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Abstract Background Glioblastoma multiforme (GBM) is the most malignant brain tumor, with a poor prognosis and life expectancy of 14–16 months after diagnosis. The standard treatment for GBM consists of surgery, radiotherapy, and chemotherapy with temozolomide. Most patients become resistant to treatment after some time, and the tumor recurs. Therefore, there is a need for new drugs to manage GBM. Eslicarbazepine (ESL) is a well-known antiepileptic drug belonging to the dibenzazepine group with anticancer potentials. In this study, for the first time, we evaluated the potential effects of ESL on C6 cell growth, both in vitro and in vivo, and examined its molecular effects. Methods To determine the effect of ESL on the c6 cell line, cell viability, proliferation, and migration were evaluated by MTT assay, colony formation, and wound healing assay. Also, apoptosis and cell cycle were examined by flow cytometry, qRT-PCR, and western blotting. In addition, an intracranial model in Wistar rats was used to investigate the effect of ESL in vivo, and the tumor size was measured using both Caliper and MRI. Results The obtained results are extremely consistent and highly encouraging. C6 cell viability, proliferation, and migration were significantly suppressed in ESL-treated C6 cells (p

This study was conducted with aim of investigating the consequences of sleep deprivation (SD) on cognitive functions. For this purpose, adult male rats were subjected to SD protocol for 5 h. The SD and the control rats were trained in the Morris water maze (MWM) to assess spatial behavioral deficits due to the SD protocol. To determine the role of astrocytes in spatial navigation deficits associated with SD, an inhibitor of astrocyte activation, fluorocitrate (FC), or a suppressor of astrocyte activation, vitamin D, was injected into the dorsal-CA1 hippocampus before subjecting rats to the SD protocol and the effects of these compounds on spatial navigation deficits associated with SD in the MWM were assessed. As expected, 5 h of SD impaired the Morris water navigation task in rats. FC injection into the dorsal-CA1 hippocampus before the SD protocol did not prevent the SD-induced cognitive deficits. Interestingly, injection of vitamin D into the dorsal-CA1 hippocampus prior to the SD protocol alleviated the SD-induced severe spatial navigation deficit in the MWM. Sequential injection of FC and vitamin D prior to the SD protocol did not reduce the SD-induced spatial memory impairment, suggesting a role for astrocytes. In sum, vitamin D can improve cognitive dysfunction associated with sleep deprivation, possibly dependent on astrocyte function. The results show that maintaining adequate levels of vitamin D offers a promising avenue to improve cognitive function in sleep-deprived conditions.

There is growing evidence that the hippocampus comprises diverse neural circuits that exhibit longitudinal variation in their properties, however, the intermediate region of the hippocampus has received comparatively little attention. Therefore, this study was designed to compared short- and long-term synaptic plasticity between the dorsal and intermediate regions of the hippocampus in normal and PTZ-kindled rats. Short-term plasticity was assessed by measuring the ratio of field excitatory postsynaptic potentials’ (fEPSPs) slope in response to paired-pulse stimulation at three different inter-pulse intervals (20, 80, and 160 ms), while long-term plasticity was assessed using primed burst stimulation (PBS). The results showed that the basal synaptic strength differed between the dorsal and intermediate regions of the hippocampus in both control and kindled rats. In the control group, paired-pulse stimulation of Schaffer collaterals resulted in a significantly lower fEPSP slope in the intermediate part of the hippocampus compared to the dorsal region. Additionally, the magnitude of long-term potentiation (LTP) was significantly lower in the intermediate part of the hippocampus compared to the dorsal region. In PTZ-kindled rats, both short-term facilitation and long-term potentiation were impaired in both regions of the hippocampus. Interestingly, there was no significant difference in synaptic plasticity between the dorsal and intermediate regions in PTZ-kindled rats, despite impairments in both regions. This suggests that seizures eliminate the regional difference between the dorsal and intermediate parts of the hippocampus, resulting in similar electrophysiological activity in both regions in kindled animals. Future studies should consider this when investigating the responses of the dorsal and intermediate regions of the hippocampus following PTZ kindling.

This study aimed to investigate the effects of intranasal air-puffing on cognitive impairments and brain cortical activity following one night of partial sleep deprivation (PSD) in adults. A total of 26 healthy adults underwent the numerical Stroop test (NST) and electroencephalography (EEG) before and after one night of PSD. Following PSD, subjects in the treatment group (n = 13) received nasal air-puffs (5 Hz, 3 min) before beginning the NST and EEG recording. Administration of nasal air-puffs in the treatment group restored the PSD-induced increase in error rate and decrease in reaction time and missing rate in the NST. Intranasal air-puffs recovered the PSD-induced augmentation of delta and theta power and the reduction of beta and gamma power in the EEG, particularly in the frontal lobes. Intranasal air-puffing also almost reversed the PSD-induced decrease in EEG signal complexity. Furthermore, it had a restorative effect on PSD-induced alteration in intra-default mode network functional connectivity in the beta and gamma frequency bands. Rhythmic nasal air-puffing can mitigate acute PSD-induced impairments in cognitive functions. It exerts part of its ameliorating effect by restoring neuronal activity in cortical brain areas involved in cognitive processing.

