Publications by authors named "Tahereh Ghadiri"

19 Publications

  • Page 1 of 1

Hippocampal neurodegeneration and rhythms mirror each other during acute spinal cord injury in male rats.

Brain Res Bull 2021 Jul 10;172:31-42. Epub 2021 Apr 10.

Research Center of Psychiatry and Behavioral Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.

Spinal Cord Injury (SCI), triggers neurodegenerative changes in the spinal cord, and simultaneously alters oscillatory manifestations of motor cortex. However, these disturbances may not be limited to motor areas and other parts such as hippocampus, which is vital in the neurogenesis and cognitive function, may be affected in the neurogenic and oscillatory manners. Addressing this remarkable complication of SCI, we evaluated the hippocampal neurogenesis and rhythms through acute phase of SCI. In the present study, we used 40 male rats (Sham.W1 = 10, SCI.W1 = 10, Sham.W2 = 10, SCI.W2 = 10), and findings revealed that contusive SCI declines hippocampal rhythms (Delta, Theta, Beta, Gamma) power and max-frequency. Also, there was a significant decrease in the DCX + and BrdU + cells of the dentate gyrus; correlated significantly with rhythms power decline. Considering the TUNEL assay analysis, there were significantly greater apoptotic cells, in the CA1, CA3, and DG regions of injured animals. Furthermore, according to the western blotting analysis, the expression of receptors (NMDA, GABAA, Muscarinic1), which are essential in the neurogenesis and generation of rhythms significantly attenuated following SCI. Our study demonstrated that acute SCI, alters the power and max-frequency of hippocampal rhythms parallel with changes in the hippocampal neurogenesis, apoptosis, and receptors expression.
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http://dx.doi.org/10.1016/j.brainresbull.2021.04.004DOI Listing
July 2021

Evaluation of the neuroprotective effects of Vitamin E on the rat substantia nigra neural cells exposed to electromagnetic field: An ultrastructural study.

Electromagn Biol Med 2021 Apr 2:1-10. Epub 2021 Apr 2.

Department of Anatomical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.

Electromagnetic fields (EMFs) could induce oxidative stress (OS) in human tissues. Lipid peroxidation (LPO) is the main hallmark of OS that harms neural cell components, primarily lipids in the myelin sheaths and membranes. Vitamin E is a lipophilic antioxidant that protects cells from OS-related damages and inhibits the LPO process. In this study, male rats were assigned into three groups of Control, EMF, and EMF+ Vitamin E. The EMF producer equipment produced an alternate current of 50 Hz, 3 Mili Tesla (mT). At the end of the experiment, half of the substantia nigra in every sample was used for measurement of the malondialdehyde (MDA) level as the end-product of the LPO and activity of superoxide dismutase (SOD) enzyme. The next half of the tissue was prepared for transmission electron microscopy (TEM). In the EMF group, MDA level was enhanced and SOD value decreased significantly compared to the control group, but Vitamin E could restore these changes. In rats undergone EMF, heterochromatic nucleus and destruction in some portions of the nuclear membrane were detected. The segmental separation or destruction of myelin sheath lamellae was observed in nerve fibers. In treated animals, the nucleus was round, less heterochromatic, with a regular membrane. Separation of myelin sheath lamellae in some nerve fibers was slighter than the radiation group. Considering the results, EMF exposure induces LPO and triggers ultrastructural changes in the cell membranes, nucleus, and myelin sheath of substantia nigra cells, but Vitamin E consumption weakens these neuropathological alterations.
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http://dx.doi.org/10.1080/15368378.2021.1907404DOI Listing
April 2021

Modulatory properties of extracellular matrix glycosaminoglycans and proteoglycans on neural stem cells behavior: Highlights on regenerative potential and bioactivity.

Int J Biol Macromol 2021 Feb 8;171:366-381. Epub 2021 Jan 8.

Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran; Department of Neurosciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Despite the poor regenerative capacity of the adult central nervous system (CNS) in mammals, two distinct regions, subventricular zone (SVZ) and the subgranular zone (SGZ), continue to generate new functional neurons throughout life which integrate into the pre-existing neuronal circuitry. This process is not fixed but highly modulated, revealing many intrinsic and extrinsic mechanisms by which this performance can be optimized for a given environment. The capacity for self-renewal, proliferation, migration, and multi-lineage potency of neural stem cells (NSCs) underlines the necessity of controlling stem cell fate. In this context, the native and local microenvironment plays a critical role, and the application of this highly organized architecture in the CNS has been considered as a fundamental concept in the generation of new effective therapeutic strategies in tissue engineering approaches. The brain extracellular matrix (ECM) is composed of biomacromolecules, including glycosaminoglycans, proteoglycans, and glycoproteins that provide various biological actions through biophysical and biochemical signaling pathways. Herein, we review predominantly the structure and function of the mentioned ECM composition and their regulatory impact on multiple and diversity of biological functions, including neural regeneration, survival, migration, differentiation, and final destiny of NSCs.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.01.006DOI Listing
February 2021

A Review on the Neurological Manifestations of COVID-19 Infection: a Mechanistic View.

Mol Neurobiol 2021 Feb 26;58(2):536-549. Epub 2020 Sep 26.

Department of Neuroscience and Cognition, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.

There is increasing evidence of neurological manifestations and complications in patients with coronavirus disease 19 (COVID-19). More than one-quarter of patients with COVID-19 developed various neurological symptoms, ranging from headache and dizziness to more serious medical conditions, such as seizures and stroke. The recent investigations introduced hyposmia as a potential early criterion of infection with COVID-19. Despite the high mortality and morbidity rate of COVID-19, its exact mechanism of action and pathogenesis is not well characterized. The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could interact with angiotensin-converting enzyme 2 (ACE2) in the endothelial, neural, and glial cells. In the present study, we reviewed the most common neurological manifestations and complications that emerged after infection with the SARS-CoV-2 and discussed their possible relation to the expression and function of ACE2. Comprehensive and detailed studies are required to uncover how this virus invades the neural system as well as other critical organs.
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http://dx.doi.org/10.1007/s12035-020-02149-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519857PMC
February 2021

A potential entanglement between the spinal cord and hippocampus: Theta rhythm correlates with neurogenesis deficiency following spinal cord injury in male rats.

J Neurosci Res 2020 12 1;98(12):2451-2467. Epub 2020 Sep 1.

Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.

Cognitive deficits due to spinal cord injury (SCI) have been elucidated in both animals and humans with SCI. Such disorders may cause concomitant oscillatory changes in regions of the brain involving in cognition; a subject that has not been directed mechanistically. One of the crucial oscillations, having a prominent role in cognition, particularly spatial memory, is hippocampal theta rhythm. Our research revealed that SCI could induce changes not only in the neurogenesis and apoptosis rate of the hippocampus but also in theta power as well as receptors involving in the generation of this rhythm. Herein we used 24 male Wistar rats (Sham/SCI = 12) and examined the effect of spinal cord contusion on hippocampal theta rhythm, spatial memory, and neurodegeneration. We proved that SCI eliminates hippocampus-dependent theta power through spatial working memory, and correlates significantly with neurodegeneration and expression of receptors (NMDA, GABAA, Muscarinic1/M1), which are in turn essential in generation of theta rhythm. The immunohistochemistry analysis also demonstrated a significant decrease in DCX+ and BrdU+ cells; however, according to TUNEL assay, apoptosis is significantly higher in SCI-induced animals. The western blotting analysis further showed a significant reduction of the abovementioned receptors in the hippocampus. We also verified that SCI impairs the spatial memory, proved by poor performance in the Y-maze task. As well as, based on the local field potential recordings analysis, SCI decreases the power of theta rhythm. Eventually, this study demonstrated that chronic brain neurodegeneration occurs after SCI accompanied by theta rhythm and cognitive deficiency.
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http://dx.doi.org/10.1002/jnr.24719DOI Listing
December 2020

Combination of curcumin with autologous transplantation of adult neural stem/progenitor cells leads to more efficient repair of damaged cerebral tissue of rat.

Exp Physiol 2020 09 31;105(9):1610-1622. Epub 2020 Jul 31.

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

New Findings: What is the central question of this study? Can the neuroprotective agent curcumin affect restorative action of neural stem/progenitor cells in the injured rat brain? What is the main finding and its importance? In the presence of curcumin, transplantation of neural stem/progenitor cells in the context of PuraMatrix reduced lesion size and reactive inflammatory responses, and boosted survival rate of grafted neurons. In addition it improved the neurological status of injured animals. This could be beneficial in designing new therapeutic approaches for brain injury based on this combination therapy.

