Publications by authors named "Soraya Mehrabi"

22 Publications

  • Page 1 of 1

The Roles of Serotonin in Neuropsychiatric Disorders.

Cell Mol Neurobiol 2021 Mar 2. Epub 2021 Mar 2.

Division of Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.

The serotonergic system extends throughout the central nervous system (CNS) and the gastrointestinal (GI) tract. In the CNS, serotonin (5-HT, 5-hydroxytryptamine) modulates a broad spectrum of functions, including mood, cognition, anxiety, learning, memory, reward processing, and sleep. These processes are mediated through 5-HT binding to 5-HT receptors (5-HTRs), are classified into seven distinct groups. Deficits in the serotonergic system can result in various pathological conditions, particularly depression, schizophrenia, mood disorders, and autism. In this review, we outlined the complexity of serotonergic modulation of physiologic and pathologic processes. Moreover, we provided experimental and clinical evidence of 5-HT's involvement in neuropsychiatric disorders and discussed the molecular mechanisms that underlie these illnesses and contribute to the new therapies.
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http://dx.doi.org/10.1007/s10571-021-01064-9DOI Listing
March 2021

Combination Therapy of Killing Diseases by Injectable Hydrogels: From Concept to Medical Applications.

Adv Healthc Mater 2021 02 4;10(3):e2001571. Epub 2020 Dec 4.

Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, FI-00014, Finland.

The complexity of hard-to-treat diseases strongly undermines the therapeutic potential of available treatment options. Therefore, a paradigm shift from monotherapy toward combination therapy has been observed in clinical research to improve the efficiency of available treatment options. The advantages of combination therapy include the possibility of synchronous alteration of different biological pathways, reducing the required effective therapeutic dose, reducing drug resistance, and lowering the overall costs of treatment. The tunable physical properties, excellent biocompatibility, facile preparation, and ease of administration with minimal invasiveness of injectable hydrogels (IHs) have made them excellent candidates to solve the clinical and pharmacological limitations of present systems for multitherapy by direct delivery of therapeutic payloads and improving therapeutic responses through the formation of depots containing drugs, genes, cells, or a combination of them in the body after a single injection. In this review, currently available methods for the design and fabrication of IHs are systematically discussed in the first section. Next, as a step toward establishing IHs for future multimodal synergistic therapies, recent advances in cancer combination therapy, wound healing, and tissue engineering are addressed in detail in the following sections. Finally, opportunities and challenges associated with IHs for multitherapy are listed and further discussed.
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http://dx.doi.org/10.1002/adhm.202001571DOI Listing
February 2021

Thermo-responsive chitosan hydrogel for healing of full-thickness wounds infected with XDR bacteria isolated from burn patients: In vitro and in vivo animal model.

Int J Biol Macromol 2020 Dec 1;164:4475-4486. Epub 2020 Sep 1.

Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran. Electronic address:

Treatment of non-healing skin wounds infected with extensively drug-resistant (XDR) bacteria remains as a big challenge. To date, different biomaterials have been applied for treatment of post-wound infections, nevertheless their efficacy for treatment of the wounds infected with XDR isolates has not been determined yet. In this study, the potential of the thermo-responsive chitosan (TCTS) hydrogel for protection of full-thickness wounds XDR bacteria isolated from burn patients was evaluated both in vitro and in vivo in a rat model. Antibacterial activity of the TCTS hydrogel against standard strain and clinical isolates of Acinetobacter baumannii, cytobiocompatibility for Hu02 fibroblast cells, degradation rate and swelling ratio were determined in vitro. MTT assay and disk diffusion test indicated no detectable cytotoxicity and antibacterial activity in vitro, respectively. In vivo study showed significant acceleration of wound healing, re-epithelialization, wound closure, and decreased colony count in the TCTS hydrogel group compared with control. This study suggests TCTS hydrogel as an excellent wound dressing for management of the wounds infected with XDR bacteria, and now promises to proceed with clinical investigations.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.08.239DOI Listing
December 2020

The Interplay of Tau Protein and β-Amyloid: While Tauopathy Spreads More Profoundly Than Amyloidopathy, Both Processes Are Almost Equally Pathogenic.

Cell Mol Neurobiol 2020 Jul 22. Epub 2020 Jul 22.

Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.

Alzheimer's disease (AD) is a neurodegenerative disorder, in which amyloid precursor protein (APP) misprocessing and tau protein hyperphosphorylation are well-established pathogenic cascades. Despite extensive considerations, the central mediator of neuronal cell death upon AD remains under debate. Therefore, we examined the direct interplay between tauopathy and amyloidopathy processes. We employed primary culture neurons and examined pathogenic P-tau and Aβ oligomers upon hypoxia treatment by immunofluorescence and immunoblotting. We observed both tauopathy and amyloidopathy processes upon the hypoxia condition. We also applied Aβ or P-tau onto primary cultured neurons. We overexpressed P-tau in SH-SY5Y cells and found Aβ accumulation. Furthermore, adult male rats received Aβ or pathogenic P-tau in the dorsal hippocampus and were examined for 8 weeks. Learning and memory performance, as well as anxiety behaviors, were assessed by Morris water maze and elevated plus-maze tests. Both Aβ and pathogenic P-tau significantly induced learning and memory deficits and enhanced anxiety behavior after treatment 2 weeks. Aβ administration induced robust tauopathy distribution in the cortex, striatum, and corpus callosum as well as CA1. On the other hand, P-tau treatment developed Aβ oligomers in the cortex and CA1 only. Our findings indicate that Aβ and pathogenic P-tau may induce each other and cause almost identical neurotoxicity in a time-dependent manner, while tauopathy seems to be more distributable than amyloidopathy.
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http://dx.doi.org/10.1007/s10571-020-00906-2DOI Listing
July 2020

Valproic acid administration exerts protective effects against stress-related anhedonia in rats.

J Chem Neuroanat 2020 04 13;105:101768. Epub 2020 Feb 13.

Department of Biotechnology, School of Allied Medical Science, Iran University of Medical Science, Tehran, Iran.

Anhedonia or inability to experience pleasure is the sign of various neuropsychiatric conditions. Current treatment options do not provide adequate control of anhedonia. The present study was conducted to evaluate the protective effects of valproic acid (VPA) as a nonspecific histone deacetylase (HDAC) inhibitor to reverse the effects of stress on induction of anhedonia and explore possible mechanisms. To induce anhedonia, a rat model of chronic unpredictable mild stress (CUMS) was established. Animals were assigned into no stress, stress (6 weeks of CUMS) and two treatment groups. VPA treatment was carried out for 4 continuous weeks (200 mg/kg/day). Behavioral assessments were performed using sucrose consumption (SCT) and new object recognition (NOR) tests. The expression of genes was evaluated using qRT-PCR. The cell density was determined using Nissl staining. Rats with CUMS showed depressive-like behaviors and impaired memory performance compared with the non-stressed group (p < 0.01). Moreover, they had significantly higher levels of HDAC3 and MC4R expression in the nucleus accumbens (NAc) compared to the non-stressed group (p < 0.01). The NAc cell density was significantly higher in the non-stressed rats (p < 0.05). Corticosterone plasma level was increased in the CUMS compared to the non-stressed group (p < 0.05). In the CUMS + VPA subgroup, the corticosterone (CORT) plasma level was lower compared with the CUMS + Saline and/or the CUMS groups (p < 0.05). These findings suggest that VPA can improve anhedonia and stress. Although the protective effect of VPA might link to decreasing HDAC3 and MC4R genes expression in NAc.
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http://dx.doi.org/10.1016/j.jchemneu.2020.101768DOI Listing
April 2020

Effect of mesenchymal stem cells on glial cells population in cuprizone induced demyelination model.

Neuropeptides 2019 Jun 13;75:75-84. Epub 2019 Apr 13.

Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran; Cellular and Molecular Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran. Electronic address:

Mesenchymal stem cells (MSCs) have a notable potential to modulate immune responses and protect the central nervous system (CNS), mostly by secreting factors that affect inflammation. MSCs have the ability to improve several autoimmune diseases in animal models including multiple sclerosis (MS). MS is a disease of the CNS among adult humans and it is characterized by demyelination, neuroinflammation and gliosis. In this study, we first induced chronic demyelination by cuprizone, followed by intraventricular injection of MSC. Our results showed that MSC significantly decreased microgliosis and astrocytosis by secreting cytokines that have neuroprotective activity including TGF-β and CX3CL1. Also, downregulation of IL-1β and TNF-α as inflammatory chemokines was seen along with decreased astrocytes and microglia activation. Finally, these results showed that trophic factors secreted by MSC can increase oligodendrocyte population and remyelination rate by reducing pro-inflammatory factors. These findings demonstrate that MSC could decrease inflammation, gliosis and demyelination with neuroprotective and immunomodulating properties in chronic cuprizone demyelination model. Therefore MSC transplantation can be considered as a suitable approach for enhancing myelination and reducing inflammation in diseases such as MS.
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http://dx.doi.org/10.1016/j.npep.2019.04.001DOI Listing
June 2019

The Effect of Alpha-Tocopherol on Morphine Tolerance-induced Expression of c-fos Proto-oncogene from a Biotechnological Perspective.

Recent Pat Biotechnol 2019 ;13(2):137-148

Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.

Background: The increase of oxidant compounds is the most well-known reasons for the tolerance to the analgesic properties of Morphine. Additionally, the production of proxy-nitrite impairs receptors, proteins and enzymes involved in the signaling pathways of analgesia, apoptosis and necrosis. Also, we revised all patents relating to opioid tolerance control methods.

Objective: The aim of this study was to assess the effects of Alpha-tocopherol as an anti-oxidant agent to reduce Morphine tolerance.

Method: Forty male rats randomly divided into four groups. 10 mg/kg of morphine was injected subcutaneously to create the desired level of tolerance. After modeling, 70 mg/kg Alpha- Tocopherol was injected intraperitoneal. Also, the hot plate recorded pain threshold alterations was used to evaluate the behavioral test. All tissue samples were extracted from the spinal cord, thalamus and frontal cortex for molecular and gene expression evaluations. Also, the effect of Alpha- Tocopherol on the apoptosis and necrosis parameters was analyzed using nissl staining and tunel test.

Results: The time latency results showed that there were no significant differences in the different days in groups treated with Morphine plus Alpha-Tocopherol. However, our data highlighted that the pain threshold and their time latency in respond to it had substantially increased in comparison with the control group. Furthermore, we found that the Alpha-Tocopherol obviously decreased c-fos gene expression, especially in the spinal cord.

Conclusion: Thus, co-administration of Alpha-Tocopherol with Morphine can decrease the adverse effects of nitrite proxy, which is released due to repeated injections of Morphine.
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http://dx.doi.org/10.2174/1872208312666181120105333DOI Listing
June 2019

Mesenchymal stem cell mediated effects on microglial phenotype in cuprizone-induced demyelination model.

J Cell Biochem 2019 08 8;120(8):13952-13964. Epub 2019 Apr 8.

Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.

Microglial cells have an essential role in neurodegenerative disorders, such as multiple sclerosis. They are divided into two subgroups: M1 and M2 phenotypes. Mesenchymal stem cells (MSC), with neuroprotective and immunomodulating properties, could improve these diseases. We evaluate the immunomodulating effects of MSC on microglial phenotypes and the improvement of demyelination in a cuprizone (CPZ) model of multiple sclerosis (MS). For inducing the chronic demyelination model, C57BL6 mice were given a diet with 0.2% CPZ (w/w) for 12 weeks. In the MSC group, cells were transplanted into the right lateral ventricle of mice. The expression of targeted genes was assessed by real-time polymerase chain reaction. M1 and M2 microglial phenotypes were assessed by immunohistochemistry of inducible nitric oxide synthase (iNOS) and Arg-1, respectively. Remyelination was studied by luxal fast blue (LFB) staining and electron microscopy (EM). We found that MSC transplantation reduced the expression level of M1-specific messenger RNA (mRNA; iNOS and CD86) but increased the expression level of M2 specific genes (CD206, Arg-1, and CX3CR1) in comparison to the CPZ group. Moreover, cell therapy significantly decreased the M1 marker (iNOS cells), but M2 marker (Arg-1 cells) significantly increased in comparison with the CPZ group. In addition, MSC treatment significantly increased the CX3CL1 expression level in comparison with the CPZ group and led to improvement in remyelination, which was confirmed by LFB and EM images. The results showed that MSC transplantation increases the M2 and decreases the M1 phenotype in MS. This change was accompanied by decrease in demyelination and axonal injury and indicated that MSCs have a positive effect on MS by modification of microglia cells.
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http://dx.doi.org/10.1002/jcb.28670DOI Listing
August 2019

Effect of Co-administration of Bumetanide and Phenobarbital on Seizure Attacks in Temporal Lobe Epilepsy.