Objective: The mechanisms behind seizure suppression by deep brain stimulation (DBS) are not fully revealed, andthe most optimal stimulus regimens and anatomical targets are yet to be determined. We investigated the modulatoryeffect of low-frequency DBS (L-DBS) in the ventral tegmental area (VTA) on neuronal activity in downstreamand upstream brain areas in chemically kindled mice by assessing c-Fos immunoreactivity.Materials and Methods: In this experimental study, 4-6 weeks old BL/6 male mice underwent stereotaxic implantationof a unilateral stimulating electrode in the VTA followed by pentylenetetrazole (PTZ) administration every other dayuntil they showed stage 4 or 5 seizures following 3 consecutive PTZ injections. Animals were divided into control,sham-implanted, kindled, kindled-implanted, L-DBS, and kindled+L-DBS groups. In the L-DBS and kindled+L-DBSgroups, four trains of L-DBS were delivered 5 min after the last PTZ injection. 48 hours after the last L-DBS, mice weretranscardially perfused, and the brain was processed to evaluate c-Fos expression by immunohistochemistry.Results: L-DBS in the VTA significantly decreased the c-Fos expressing cell numbers in several brain areas includingthe hippocampus, entorhinal cortex, VTA, substantia nigra pars compacta, and dorsal raphe nucleus but not in theamygdala and CA3 area of the ventral hippocampus compared to the sham group.Conclusion: These data suggest that the possible anticonvulsant mechanism of DBS in VTA can be through restoringthe seizure-induced cellular hyperactivity to normal.

Abstract Pharmacoresistant temporal lobe epilepsy affects millions of people around the world with uncontrolled seizures and comorbidities, like anxiety, being the most problematic aspects calling for novel therapies. The intrahippocampal kainic acid model of temporal lobe epilepsy is an appropriate rodent model to evaluate the effects of novel interventions, including glycolysis inhibition, on epilepsy-induced alterations. Here, we investigated kainic acid-induced changes in the dorsal hippocampus (dHPC) and basolateral amygdala (BLA) circuit and the efficiency of a glycolysis inhibitor, 2-deoxy D-glucose (2-DG), in resetting such alterations using simultaneous local field potentials (LFP) recording and elevated zero-maze test. dHPC theta and gamma powers were lower in epileptic groups, both in the baseline and anxiogenic conditions. BLA theta power was higher in baseline condition while it was lower in anxiogenic condition in epileptic animals and 2-DG could reverse it. dHPC-BLA coherence was altered only in anxiogenic condition and 2-DG could reverse it only in gamma frequency. This coherence was significantly correlated with the time in which the animals exposed themselves to the anxiogenic condition. Further, theta-gamma phase-locking was lower in epileptic groups in the dHPC-BLA circuit and 2-DG could considerably increase it.

Abstract Neural synchrony in brain circuits is the mainstay of cognition, including memory processes. Alzheimer's disease (AD) is a progressive neurodegenerative disorder that disrupts neural synchrony in specific circuits, associated with memory dysfunction before a substantial neural loss. Recognition memory impairment is a prominent cognitive symptom in the early stages of AD. The entorhinal–hippocampal circuit is critically engaged in recognition memory and is known as one of the earliest circuits involved due to AD pathology. Notably, the olfactory bulb is closely connected with the entorhinal–hippocampal circuit and is suggested as one of the earliest regions affected by AD. Therefore, we recorded simultaneous local field potential from the olfactory bulb (OB), entorhinal cortex (EC), and dorsal hippocampus (dHPC) to explore the functional connectivity in the OB-EC-dHPC circuit during novel object recognition (NOR) task performance in a rat model of AD. Animals that received amyloid-beta (Aβ) showed a significant impairment in task performance and a marked reduction in OB survived cells. We revealed that Aβ reduced coherence and synchrony in the OB-EC-dHPC circuit at theta and gamma bands during NOR performance. Importantly, our results exhibit that disrupted functional connectivity in the OB-EC-dHPC circuit was correlated with impaired recognition memory induced by Aβ. These findings can elucidate dynamic changes in neural activities underlying AD, helping to find novel diagnostic and therapeutic targets.