Abstract: Traumatic brain injury (TBI) is catastrophic neurological damage associated with substantial morbidity and mortality. To date, there is no specific treatment for restoring lost brain tissue. In light of the complex pathology of brain injury, the present study evaluated the effects of combination therapy using autologous neural stem/progenitor cells (NS/PCs), PuraMatrix (PM) and curcumin in an animal model of brain injury. After stereotactic biopsy of subventricular zone tissue and culture of NS/PCs, 36 male Wistar rats (150-200 g) were randomly divided into six groups receiving dimethyl sulfoxide (DMSO),  curcumin (100 mg kg in DMSO), PM + curcumin (100 mg kg in DMSO), NS/PCs + curcumin (100 mg kg in DMSO), NS/PCs + PM + curcumin (100 mg kg in DMSO) and NS/PCs + PM + curcumin (1 µm) following acute brain injury. The animals were evaluated in term of neurological status for 4 weeks, then decapitated. Nissl and TUNEL staining and immunohistochemistry for bromodeoxyuridine, glial fibrillary acidic protein, doublecortin, Map2, Olig2, Iba1 and CD68 were performed. We found that combination therapy by NS/PCs + PM + curcumin reduced the lesion size, astrogliosis, macrophage and microglial reaction as well as the number of apoptotic cells. Moreover, the transplanted cells were able to survive and differentiate after 4 weeks. Besides these findings, transplantation of NS/PCs in the context of PM and curcumin improved the neurological status of injured animals. In conclusion, our data suggest that this combination therapy can be beneficial in developing future therapeutic approaches for brain injury.
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http://dx.doi.org/10.1113/EP088697DOI Listing
September 2020

MicroRNA alterations in neuropathologic cognitive disorders with an emphasis on dementia: Lessons from animal models.

J Cell Physiol 2021 Feb 30;236(2):806-823. Epub 2020 Jun 30.

Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran.

Cognitive dysfunction is a state of losing or having difficulties in remembering, learning, focusing, or making decisions that impact individual healthy life. Small single-stranded and nonprotein coding RNAs, microRNAs (miRNAs) participate actively in regulatory processes, incorporate cognitive signaling pathways, and intensely affect cognitive evolution. miRNAs exert their modification activities through translational or transcriptional processes. Reportedly, cognitive impairment and dementia are rising, especially in developing countries. Herein we provided a brief review of original studies addressing miRNA changes in the most common neurological diseases with a focus on dementia and Alzheimer's disease. It must be noted that an increase in the level of certain miRNAs but a decrease in other ones deteriorate cognitive performance. The current review revealed that induction of miR-214-3p, miR-302, miR-21, miR- 200b/c, miR-207, miR-132, miR-188-3p and 5p, and miR-873 improved cognitive impairment in various cognitive tasks. On the other hand, intentionally lowering the level of miR-34a, miR-124, miR-574, and miR-191a enhanced cognitive function and memory. Synaptic dysfunction is a core cause of cognitive dysfunction; miRNA-34, miRNA-34-c, miRNA-124, miRNA-188-5p, miRNA-210-5p, miRNA-335-3p, and miRNA-134 strongly influence synaptic-related mechanisms. The downregulation of miRNA-132 aggregates both amyloid and tau in tauopathy. Concerning the massive burden of neurological diseases worldwide, the future challenge is the translation of animal model knowledge into the detection of pathophysiological stages of neurocognitive disorders and designing efficient therapeutic strategies. While the delivery procedure of agomir or antagomir miRNAs into the brain is invasive and only applied in animal studies, finding a safe and specific delivery route is a priority.
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http://dx.doi.org/10.1002/jcp.29908DOI Listing
February 2021

Neuronal injury and death following focal mild brain injury: The role of network excitability and seizure.

Iran J Basic Med Sci 2020 Jan;23(1):63-70

Faculty of Pharmacy, Department of Toxicology, Tehran University of Medical Sciences, Tehran, Iran.