Basic Clin Neurosci 2018 Nov-Dec;9(6):408-416. Epub 2018 Nov 1.

Department of Tissue Engineering & Regenerative Medicine, School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.

Introduction: The resistance of temporal lobe epilepsy to classic drugs is thought to be due to disruption in the excitation/inhibition of this pathway. Two chloride transporters, NKCC1 and KCC2, are expressed differently for the excitatory state of Gamma-Amino Butyric Acid (GABA). The present study explored the effect of bumetanide as a selective NKCC1 inhibitor either alone or in combination with the phenobarbital in the pilocarpine model of epilepsy.

Methods: An animal model of Status Epilepticus (SE) was induced with pilocarpine in Wistar male rats followed by phenobarbital and or bumetanide or saline administration for 45 days after the induction of SE by Intraperitoneal (IP) injection. The rats were monitored, their behavior was recorded, and after 24 hours they were sacrificed to study the expression of NKCC1 and KCC2 using real time PCR.

Results: The data showed that the effects of a combination of bumetanide with phenobarbital on frequency rate and duration of seizure attack were more than those of the phenobarbital alone. In addition, in the bumetanide and combined treatment groups, NKCC1 expression decreased significantly, compared with untreated epileptic animals. A delayed decrement in NKCC1/KCC2 expression ratio after bumetanide application was also observed.

Conclusion: The combination of bumetanide with phenobarbital increases the inhibition of SE and maximizes the potential of GABA signaling pathway, and can be considered as an effective therapeutic strategy in patients with epilepsy.
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http://dx.doi.org/10.32598/bcn.9.6.408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359685PMC
November 2018

Transplantation of Adipose Tissue-Derived Stem Cells into Brain Through Cerebrospinal Fluid in Rat Models: Protocol Development and Initial Outcome Data.

Curr Stem Cell Res Ther 2019 ;14(2):191-195

Cellular and Molecular Research center, Iran University of Medical Sciences, Tehran, Iran.

Background: Cell therapy is an important strategy for the treatment of incurable diseases including those that occur in the Central Nervous System (CNS). Among different strategies, the method of delivering or transplantation of cells into the brain has shown significant effects on regeneration. In this study, a new protocol has been developed for the transplantation of adipose tissuederived stem cells into the brain through Cerebrospinal Fluid (CSF) in rat models.

Methods: For this purpose, a wide range of ages (7-30 days old) of male neonates of Wistar rats was used. Moreover, human adipose tissue was obtained from a superficial layer of abdomen through liposuction surgery. The size of the inserted part of needle to access middle cranial fossa and subarachnoid space in animals with an average weight of 10-80 g was determined. In addition, to confirm the entrance of needle into the subarachnoid space, CSF was aspirated slowly and then injection was done within two minutes.

Results: The findings showed the presence of transplanted human Adipose-Derived Stem Cells (hADSC) in the cerebellum and basal ganglia following three days and also after two months that confirmed the entrance of transplanted cells into the cerebrospinal fluid and migration of them into the brain tissue. All the animals survived after the transplantation process, with the lowest side effects compared to the available conventional methods.

Conclusion: It can be concluded that the cells could be efficiently transplanted into CSF through subarachnoid space by injection via superior orbital fissure with a minimally invasive technique.
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http://dx.doi.org/10.2174/1574888X13666180720112322DOI Listing
July 2019

Blockade of p75 Neurotrophin Receptor Reverses Irritability and Anxiety-Related Behaviors in a Rat Model of Status Epilepticus

Iran Biomed J 2018 07 7;22(4):264-74. Epub 2017 Nov 7.

