. In this context, understanding the pathological processes underlying this connection will allow for the targeting of the common and shared pathological pathways involved in both conditions, which may provide a new avenue in the management of neurological disorders. This review provides an outlook of what is known so far about the bidirectional association between epilepsy and MS.
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Background Generation of oligodendrocytes is a sophisticated multistep process, the mechanistic underpinnings of which are not fully understood and demand further investigation. To systematically profile proteome dynamics during human... more
Background Generation of oligodendrocytes is a sophisticated multistep process, the mechanistic underpinnings of which are not fully understood and demand further investigation. To systematically profile proteome dynamics during human embryonic stem cell differentiation into oligodendrocytes, we applied in-depth quantitative proteomics at different developmental stages and monitored changes in protein abundance using a multiplexed tandem mass tag-based proteomics approach. Findings Our proteome data provided a comprehensive protein expression profile that highlighted specific expression clusters based on the protein abundances over the course of human oligodendrocyte lineage differentiation. We identified the eminence of the planar cell polarity signalling and autophagy (particularly macroautophagy) in the progression of oligodendrocyte lineage differentiation—the cooperation of which is assisted by 106 and 77 proteins, respectively, that showed significant expression changes in thi...
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Multiple sclerosis is an inflammatory disease of the central nervous system (CNS) in which multiple sites of blood-brain barrier (BBB) disruption, focal inflammation, demyelination and tissue destruction are the hallmarks. Here we show... more
Multiple sclerosis is an inflammatory disease of the central nervous system (CNS) in which multiple sites of blood-brain barrier (BBB) disruption, focal inflammation, demyelination and tissue destruction are the hallmarks. Here we show that sphingosine-1-phosphate receptor 2 (S1PR2) has a negative role in myelin repair as well as an important role in demyelination by modulating BBB permeability. In lysolecithin-induced demyelination of adult mouse spinal cord, S1PR2 inactivation by either the pharmacological inhibitor JTE-013 or S1PR2 gene knockout led to enhanced myelin repair as determined by higher numbers of differentiated oligodendrocytes and increased numbers of remyelinated axons at the lesion sites. S1PR2 inactivation in lysolecithin-induced demyelination of the optic chiasm, enhanced oligodendrogenesis and improved the behavioral outcome in an optokinetic reflex test. In order to see the effect of S1PR2 inactivation on demyelination, experimental autoimmune encephalitis (EAE) was induced by MOG-peptide. S1PR2 inhibition or knockout decreased the extent of demyelinated areas as well as the clinical disability in this EAE model. Both toxin induced and EAE models showed decreased BBB leakage and reduced numbers of Iba1+ macrophages following S1PR2 inactivation. Our results suggest that S1PR2 activity impairs remyelination and also enhances BBB leakage and demyelination. The former effect could be mediated by Nogo-A, as antagonism of this factor enhances remyelination and S1PR2 can act as a Nogo-A receptor.
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Research Interests: Life Sciences, Insulin Resistance, Hippocampus, Insulin, Animals, and 15 moreMale, Neurons, Astrocytes, Rats, Time Factors, Exploratory Behavior, Alzheimer Disease, Maze Learning, Biochemistry and cell biology, Prodromal Symptoms, Gliosis, Tau proteins, Streptozocin, Receptor Insulin, and Pharmacology and pharmaceutical sciences
Opiate withdrawal syndrome is temporally associated with the hyperactivity of locus coeruleus neurons. Previous studies have shown that this hyperactivity, at least in part, results from the activity of excitatory afferents which mainly... more
Opiate withdrawal syndrome is temporally associated with the hyperactivity of locus coeruleus neurons. Previous studies have shown that this hyperactivity, at least in part, results from the activity of excitatory afferents which mainly include the orexinergic neurons of hypothalamus and glutamatergic neurons of paragigantocellularis (PGi) nucleus. The effect of intra LC orexin type 1 receptor antagonism was investigated on expression of glutamate-induced morphine withdrawal-like signs in rats. Regarding the involvement of both orexin and LC in modulation of circadian rhythm, experimental procedures were performed during the rest (day) and the active (night) phases. Male Wistar rats (250-300g) received escalating doses (6, 16, 26, 36, 46, 56, 66mg/kg, 2ml/kg) of morphine sulfate subcutaneously for 7days. Then, glutamate (100nM, 200nl) was microinjected into the LC region and the subsequent behavioral manifestations were visually monitored in both rest and active phases. SB-334867 (a...