Objectives: While traumatic brain injury (TBI) is a predisposing factor for development of post-traumatic epilepsy (PTE), the occurrence of seizures following brain trauma can infuriate adverse consequences of brain injury. However, the effect of seizures in epileptogenesis after mild TBI cannot yet be accurately confirmed. This study was designed to investigate the histopathological and molecular modifications induced by seizures on traumatized brain.

Materials And Methods: Using a new method, head was traumatized and seizures were evoked by sub-convulsive dose of pentylenetetrazole (PTZ) fifteen days after induction of focal mild TBI. Convulsion assessments were performed one hour after PTZ injection and was followed by histopathological and molecular evaluations.

Results: A significantly higher score and longer duration of seizure attacks as well as higher number of epileptiform discharges were observed in the TBI+PTZ group compared to sham and TBI groups. An elevated number of apoptotic cells was observed in the TBI+PTZ group compared to sham and TBI rats. Molecular investigations revealed higher levels of Bax/Bcl2 ratio, Caspase 3, and NF-κB in the TBI+PTZ group compared to the other animal groups. The value of Nrf2 did not change after mild TBI compared to sham and PTZ control groups. Occurrence of seizures after TBI, however, significantly decreased the level of Nrf2.

Conclusion: Our data indicated that seizure occurrence following mild TBI aggravates cell injury and death via activation of neuroinflammatory processes and may increase the risk of PTE. Additionally, our results suggest a potential protective role of Nrf2 after chemically evoked PTE.
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http://dx.doi.org/10.22038/IJBMS.2019.37558.8932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206845PMC
January 2020

Theta Oscillations Through Hippocampal/Prefrontal Pathway: Importance in Cognitive Performances.

Brain Connect 2020 05 7;10(4):157-169. Epub 2020 May 7.

Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.

Among various hippocampal rhythms, including sharp-wave ripples, gamma, and theta, theta rhythm is crucial for cognitive processing, particularly learning and memory. Theta oscillations are observable in both humans and rodents during spatial navigations. However, the hippocampus (Hip) is well known as the generator of current rhythm, and other brain areas, such as prefrontal cortex (PFC), can be affected by theta rhythm, too. The PFC is a core structure for the execution of diverse higher cortical functions defined as cognition. This region is connected to the hippocampus through the hippocampal/prefrontal pathway; hereby, theta oscillations convey hippocampal inputs to the PFC and simultaneously synchronize the activity of these two regions during memory, learning and other cognitive tasks. Importantly, thalamic nucleus reunions (nRE) and basolateral amygdala are salient relay structures modulating the synchronization, firing rate, and phase-locking of the hippocampal/prefrontal oscillations. Herein, we summarized experimental studies, chiefly animal researches in which the theta rhythm of the Hip-PFC axis was investigated using either electrophysiological assessments in rodent or integrated diffusion-weighted imaging and electroencephalography in human cases under memory-based tasks. Moreover, we briefly reviewed alterations of theta rhythm in some CNS diseases with the main feature of cognitive disturbance. Interestingly, animal studies implied the interruption of theta synchronization in psychiatric disorders such as schizophrenia and depression. To disclose the precise role of theta rhythm fluctuations through the Hip-PFC axis in cognitive performances, further studies are needed.
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http://dx.doi.org/10.1089/brain.2019.0733DOI Listing
May 2020

Progesterone modulates post-traumatic epileptogenesis through regulation of BDNF-TrkB signaling and cell survival-related pathways in the rat hippocampus.

Neurosci Lett 2019 09 17;709:134384. Epub 2019 Jul 17.