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

Background: Many recent epidemiological studies have shown that epileptic patients are more likely suffer from depression, anxiety, and irritability. However, the cellular mechanisms of epilepsy-induced psychotic behaviors are not fully elucidated. Neurotrophin receptors have been suggested to be involved in epilepsy and also in psychiatric disorders. Up-regulation of p75NTR expression and activation of p75NTR signalling cascades after the seizure have been shown, but the role of the p75 receptor in epilepsy-induced psychotic behaviors has not been documented so far. Therefore, the present work aimed to investigate the effect of p75 receptor blockade on seizure activity, irritability, and anxiety-like behaviors in a rat model of status epilepticus.

Methods: Rats were injected with pilocarpine (350 mg/ kg, i.p.) to induce status epilepticus. Then various behavioral tests were performed after the blockade of p75NTR alone or in combination with p75 antagonist and phenobarbital. Molecular analysis by PCR was performed to investigate the expression of p75 and pro-NGF.

Results: Molecular findings indicated a high level of mRNA expression for both p75 receptors and pro-NGF in the epileptic model group. Results also showed that the administration of p75 antagonist alone or in combination with phenobarbital was able to significantly influence the behavioral responses. Furthermore, 20-hours video monitoring showed a decrease in the frequency and duration of seizures in the rat group receiving p75 antagonist.

Conclusion: Taken together, the present study suggests that the blockade of the p75 receptor may affect the irritability and anxiety-related behavior in a rat model of status epilepticus.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949129PMC
http://dx.doi.org/10.22034/ibj.22.4.264DOI Listing
July 2018

Evaluation of metformin effects in the chronic phase of spontaneous seizures in pilocarpine model of temporal lobe epilepsy.

Metab Brain Dis 2018 02 27;33(1):107-114. Epub 2017 Oct 27.

Cellular and Molecular Research Center, Iran University of Medical Science, Tehran, Iran.

Temporal lobe epilepsy (TLE) is a common form of drug-resistant epilepsy that sometimes responds to dietary manipulation such as the 'ketogenic diet'. Here we have investigated the effects of metformin in the rat pilocaroin model of TLE. Male rats were treated with intra peritoneal injection of pilocarpine hydrochloride, in dose of 360 mg/kg to induce status epilepticus (SE). At 45 day after induction of SE, metformin was injected intraperitoneally in dose of 250 mg/kg/day for 5 days. We show that metformin potently reduces the progression of seizures and blocks seizure-induced over-expression of brain-derived neurotropic factor (BDNF) and its receptor, Tropomyosin receptor kinase B (TrkB). We have shown that this reduced expression pattern is mediated by the transcriptional co-repressor CtBP (C-terminal binding protein). Moreover, metformin decreased mechanistic target of rapamycin (mTOR) activation through activation of AMP-activated protein kinase (AMPK) signaling pathway. Our findings have been shown that metformin has anticonvulsant and antiepileptic properties, and suggesting that antiglycolytic compounds such as metformin may represent a new class of drugs for treating epilepsy.
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http://dx.doi.org/10.1007/s11011-017-0132-zDOI Listing
February 2018

Effect of bumetanide, a selective NKCC1 inhibitor, on hallucinations of schizophrenic patients; a double-blind randomized clinical trial.

Schizophr Res 2017 06 9;184:145-146. Epub 2016 Dec 9.

Division of Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran. Electronic address:

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http://dx.doi.org/10.1016/j.schres.2016.12.002DOI Listing
June 2017

Lack of the effect of bumetanide, a selective NKCC1 inhibitor, in patients with schizophrenia: A double-blind randomized trial.

Psychiatry Clin Neurosci 2017 Jan 21;71(1):72-73. Epub 2016 Dec 21.

Division of Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.

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http://dx.doi.org/10.1111/pcn.12475DOI Listing
January 2017

Methamphetamine-induced psychosis is associated with DNA hypomethylation and increased expression of AKT1 and key dopaminergic genes.

Am J Med Genet B Neuropsychiatr Genet 2016 12 18;171(8):1180-1189. Epub 2016 Oct 18.

Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts.