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Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system that results in destruction of the myelin sheath wrapped around the axons and eventual axon degeneration. The disease is pathologically... more
Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system that results in destruction of the myelin sheath wrapped around the axons and eventual axon degeneration. The disease is pathologically heterogeneous; however, perhaps its most frustrating aspect is the lack of efficient regenerative response for remyelination. Current treatment strategies are based on anti-inflammatory or immunomodulatory medications that have the potential to reduce the numbers of newly evolving lesions. However, therapies are still required that can repair already damaged myelin for which current treatments are not effective. A prerequisite for the development of such new treatments is understanding the reasons for insufficient endogenous repair. This review briefly summarizes the currently suggested causes of remyelination failure in MS and possible solutions.
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Enhancement of repair potential for degenerative brain diseases has been a research priority during recent years. Considering recent advancements in the field of direct transdifferentiation, conversion of astrocytes as a prominent... more
Enhancement of repair potential for degenerative brain diseases has been a research priority during recent years. Considering recent advancements in the field of direct transdifferentiation, conversion of astrocytes as a prominent component of glial scars to the progenitor cells that contribute to the repair mechanisms seems interesting. Recently, we have reported miR-302/367-mediated in vivo conversion of astrocytes into neuroblasts and neurons. In the current study, we used miR-302/367 and valproate (VPA) to show the possibility of conversion of astrocytes to oligodendrocyte progenitor cells and myelinating cells in a cuprizone (CPZ)-induced model of demyelination. Evaluation of behavioural impairment following CPZ and consequent to the treatments showed functional recovery from impairments. Enhanced remyelination was detected by luxol fast blue staining and immunostaining against two mature myelin markers, myelin basic protein and proteolipid protein. Tracing of transduced cells with green fluorescent protein showed their contribution toward generation of new myelinating cells. These findings have suggested that in vivo specific targeting of astrocytes for forced expression of the miR-302/367 cluster and VPA administration may increase the brain&#39;s potential for repairing myelin insults by the generation of oligodendroglia from astrocytes. This finding may open a new avenue for enhancement of brain repair in neurodegenerative diseases such as multiple sclerosis. Copyright © 2017 John Wiley &amp; Sons, Ltd.
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The impact of mechanical forces on pathogenesis of airway remodeling and the functional consequences in asthma remains to be fully established. In the present study, we investigated the effect of repeated bronchoconstriction induced by... more
The impact of mechanical forces on pathogenesis of airway remodeling and the functional consequences in asthma remains to be fully established. In the present study, we investigated the effect of repeated bronchoconstriction induced by methacholine (MCh) on airway remodeling and airway hyperresponsiveness (AHR) in rats with or without sensitization to an external allergen. We provide evidence that repeated bronchoconstriction, using MCh, alone induces airway inflammation and remodeling as well as AHR in non-allergen-sensitized rats. Also, we found that the airways are structurally and functionally altered by bronchoconstriction induced by either allergen or MCh in allergen-sensitized animals. This finding provides a new animal model for the development of airway remodeling and AHR in mammals and can be used for studying the complex reciprocal relationship between bronchoconstriction and airway inflammation. Further studies on presented animal models are required to clarify the exact mechanisms underlying airway remodeling due to bronchoconstriction and the functional consequences.