Abstract Herein proteomic profiling of the rat hippocampus from the kindling and pilocarpine models of epilepsy was performed to achieve new potential targets for treating epileptic seizures. A total of 144 differently expressed proteins in both left and right hippocampi by two-dimensional electrophoresis coupled to matrix-assisted laser desorption-mass spectrometry were identified across the rat models of epilepsy. Based on network analysis, the majority of differentially expressed proteins were associated with Ca2+ homeostasis. Changes in ADP-ribosyl cyclase (ADPRC), lysophosphatidic acid receptor 3 (LPAR3), calreticulin, ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), synaptosomal nerve-associated protein 25 (SNAP 25) and transgelin 3 proteins were probed by Western blot analysis and validated using immunohistochemistry. Inhibition of calcium influx by 8-Bromo-cADP-Ribose (8-Br-cADPR) and 2-Aminoethyl diphenylborinate (2-APB) which act via the ADPRC and LPAR3, respectively, attenuated epileptic seizures. Considering a wide range of molecular events and effective role of calcium homeostasis in epilepsy, polypharmacy with multiple realistic targets should be further explored to reach the most effective treatments.

Introduction: In this study, the role of A1 adenosine receptors in improving the effect of Low-Frequency Electrical Stimulation (LFS) on seizure-induced hyperexcitability of hippocampal CA1 pyramidal neurons was investigated. Methods: A semi-rapid hippocampal kindling model was used to induce seizures in male Wistar rats. Examination of the electrophysiological properties of CA1 pyramidal neurons of the hippocampus using whole-cell patch-clamp recording 48 h after the last kindling stimulation revealed that the application of LFS as two packages of stimulations at a time interval of 6 h for two consecutive days could significantly restore the excitability CA1 pyramidal neurons evidenced by a decreased in the of the number of evoked action potentials and enhancement of amplitude, maximum rise slope and decay slope of the first evoked action potential, rheobase, utilization time, adaptation index, first-spike latency, and post-AHP amplitude. Selective locked of A1 receptors by the administration of 8-Cyclopentyl-1,3-dimethylxanthine (1 μM, 1 μl, i.c.v.) before applying each LFS package, significantly reduced LFS effectiveness in recovering these parameters. Results: On the other hand, selective activation of A1 receptors by an injection of N6-cyclohexyladenosine (10 μM, 1 μl, i.c.v.), instead of LFS application, could imitate LFS function in improving these parameters. Conclusion: It is suggested that LFS exerts its efficacy on reducing the neuronal excitability, partially by activating the adenosine system and activating its A1 receptors.

Objective(s): Cell therapy has provided clinical applications to the treatment of motor neuron diseases. The current obstacle in stem cell therapy is to direct differentiation of stem cells into neurons in the neurodegenerative disorders. Biomaterial scaffolds can improve cell differentiation and are widely used in translational medicine and tissue engineering. The aim of this study was to compare the efficiency of two-dimensional with a three-dimensional culture system in their ability to generate functional motor neuron-like cells from adipose-derived stem cells. Materials and Methods: We compared motor neuron-like cells derived from rat adipose tissue in differentiation, adhesion, proliferation, and functional properties on two-dimensional with three-dimensional culture systems. Neural differentiation was analyzed by immunocytochemistry for immature (Islet1) and mature (HB9, ChAT, and synaptophysin) motor neuron markers. Results: Our results indicated that the three-dimensional environment exhibited an increase in the number of Islet1. In contrast, two-dimensional culture system resulted in more homeobox gene (HB9), Choline Acetyltransferase (ChAT), and synaptophysin positive cells. The results of this investigation showed that proliferation and adhesion of motor neuron-like cells significantly increased in three-dimensional compared with two-dimensional environments. Conclusion: The findings of this study suggested that three-dimension may create a proliferative niche for motor neuron-like cells. Overall, this study strengthens the idea that three-dimensional culture may mimic neural stem cell environment for neural tissue regeneration.

Objective(s): Seizure detection during online recording of electrophysiological parameters is very important in epileptic patients. In the present study, online analysis of field potential recordings was used for detecting spontaneous seizures in epileptic animals.Materials and Methods: Epilepsy was induced in rats by pilocarpine injection. During the chronic period of the pilocarpine model, local field potential (LFP) recording was run for at least 24 hr. At the same time, video monitoring of the animals was done to determine the real time of seizure occurrence. Both power and sample entropy of LFP were used for online analysis.Results: Obtained results showed that changes in LFP power are a better index for seizure detection. In addition, when we used one hundred consecutive epochs (each epoch equals 10 ms) of LFP for data analysis, the best detection was achieved.Conclusion: It may be suggested that power is a suitable parameter for online analysis of LFP in order to detect the spontaneous seizures correctly.