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

Female sex hormone, progesterone, in addition to seizure modifying activity is also known as a potential protective agent against various brain injury conditions. Considering the predisposal role of traumatic brain injury (TBI) on developing post-traumatic epilepsy (PTE), the effect of progesterone on post-traumatic epileptogenesis is not investigated yet. Male Wistar rats were given a moderate focal weight drop injury (500 gr) or sham surgery and then progesterone (16 and 32mg/kg) was given daily for two consecutive weeks. On day 15 of injury, seizures were induced by administration of a GABAA receptor antagonist, pentylenetetrazole (PTZ, 30 mg/kg). Seizures were then assessed over a 1-h period using the Racine clinical rating scale. Traumatized animals that received 32 mg/kg progesterone had reduced score, duration of seizures and almost did not show tonic-clonic seizures during 60 min versus the untreated trauma group. In line with behavioral alterations, 32 mg/kg progesterone enhanced the amount of Nrf2 and HO-1 proteins and decreased the level of NF-kB, BDNF, Caspase 3 and ratio of Bax/Bcl-2 in the ipsilateral hippocampus. Additionally, the number of TUNEL-positive apoptotic cells, as well as injured dark neurons in the parietal cortex and hippocampal CA1 of 32 mg/kg-treated animals showed a significant reduction. Administration of 16 mg/kg progesterone elevated production of BDNF, Bax and Caspase 3 and decreased anti-apoptotic Bcl-2 protein. Taken together, an early administration of 32 mg/kg of progesterone after TBI for two weeks post-injury modified seizure activity. Our findings suggest that post-traumatic anti-epileptogenesis property of a high dose of progesterone partly occurs through the manipulation of BDNF-TrkB axis along with control of cell survival pathways.
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http://dx.doi.org/10.1016/j.neulet.2019.134384DOI Listing
September 2019

Mechanisms of spinal cord injury regeneration in zebrafish: a systematic review.

Iran J Basic Med Sci 2017 Dec;20(12):1287-1296

Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, 11365-3876, Iran.

Objectives: To determine the molecular and cellular mechanisms of spinal cord regeneration in zebrafish.

Materials And Methods: Medical databases of PubMed and Scopus were searched with following key words: Zebrafish; spinal cord injuries; regeneration; recovery of function. The map of mechanisms was performed using Xmind software.

Results: Wnt/ß-catenin signaling, L1.1, L1.2, Major vault protein (MVP), contactin-2 and High mobility group box1 (HMGB1) had positive promoting effects on axonal re-growth while Ptena had an inhibitory effect. Neurogenesis is stimulated by Wnt/ß-catenin signaling as well as HMGB1, but inhibited by Notch signaling. Glial cells proliferate in response to fibroblast growth factor (FGF) signaling and Lysophosphatidic acid (LPA). Furthermore, fgf signaling pathway causes glia bridge formation in favor of axonal regeneration. LPA and HMGB1 in acute phase stimulate inflammatory responses around injury and suppress regeneration. LPA also induces microglia activation and neuronal death in addition to glia cell proliferation, but prevents neurite sprouting.

Conclusion: This study provides a comprehensive review of the known molecules and mechanisms in the current literature involved in the spinal cord injury (SCI) regeneration in zebrafish, in a time course manner. A better understanding of the whole determining mechanisms for the SCI regeneration should be considered as a main goal for future studies.
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http://dx.doi.org/10.22038/IJBMS.2017.9620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722987PMC
December 2017

The Modulatory Effect of Metabotropic Glutamate Receptor Type-1α on Spike-Wave Discharges in WAG/Rij Rats.

Mol Neurobiol 2017 03 16;54(2):846-854. Epub 2016 Jan 16.

Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran.

Modulatory function of metabotropic glutamate type 1 (mGlu1) receptors plays a crucial role in the pathophysiology of some neurological disorders, including schizophrenia and epilepsy. In this study, the expression of mGlu1α receptors in the thalamic nuclei was assessed during development of absence seizures in the WAG/Rij rats, a valid genetic animal model of absence epilepsy. In addition, the effect of pharmacological modulation of mGlu1α receptors in the laterodorsal (LD) nucleus of the thalamus on the characteristic features of bioelectrical brain activities in the WAG/Rij rats was assessed. The expression of mGlu1α receptors in the LD was assessed in four experimental groups of both WAG/Rij and Wistar rats with 2 and 6 months of age. Agonist and antagonist of mGlu1α receptors were infused in LD in the six months old WAG/Rij (epileptic) rats. The protein level of mGlu1α receptors in the thalamus of the 6-month-old WAG/Rij rats was lower than non-epileptic animals. In addition, the distribution of mGlu1α receptors in different thalamic nuclei was lower in the 6-month-old WAG/Rij compared to age-matched Wistar rats. The gene expression of mGlu1α receptor was also significantly lower in 6-month-old WAG/Rij rats in the LD compared to other animal groups. The microinjection of mGlu1α receptors agonist and antagonist in the LD reduced the duration of spike-wave discharges (SWDs) and increased the amplitude and duration of SWDs, respectively, in 6-month-old WAG/Rij rats. The alterations of mGlu1α receptors expression in the thalamus of epileptic WAG/Rij rats as well as its modulatory effects in the generation of SWDs suggest the potential of mGlu1 receptors as a therapeutic target in absence epilepsy.
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http://dx.doi.org/10.1007/s12035-016-9692-xDOI Listing
March 2017

The Effect of Melatonin on Behavioral, Molecular, and Histopathological Changes in Cuprizone Model of Demyelination.