Methamphetamine, one of the most frequently used illicit drugs worldwide, can induce psychosis in a large fraction of abusers and it is becoming a major problem for the health care institutions. There is some evidence that genetic and epigenetic factors may play roles in methamphetamine psychosis. In this study, we examined methamphetamine-induced epigenetic and expression changes of several key genes involved in psychosis. RNA and DNA extracted from the saliva samples of patients with methamphetamine dependency with and without psychosis as well as control subjects (each group 25) were analyzed for expression and promoter DNA methylation status of DRD1, DRD2, DRD3, DRD4, MB-COMT, GAD1, and AKT1 using qRT-PCR and q-MSP, respectively. We found statistically significant DNA hypomethylation of the promoter regions of DRD3 (P = 0.032), DRD4 (P = 0.05), MB-COMT (P = 0.009), and AKT1 (P = 0.0008) associated with increased expression of the corresponding genes in patients with methamphetamine psychosis (P = 0.022, P = 0.034, P = 0.035, P = 0.038, respectively), and to a lesser degree in some of the candidate genes in non-psychotic patients versus the control subjects. In general, methamphetamine dependency is associated with reduced DNA methylation and corresponding increase in expression of several key genes involved in the pathogenesis of psychotic disorders. While these epigenetic changes can be useful diagnostic biomarkers for psychosis in methamphetamine abusers, it is also consistent with the use of methyl rich diet for prevention or suppression of psychosis in these patients. However, this needs to be confirmed in future studies. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.b.32506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115129PMC
December 2016

Brain Derived Neurotrophic Factor Modification of Epileptiform Burst Discharges in a Temporal Lobe Epilepsy Model.

Basic Clin Neurosci 2016 Apr;7(2):115-20

Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.; Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.

Introduction: Transforming Growth Factor-Beta 1 (TGF-β1) is a pleiotropic cytokine with potent anti-inflammatory property, which has been considered as an essential risk factor in the inflammatory process of Ischemic Stroke (IS), by involving in the pathophysiological progression of hypertension, atherosclerosis, and lipid metabolisms. -509C/T TGF-β1 gene polymorphism has been found to be associated with the risk of IS. The aim of this meta-analysis was to provide a relatively comprehensive account of the relation between -509C/T gene polymorphisms of TGF-β1 and susceptibility to IS.

Methods: Male Wistar rats were divided into sham (receiving phosphate buffered saline within dorsal hippocampus), pilocarpine (epileptic model of TLE), single injection BDNF (epileptic rats which received single high dose of BDBF within dorsal hippocampus), and multiple injections BDNF (epileptic rats which received BDNF in days 10, 11, 12, and 13 after induction of TLE) groups. Their electrocorticogram was recorded and amplitude, frequency, and duration of spikes were evaluated.

Results: Amplitude and frequency of epileptiform burst discharges were significantly decreased in animals treated with BDNF compared to pilocarpine group.

Conclusion: Our findings suggested that BDNF may modulate the epileptic activity in the animal model of TLE. In addition, it may have therapeutic effect for epilepsy. More studies are necessary to clarify the exact mechanisms of BDNF effects.
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http://dx.doi.org/10.15412/J.BCN.03070205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892316PMC
April 2016

Activation and Regulation of NLRP3 Inflammasome by Intrathecal Application of SDF-1a in a Spinal Cord Injury Model.

Mol Neurobiol 2016 07 14;53(5):3063-3075. Epub 2015 May 14.

Institute of Neuroanatomy, RWTH Aachen University, 52074, Aachen, Germany.

Stromal cell-derived factor-1 alpha (SDF-1a) or CXCL12 is an important cytokine with multiple functions in the brain during development and in adulthood. The inflammatory response initiated by spinal cord injury (SCI) involves the processing of interleukin-1beta (IL-1ß) and IL-18 mediated by caspase-1 which is under the control of an intracellular multiprotein complex termed inflammasome. Using an SCI rat model, we found improved functional long-term recovery which is paralleled by a reduction of apoptosis after intrathecal treatment with SDF-1a. An intriguing aspect is that SDF-1a changed the number of neuroinflammatory cells in the damaged area. We further examined the cellular localization and sequential expression of several inflammasomes during SCI at 6 h, 24 h, 3 days, and 7 days as well as the role of SDF-1a as a regulatory factor for inflammasomes. Using 14-week old male Wistar rats, spinal cord contusion was applied at the thoracic segment 9, and animals were subsequently treated with SDF-1a via intrathecal application through an osmotic pump. SCI temporally increased the expression of the inflammasomes NLRP3, ASC, the inflammatory marker tumor necrosis factor-a (TNF-a), interleukin-1ß (IL-1β) and IL-18. SDF-1a significantly reduced the levels of IL-18, IL-1b, TNF-a, NLRP3, ASC, and caspase-1. Immunofluorescence double-labeling demonstrated that microglia and neurons are major sources of the ASC and NLRP3 respectivley. Our data provide clear evidence that SCI stimulates a complex scenario of inflammasome activation at the injured site and that SDF-1a-mediated neuroprotection presumably depends on the attenuation of the inflammasome complex.
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http://dx.doi.org/10.1007/s12035-015-9203-5DOI Listing
July 2016