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Adenosine is an endogenous, autacoid purine nucleoside which performs many important biological roles, particularly during stressful events. Adenosine can signal through four adenosine receptor (AR) subtypes: A1, A2A, A2B, and A3. Of... more
Adenosine is an endogenous, autacoid purine nucleoside which performs many important biological roles, particularly during stressful events. Adenosine can signal through four adenosine receptor (AR) subtypes: A1, A2A, A2B, and A3. Of these, adenosine A1 receptor (A1AR) has a broad, wide distribution throughout different vertebrate cell types and the highest affinity to adenosine. The A1AR-dependent action of adenosine is well documented in reports from numerous studies that have used different selective A1AR agonists and antagonists as well as in animals that have a genetically manipulated A1AR gene. Despite its wide distribution and function, A1AR homo/hetero-oligomerization with other adenosine and non-adenosine receptors extends its biological role during developmental, physiological, and pathological situations. In this review, we initially discuss the A1AR structure and most important signaling pathway triggered by its activation. Next, we summarize some of the most well-known biological effects of A1AR in the central nervous system (CNS) during development and adulthood, in addition to its role in nervous system regeneration and repair.
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Recent evidence indicates that demyelination occurs in epilepsy patients and kindling animal models. Regarding the well-known literature on anti-inflammatory and myelin protective effects of fingolimod (FTY720) in multiple sclerosis... more
Recent evidence indicates that demyelination occurs in epilepsy patients and kindling animal models. Regarding the well-known literature on anti-inflammatory and myelin protective effects of fingolimod (FTY720) in multiple sclerosis patients and animal models, we hypostatized whether FTY720 administration could exert myelin protective effects in pentylenetetrazol (PTZ)-induced kindling model. To end this, animals received 0.3 or 1mg/kg dosage of FTY720, 1h before PTZ injections. In another approach, after achieving fully kindling stage, FTY720 was administrated i.p. once daily for 7 consecutive days. Treatment with FTY720 (especially lower dose) reduced the frequency of seizures and epileptiform discharges in both approaches. We found that FTY720 administration decreases cell death and glial activation in CA1 and CA3 regions of hippocampus. Myelin protection effect was shown by increasing myelin levels. Furthermore, post-treatment of FTY720 enhanced endogenous remyelination and the number of oligodendrocyte precursor cells in fully kindled animals. Together, these results demonstrate that FTY720 behind the anti-inflammatory and neuroprotection effects has beneficial role in myelin protection and remyelination enhancement in PTZ kindling model of seizure and it may be provide a new therapeutic option for demyelination associated with epilepsy.
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Hippocampal insults have been observed in multiple sclerosis (MS) patients. Fibroblast growth factor-2 (FGF2) induces neurogenesis in the hippocampus and en- hances the proliferation, migration and differentiation of oligodendrocyte... more
Hippocampal insults have been observed in multiple sclerosis (MS) patients. Fibroblast growth factor-2 (FGF2) induces neurogenesis in the hippocampus and en- hances the proliferation, migration and differentiation of oligodendrocyte progenitor cells (OPCs). In the current study, we have investigated the effect of FGF2 on the processes of gliotoxin induced demyelination and subsequent remyelination in the hippocampus. In this experimental study adult male Sprague-Dawley rats re- ceived either saline or lysolecithin (LPC) injections to the right hippocampi. Animals re- ceived intraperitoneal (i.p.) injections of FGF2 (5 ng/g) on days 0, 5, 12 and 26 post-LPC. Expressions of myelin basic protein (Mbp) as a marker of myelination, Olig2 as a marker of OPC proliferation, Nestin as a marker of neural progenitor cells, and glial fibrillary acidic protein (Gfap) as a marker of reactive astrocytes were investigated in the right hippocampi by reverse transcriptase-polymerase chain reaction (RT...
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Memory and cognitive impairments are some of devastating outcomes of Multiple Sclerosis (MS) plaques in hippocampus, the gray matter part of the brain. The present study aimed to evaluate the intrahippocampal injection of Ethidium Bromide... more
Memory and cognitive impairments are some of devastating outcomes of Multiple Sclerosis (MS) plaques in hippocampus, the gray matter part of the brain. The present study aimed to evaluate the intrahippocampal injection of Ethidium Bromide (EB) as a simple and focal model to assess cognition and gray matter demyelination. Thirty Wistar rats were divided into three groups: control group, which received saline, as solvent of EB, into the hippocampus; and two experimental groups, which received 3 μL of EB into the hippocampus, and then, were evaluated 7 and 28 days after EB injection (n=10 in each group), using a 5-day protocol of Morris Water Maze (MWM) task as well as Transmission Electron Microscopy (TEM) assay. Seven days after EB injection, the behavioral study revealed a significance increase in travelled distance for platform finding in the experimental group compared to the control group. In addition, the nucleus of oligodendrocyte showed the typical clumped chromatin, probably ...