Mol Neurobiol 2016 09 27;53(7):4675-84. Epub 2015 Aug 27.

Shefa Neuroscience Research Center, Khatam-Alanbia Hospital, Tehran, Iran.

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system. The protective effects of melatonin (MLT) on various neurodegenerative diseases, including MS, have been suggested. In the present study, we examined the effect of MLT on demyelination, apoptosis, inflammation, and behavioral dysfunctions in the cuprizone toxic model of demyelination. C57BL/6J mice were fed a chaw containing 0.2 % cuprizone for 5 weeks and received two doses of MLT (50 and 100 mg/kg) intraperitoneally for the last 7 days of cuprizone diet. Administration of MLT improved motor behavior deficits induced by cuprizone diet. MLT dose-dependently decreased the mean number of apoptotic cells via decreasing caspase-3 and Bax as well as increasing Bcl-2 levels. In addition, MLT significantly enhanced nuclear factor-κB activation and decreased heme oxygenase-1 level. However, MLT had no effect on interleukin-6 and myelin protein production. Our data revealed that MLT improved neurological deficits and enhanced cell survival but was not able to initiate myelin production in the cuprizone model of demyelination. These findings may be important for the design of potential MLT therapy in demyelinating disorders, such as MS.
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http://dx.doi.org/10.1007/s12035-015-9404-yDOI Listing
September 2016

Effect of castration on the susceptibility of male rats to the sleep deprivation-induced impairment of behavioral and synaptic plasticity.

Neurobiol Learn Mem 2015 Sep 12;123:140-8. Epub 2015 Jun 12.

Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran.

In both human and animal studies, the effect of sleep deficiency on cognitive performances has mostly been studied during adulthood in males, but very little data exist concerning the effects of poor sleep in gonadal hormones-depleted status, such as aging or gonadectomized (GDX) male animal models. The present study investigated the potential modulatory effects of the endogenous male sex hormones on the 48h REM sleep deprivation (SD)-induced cognitive and synaptic impairments by comparing the gonadally intact with castrated male rats, a rodent model of androgen-deprived male animals. The multiple platform method was used for inducing REM-SD and spatial performances were evaluated using Morris water maze (MWM) task. Early long-term potentiation (E-LTP) was measured in area CA1 of the hippocampus and PCR and western blotting assays were employed to assess brain derived neurotrophic factor (BDNF) gene and protein expression in the hippocampus. To reveal any influence of sleep loss on stress level, we also evaluated the plasma corticosterone levels of animals. Regardless of reproductive status, REM-SD significantly disrupted short-term memory and LTP, as well as hippocampal BDNF expression. The corticosterone levels were not significantly changed following REM-SD neither in intact nor in GDX male rats. These findings suggest that depletion of male sex steroid hormones by castration does not lead to any heightened sensitivity of male animals to the deleterious effects of 48h REM-SD on cognitive and synaptic performances.
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http://dx.doi.org/10.1016/j.nlm.2015.05.008DOI Listing
September 2015

Effects of TRPV1 on the hippocampal synaptic plasticity in the epileptic rat brain.

Synapse 2015 Jul 20;69(7):375-83. Epub 2015 May 20.

Shefa Neuroscience Research Center, Khatam-Al-Anbia Hospital, Tehran, Iran.