Vitamin D3 influence the Th1/Th2 ratio in C57BL/6 induced model of experimental autoimmune encephalomyelitis.

Iran J Basic Med Sci 2014 Oct;17(10):785-92

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

Objectives: Multiple Sclerosis (MS) is known as a progressive inflammatory CNS disease. Cytokines belong to Th1 or Th2 family and inflammatory cells, play significant role in pathophysiology of MS. Thus, any treatment supposed to influence the relation between Th1 to Th2 cytokines expression. Although vitamin D has been prescribed as a therapeutic supplement of MS for a long time, it is not clear how much it may affect the Th1/Th2 ratio. To answer this question the present research was designed.

Materials And Methods: Thirty C57BL/6 adult female mice were used. The animals were randomly divided into trial and control groups. Experimental Autoimmune Encephalomyelitis (EAE) modeling for MS and clinical scoring as cited by others was used. Based on scoring and step of the disease vitamin D3 prescription (5 mg/kg) started and continued for three weeks.

Results: By using ELISA and RT-PCR the brain level of TNF-α, IL-10, IL-4 and IL-12 determined. Significant decrease of clinical symptoms in trial group which received vitamin D was seen comparing to control animals (P<0.05). The level of TNF-α but not IL-10 significantly decreased following vitamin D3 administration. By comparing the level of Th1 and Th2 Interleukins and counting the ratio of them we found that in treated animals the ratio was significantly less than non-treated (P=0.01).

Conclusion: According to the results, vitamin D3 may be able to suppress the inflammatory ways that lead to progression of MS. Whether this ability is clinically valuable in human subjects is not clear and needs more clinical research.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340987PMC
October 2014

BDNF modifies hippocampal KCC2 and NKCC1 expression in a temporal lobe epilepsy model.

Acta Neurobiol Exp (Wars) 2014 ;74(3):276-87

Department of Neuroscience, School of Advanced Technologies in Medicine,

Excitatory GABA actions, induced by altered expression of chloride transporters (KCC2/NKCC1), can contribute to seizure generation in temporal lobe epilepsy. In the present study, we evaluated whether BDNF administration can affect KCC2/NKCC1 expression, ictogenesis and behavioral alterations in this paradigm. Status epilepticus was induced in male rats with pilocarpine, followed by a treatment of either a single high dose or multiple injections of BDNF during the latent phase of temporal lobe epilepsy. Chloride transporters expression, spontaneous recurrent seizures, and hyperexcitability post-seizural behaviors were evaluated after treatment. NKCC1 protein expression was markedly upregulated, whereas that of KCC2 was significantly downregulated in epileptic hippocampi compared to intact controls. Application of BDNF (both single high dose and multiple injections) increased KCC2 expression in epileptic hippocampi, while NKCC1 expression was downregulated exclusively by the single high dose injection of BDNF. Development of spontaneous recurrent seizures was delayed but not prevented by the treatment, and hyperexcitability behaviors were ameliorated for a short period of time. To prevent GABA-A mediated depolarization and design appropriate treatment strategies for temporal lobe epilepsy, chloride transporters can be considered as a target. Future studies are warranted to investigate any possible therapeutic effects of BDNF via altering chloride transporters expression.
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May 2015

Neuronal differentiation of rat hair follicle stem cells: the involvement of the neuroprotective factor Seladin-1 (DHCR24).

Iran Biomed J 2014 07;18(3):136-42

Iran National Science Foundation, Tehran, Iran.