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The functional relevance of sigma-1 (σ1 ) receptor expression in the rat hippocampal CA1 during adolescence (i.e., 35-60 days old) was explored. A selective antagonist for the σ1 receptor subtype, BD-1047, was applied to study hippocampal... more
The functional relevance of sigma-1 (σ1 ) receptor expression in the rat hippocampal CA1 during adolescence (i.e., 35-60 days old) was explored. A selective antagonist for the σ1 receptor subtype, BD-1047, was applied to study hippocampal long-term potentiation (LTP) and spatial learning performance. Changes in the expression of the σ1 receptor subtype and its function were compared between castrated and sham-castrated rats. Castration reduced the magnitude of both field excitatory postsynaptic potential (fEPSP)-LTP and population spike (PS)-LTP at 35 days (d). BD-1047 decreased PS-LTP in sham-castrated rats, whereas BD-1047 reversed the effect of castration on fEPSP-LTP at 35 d. In addition, BD1047 impaired spatial learning and augmented σ1 receptor mRNA levels in castrated rats at 35 d. Surprisingly, neither castration nor BD1047 had an effect on fEPSP-LTP and PS-LTP, spatial learning ability or gene expression levels at 45 d. Castration had no effect on fEPSP-LTP but reduced PS-LTP at 60 d. BD1047 increased the magnitude of fEPSP-LTP, but had no effect on PS-LTP in castrated rats at 60 d. However, BD1047 reduced spatial learning ability, and σ1 receptor mRNA levels were decreased in castrated rats at 60 d. This study shows that σ1 receptors play a role in the regulation of both CA1 synaptic efficacy and spatial learning performance. The regulatory role of σ1 receptors in activity-dependent CA1-LTP is locality- and age-dependent, whereas its role in spatial learning ability is only age-dependent. Prepubertal castration-associated changes in the expression and function of the σ1 receptor during adolescence may play a developmental role in the regulation of hippocampal area CA1 activity and plasticity. © 2016 Wiley Periodicals, Inc.
Research Interests: Cognitive Science, Long Term Potentiation, Gene expression, Swimming, Hippocampus, and 11 moreAnimals, Male, Spatial Learning, Learning Disorders, Wistar Rats, Sexual Maturation, Neurosciences, Excitatory Postsynaptic Potentials, real time polymerase chain reaction, Tissue culture techniques, and orchiectomy
Epileptic seizures are characterized with cognitive disorders. In this study we investigated the effect of electrical low frequency stimulation (LFS), as a potential anticonvulsant agent, on kindled seizure-induced cognitive impairments.... more
Epileptic seizures are characterized with cognitive disorders. In this study we investigated the effect of electrical low frequency stimulation (LFS), as a potential anticonvulsant agent, on kindled seizure-induced cognitive impairments. Animals were kindled through electrical stimulation of hippocampal CA1 area in a semi-rapid manner (12 stimulations/day). One group of animals received LFS 4 times at 0.5, 6.5, 24 and 30h following the last kindling stimulation. Applied LFS was consisted of 4 packages at 5min intervals. Each package contained 200 monophasic square wave pulses of 0.1ms duration at 1Hz. The Y-maze test was performed in all animals to measure the spontaneous alternation behavior. Kindled animals showed significant impairment in spontaneous alternation behavior compared to the control group. Application of LFS improved the observed impairment in spontaneous alternation behavior in kindled animals, so that there was no significant difference between kindled+LFS and control group. The observed improving effect of LFS was accompanied with a significant increase in calcineurin gene expression within the hippocampal area. Therefore, it may be postulated that application of LFS in kindled animals, which resulted in increment of calcineurin gene expression, can improve the seizure-induced impairment in spontaneous alternation behavior in Y-maze test.