Temporal lobe epilepsy is often presented by medically intractable recurrent seizures due to dysfunction of temporal lobe structures, mostly the temporomesial structures. The role of transient receptor potential vaniloid 1 (TRPV1) activity on synaptic plasticity of the epileptic brain tissues was investigated. We studied hippocampal TRPV1 protein content and distribution in the hippocampus of epileptic rats. Furthermore, the effects of pharmacologic modulation of TRPV1 receptors on field excitatory postsynaptic potentials have been analyzed after induction of long term potentiation (LTP) in the hippocampal CA1 and CA3 areas after 1 day (acute phase) and 3 months (chronic phase) of pilocarpine-induced status epilepticus (SE). A higher expression of TRPV1 protein in the hippocampus as well as a higher distribution of this channel in CA1 and CA3 areas in both acute and chronic phases of pilocarpine-induced SE was observed. Activation of TRPV1 using capsaicin (1 µM) enhanced LTP induction in CA1 region in non-epileptic rats. Inhibition of TRPV1 by capsazepine (10 µM) did not affect LTP induction in non-epileptic rats. In acute phase of SE, activation of TRPV1 enhanced LTP in both CA1 and CA3 areas but TRPV1 inhibition did not affect LTP. In chronic phase of SE, application of TRPV1 antagonist enhanced LTP induction in CA1 and CA3 regions but TRPV1 activation had no effect on LTP. These findings indicate that a higher expression of TRPV1 in epileptic conditions is accompanied by a functional impact on the synaptic plasticity in the hippocampus. This suggests TRPV1 as a potential target in treatment of seizure attacks.
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http://dx.doi.org/10.1002/syn.21825DOI Listing
July 2015

Protective Effect of a cAMP Analogue on Behavioral Deficits and Neuropathological Changes in Cuprizone Model of Demyelination.

Mol Neurobiol 2015 Aug 17;52(1):130-41. Epub 2014 Aug 17.

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

Multiple sclerosis (MS) is an inflammatory demyelinating disease that leads to neuronal cell loss. Cyclic AMP and its analogs are well known to decrease inflammation and apoptosis. In the present study, we examined the effects of bucladesine, a cell-permeable analogue of cyclic adenosine monophosphate (cAMP), on myelin proteins (PLP, PMP-22), inflammation, and apoptotic, as well as anti-apoptotic factors in cuprizone model of demyelination. C57BL/6J mice were fed with chow containing 0.2% copper chelator cuprizone or vehicle by daily oral gavage for 5 weeks to induce reversible demyelination predominantly of the corpus callosum. Bucladesine was administered intraperitoneally at different doses (0.24, 0.48, or 0.7 μg/kg body weight) during the last 7 days of 5-week cuprizone treatment. Bucladesine exhibited a protective effect on myelination. Furthermore, bucladesine significantly decreased the production of interleukin-6 pro-inflammatory mediator as well as nuclear factor-κB activation and reduced the mean number of apoptotic cells compared to cuprizone-treated mice. Bucladesine also decreased production of caspase-3 as well as Bax and increased Bcl-2 levels. Our data revealed that enhancement of intracellular cAMP prevents demyelination and plays anti-inflammatory and anti-apoptotic properties in mice cuprizone model of demyelination. This suggests the modulation of intracellular cAMP as a potential target for treatment of MS.
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http://dx.doi.org/10.1007/s12035-014-8857-8DOI Listing
August 2015

A novel traumatic brain injury model for induction of mild brain injury in rats.

J Neurosci Methods 2014 Aug 4;233:18-27. Epub 2014 Jun 4.

Shefa Neuroscience Research Center, Tehran, Iran; Institute of Physiology I, Department of Neurosurgery, Epilepsy Research Center, Münster University, Germany; Institute of Physiology I, Department of Neurology, Epilepsy Research Center, Münster University, Germany. Electronic address:

Background: Due to the marked heterogeneity of human traumatic brain injury (TBI), none of the available animal model can reproduce the entire spectrum of TBI, especially mild focal TBI. This study was designed to develop a modified TBI weight drop model for induction of focal mild cerebral injury.

New Method: A stereotaxic coupled weight drop device was designed. Principle arm of device carries up to 500g weights which their force was conveyed to animal skull through a thin nail like metal tip. To determine the optimal configuration of the device to induce mild TBI, six different trials were designed. The optimal configuration of the instrument was used for evaluation of behavioral, histopathological and molecular changes of mild TBI.

Results: Neurologic and motor coordination deficits observed sharply within 24h post injury period. Histological studies revealed a remarkable increase in the number of dark neurons in trauma site. TBI increased the expression of apoptotic proteins, Bax, BCl2 and cleaved caspase-3 in the hippocampus.