Background: The seladin-1 (selective Alzheimer disease indicator-1), also known as DHCR24, is a gene found to be down-regulated in brain region affected by Alzheimer disease (AD). Whereas, hair follicle stem cells (HFSC), which are affected in with neurogenic potential, it might to hypothesize that this multipotent cell compartment is the predominant source of seladin-1. Our aim was to evaluate seladin-1 gene expression in hair follicle stem cells.

Methods: In this study, bulge area of male Wistar rat HFSC were cultured and then characterized with Seladin-1 immunocytochemistry and flow cytometry on days 8 to 14. Next, 9-11-day cells were evaluated for seladin-1 gene expression by real-time PCR.

Results: Our results indicated that expression of the seladin-1 gene (DHCR24) on days 9, 10, and 11 may contribute to the development of HFSC. However, the expression of this gene on day 11 was more than day 10 and on 10th day was more than day 9. Also, we assessed HFSC on day 14 and demonstrated these cells were positive for β-ш tubulin, and seladin-1 was not expressed in this day.

Conclusion: HFSC express seladin-1 and this result demonstrates that these cells might be used to cell therapy for AD in future.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048477PMC
http://dx.doi.org/10.6091/ibj.1284.2014DOI Listing
July 2014

Cell therapy in spinal cord injury: a mini- reivew.

Basic Clin Neurosci 2013 ;4(2):172-6

Division of Neuroscience, Cellular and Molecular Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Spinal cord injury (SCI) is a debilitating disease which leads to progressive functional damages. Because of limited axonal regeneration in the central nervous system, there is no or little recovery expected in the patients. Different cellular and molecular approaches were investigated in SCI animal models. Cellular transplantation of stem cells can potentially replace damaged tissue and provide a suitable microenvironment for axons to regenerate. Here, we reviewed the last approaches applied by our colleagues and others in order to improve axonal regeneration following SCI. We used different types of stem cells via different methods. First, fetal olfactory mucosa, schwann, and bone marrow stromal cells were transplanted into the injury sites in SCI models. In later studies, was applied simultaneous transplantation of stem cells with chondroitinase ABC in SCI models with the aid of nanoparticles. Using these approaches, considerable functional recovery was observed. However, considering some challenges in stem cell therapy such as rejection, infection, and development of a new cancer, our more recent strategy was application of cytokines. We observed a significant improvement in motor function of rats when stromal derived factor-1 was used to attract innate stem cells to the injury site. In conclusion, it seems that co-transplantation of different cells accompanies with other factors like enzymes and growth factors via new delivery systems may yield better results in SCI.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4202537PMC
October 2014

Combination of stem cell mobilized by granulocyte-colony stimulating factor and human umbilical cord matrix stem cell: therapy of traumatic brain injury in rats.

Iran J Basic Med Sci 2011 Jul;14(4):327-39

Cellular & Molecular Research Center, Tehran University of Medical Sciences, Tehran, Iran ; Department of Anatomy, Tehran University of Medical Science, Tehran, Iran.

Objectives: Clinical studies of treating traumatic brain injury (TBI) with autologous adult stem cells led us to examine the impression of a combination therapy. This was performed by intravenous injection of human umbilical cord matrix stem cell (hUCMSC-Wharton(,)s jelly stem cell) with bone marrow cell mobilized by granulocytecolony stimulating factor (G-CSF) in rats injured with cortical compact device.

Materials And Methods: Adult male Wistar rats (n= 50) were injured with controlled cortical impact device and divided into five groups. All injections were performed 1 day after injury into the tail veins of rats. Neurological functional evaluation of animals was performed before and after injury using modified neurological severity scores (mNSS). Animals were sacrificed 42 days after TBI and brain sections were stained by Brdu immunohistochemistry.

Results: Statistically significant improvement in functional outcome was observed in treatment groups when compared with control (P< 0.01). mNSS showed no significant differences among the hUCMSC and G-CSF treated groups at any time point (end of trial). Rats with hUCMSC + G-CSF treatment had a significant improvement on mNSS at 5 and 6 week compared to other treatment group (P< 0.01).

Conclusion: Histological analysis in G-CSF+ hUCMSC treated traumatic rats exhibited significant increase in numbers of Brdu immunoreactive cells in their traumatic core compared with other labeled group.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586827PMC
July 2011