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Ursolic acid (UA) is a triterpenoid compound, which exerts its influences on the skeletal muscles. However, the mechanisms underlying these effects are still unclear. In this study, muscle satellite cells were isolated and purified by... more
Ursolic acid (UA) is a triterpenoid compound, which exerts its influences on the skeletal muscles. However, the mechanisms underlying these effects are still unclear. In this study, muscle satellite cells were isolated and purified by high-throughput pre-plating method (∼&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;60%) from 10 days old mice skeletal muscles. Evaluation of paired-box 7 (Pax7) expressions then confirmed the purification. Treatment of the cells with UA showed that UA up-regulated SIRT1 (∼35 folds) and overexpressed PGC-1α (∼175 folds) gene significantly. Moreover, the number of muscle satellite cells, which accompanied by initiation of neomyogenesis in the animal skeletal muscles, was increased (∼3.4 times). We also evaluated UA-mediated changes in the cellular energy status in the skeletal muscles. The results revealed that in the UA-treated mice, ATP and ADP contents in the various skeletal muscle tissue types, including: Gastrocnemius (Gas), Tibialis Anterior (Tib) and Gluteus Maximus (Glu) have been significantly decreased (P≤0.001); 2.2, 3.2, 2 times for ATP, and 9.6, 35.7, 11.6 times for ADP, respectively; however to compensate this process mitochondrial biogenesis occurred (12.33%±1.5 times). Furthermore, a rise in ATP/ADP ratio was observed 2.5, 4.5, 2.05 times for Gas, Tib and Glu muscles, respectively (P≤0.001). Alternatively, UA enhanced the expression of myoglobin (∼2 folds) in concert with remodeling of glycolytic muscle fibers to mainly fast IIA (∼30%) and slow-twitch (∼4%) types as well. Finally, our study indicated that UA indirectly mimicked beneficial effects of short-term calorie restriction and exercise (fast-oxidative) by directing the skeletal muscle composition toward oxidative metabolism.
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Animal models simulate different aspects of human diseases and are essential to get a better understanding of the disease, studying treatments and producing new drugs. Experimental autoimmune encephalomyelitis (EAE) is a preferred model... more
Animal models simulate different aspects of human diseases and are essential to get a better understanding of the disease, studying treatments and producing new drugs. Experimental autoimmune encephalomyelitis (EAE) is a preferred model in multiple sclerosis research. Common EAE model in Lewis rats is induced using MBP peptide as a myelin antigen which results in a monophasic disease course. In the present study, EAE was induced in Lewis rats by homogenized guinea pig spinal cord along with or without pertussis toxin (PT). When PT was used, EAE turned into remitting-relapsing form and worsen the clinical symptoms. Higher inflammation and oxidative stress marker gene expression was observed when PT was administrated.
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ATP-sensitive potassium channels are supposed to have a substantial role in improvement of cardiac performance. This study was performed to evaluate whether nandrolone decanoate (ND) and (or) exercise training could affect the expression... more
ATP-sensitive potassium channels are supposed to have a substantial role in improvement of cardiac performance. This study was performed to evaluate whether nandrolone decanoate (ND) and (or) exercise training could affect the expression of cardiac KATP channel subunits. Thirty-five male albino Wistar rats were randomly divided into 5 groups, including sedentary control (SC), sedentary vehicle (SV), sedentary ND (SND), exercise control (EC), and exercise and ND (E+ND). Exercise training was performed on a treadmill 5 times per week. ND was injected (10 mg/kg/week, i.m.) to the rats in the SND and E+ND groups. Following cardiac isolation, the expression of both sarcolemmal and mitochondrial subunits of KATP channel was measured using Western blot method. The expression of sarcolemmal, but not mitochondrial, subunits of KATP channel (Kir6.2 and SUR2) of EC group was significantly higher compared with SC group while ND administration (SND group) did not show any change in their express...