Comparison With Existing Methods: Our designed TBI device is capable to produce variable severity of TBI from mild to severe. The main advantage of the new TBI model is induction of mild local unilateral brain injury instead of traumatization of the whole brain. This model does not require craniotomy for induction of brain injury.

Conclusion: This novel animal TBI model mimics human mild focal brain injury. This model is suitable for evaluation of pathophysiology as well as screening of new therapies for mild TBI.
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http://dx.doi.org/10.1016/j.jneumeth.2014.05.035DOI Listing
August 2014

A cAMP analog reverses contextual and tone memory deficits induced by a PKA inhibitor in Pavlovian fear conditioning.

Pharmacol Biochem Behav 2013 Apr 5;105:177-82. Epub 2013 Mar 5.

Department of Pharmacology and Toxicology, Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

Despite extensive investigations, molecular mechanisms underlying the formation of fear memory are not completely understood. We have previously investigated the role of protein kinase AII (PKAII) in spatial acquisition and memory retention using Morris water maze. In the current study, we have further analyzed the role of PKA in memory consolidation using a fear conditioning response model. Experiments were performed using intrahippocampal infusions of dibutyryl cyclic AMP (bucladesine), a cell permeable analog of cAMP and H89, as a selective PKAII inhibitor, in male rats. The animals were trained for one session which included 4 consecutive trials of tone-shock pairing on the training day. Fear to the context and tone was evaluated by measuring freezing behavior 24h and 48h after training respectively. Bilateral infusion of 100 and 300μM/side of bucladesine immediately after training increased freezing percentage in rats, which indicated an improvement in memory consolidation. Administration of 10μM/side (but not 5μM/side) of H-89 impaired contextual and cued fear conditioning significantly compared to the control animals. Moreover, administration of bucladesine (100 and 300μM/side), 5min after H-89 infusion (10μM/side) reversed the impairment of contextual and auditory-cued fear conditioning in rats and freezing percentage increased to those of control animals. Altogether, these results indicate that PKA inhibitor-induced memory deficit was attenuated by a cAMP analog and that the cAMP/PKA signaling pathway has an important role for memory consolidation in fear conditioning response model.
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http://dx.doi.org/10.1016/j.pbb.2013.02.016DOI Listing
April 2013

Effects of pentoxifylline and H-89 on epileptogenic activity of bucladesine in pentylenetetrazol-treated mice.

Eur J Pharmacol 2011 Nov 21;670(2-3):464-70. Epub 2011 Sep 21.

Department of Pharmacology and Toxicology, Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

The present study shows interactive effects of pentoxifylline (PTX) as a phosphodiesterase (PDE) inhibitor, H-89 as a protein kinase A (PKA) inhibitor and bucladesine (db-cAMP) as a cAMP agonist on pentylenetetrazol (PTZ)-induced seizure in mice. Different doses of pentoxifylline (25, 50, 100 mg/kg), bucladesine (50, 100, 300 nM/mouse), and H-89 (0.05, 0.1, 0.2 mg/100g) were administered intraperitoneally (i.p.), 30 min before intravenous (i.v.) infusion of PTZ (0.5% w/v). In combination groups, the first and second components were injected 45 and 30 min before PTZ infusion. In all groups, the control animals received an appropriate volume of vehicle. Single administration of PTX had no significant effect on both seizure latency and threshold. Bucladesine significantly decreased seizure latency and threshold only at a high concentration (300 nM/mouse). Intraperitoneal administration of H-89 (0.2 mg/100g) significantly increased seizure latency and threshold in PTZ-treated animals. All applied doses of bucladesine in combination with PTX (50 mg/kg) caused a significant reduction in seizure latency. Pretreatment of animals with PTX (50 and 100 mg/kg) attenuated the anticonvulsant effect of H-89 (0.2 mg/100g) in PTZ-exposed animals. H-89 (0.05, 0.2 mg/100g) prevented the epileptogenic activity of bucladesine (300 nM) with significant increase of seizure latency and seizure threshold. In conclusion, we showed that seizure activities were affected by pentoxifylline, H-89 and bucladesine via interactions with intracellular cAMP and cGMP signaling pathways, cyclic nucleotide-dependent protein kinases, and related neurotransmitters.
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http://dx.doi.org/10.1016/j.ejphar.2011.09.026DOI Listing
November 2011
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