Introduction: Synaptic plasticity has been suggested as the primary physiological mechanism underlying memory formation. Many experimental approaches have been used to investigate whether the mechanisms underlying Long-Term Potentiation (LTP) are activated during learning. Nevertheless, little evidence states that hippocampal-dependent learning triggers synaptic plasticity. In this study, we investigated if learning and memory in the Barnes maze test are accompanied by the occurrence of LTP in Schaffer collateral to CA1 synapses in freely moving rats. Methods: The rats were implanted with a recording electrode in stratum radiatum and stimulating electrodes in Schaffer collaterals of the CA1 region in the dorsal hippocampus of the right hemisphere. Following the recovery period of at least 10 days, field potentials were recorded in freely moving animals before and after training them in Barnes maze as a hippocampal-dependent spatial learning and memory test. The slope of extracellular field Excitatory Postsynaptic Potentials (fEPSPs) was measured before and after the Barnes maze test. Results: The results showed that the fEPSP slope did not change after learning and memory in the Barnes maze test, and this spatial learning did not result in a change in synaptic potentiation in the CA1 region of the hippocampus. Conclusion: Spatial learning and memory in the Barnes maze test are not accompanied by LTP induction in Schaffer collateral-CA1 synapses.

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.

Alzheimer disease (AD) is a complex neurodegenerative disorder with no definite treatment. The expression of miR-29 family is significantly reduced in AD, suggesting a part for the family members in pathogenesis of the disease. The recent emergence of microRNA (miRNA)–based therapeutic approaches is emphasized on the efficiency of miRNA transfer to target cells. The endogenously made secretory vesicles could provide a biological vehicle for drug delivery. Characteristics such as small sizes, the ability to cross the blood–brain barrier, the specificity in binding to the right target cells, and most importantly the capacity to be engineered as drug carriers have made exosomes desirable vehicles to deliver genetic materials to the central nervous system. Here, we transfected rat bone marrow mesenchymal stem cells and HEK-293T cells (human embryonic kidney 293 cells) with recombinant expression vectors, carrying either mir-29a or mir-29b precursor sequences. A significant overexpression of miR-29 and downregulation of their targets genes, BACE1 (β-site amyloid precursor protein cleaving enzyme 1) and BIM [Bcl−2 interacting mediator of cell death (BCL2-like 11)], were confirmed in the transfected cells. Then, we confirmed the packaging of miR-29 in exosomes secreted from the transfected cells. Finally, we investigated a possible therapeutic effect of the engineered exosomes to reduce the pathological effects of amyloid-β (Aβ) peptide in a rat model of AD. Aβ–treated model rats showed some deficits in spatial learning and memory. However, in animals injected with miR-29–containing exosomes at CA1 (cornu ammonis area), the aforementioned impairments were prevented. In conclusion, our findings provide a new approach for the packaging of miR-29 in exosomes and that the engineered exosomes might have a therapeutic potential in AD.

Objective Electrical low frequency stimulation (LFS) is a new therapeutic method that moderates hyperexcitability during epileptic states. Seizure occurrence is accompanied by some changes in action potential (AP) features. In this study, we investigated the inhibitory action of LFS on epileptiform activity (EA) induced-changes in AP features in hippocampal CA1 pyramidal neurons. Materials and Methods In this experimental study, we induced EA in hippocampal slices by increasing the extracellular potassium (K+) concentration to 12 mM. LFS (1 Hz) was applied to the Schaffer collaterals at different pulse numbers (600 and 900) at the beginning of the EA. Changes in AP features recorded by whole-cell patch clamp recording were compared using phase plot analysis. Results Induction of EA depolarized membrane potential, decreased peak amplitude, as well as the maximum rise and decay slopes of APs. Administration of 1 Hz LFS at the beginning of EA prevented the above mentioned changes in AP features. This suppressive effect of LFS depended on the LFS pulse number, such that application of 900 pulses of LFS had a stronger recovery effect on AP features that changed during EA compared to 600 pulses of LFS. The constructed phase plots of APs revealed that LFS at 900 pulses significantly decreased the changes in resting membrane potential (RMP), peak amplitude, and maximum rise and decay slopes that appeared during EA. Conclusion Increasing the numbers of LFS pulses can magnify its inhibitory effects on EA-induced changes in AP features.

Introduction: The life quality of patients with epileptic seizures is highly affected by cognitive deficits. Low Frequency Stimulation (LFS) is a novel approach for the treatment of pharmacoresistant epilepsy. The main goal of this research is investigating the possible effect of LFS on seizure-induced cognitive dysfunction. Methods: To this end, the kindled animal were prepared via CA1 electrical stimulation in a semi-rapid way (12 stimulations/day). A group of animals were stimulated with LFS, 4 times at 30 s, 6 h, 24 h, and 30 h after the last kindling stimulation. Applied LFS was administered in 4 packages every 5 minutes. The packages were designed with 200 monophasic 200 monophasic square wave pulses of 0.1 ms duration at 1 Hz. The passive-avoidance test was conducted on all animals in order to measure the learning and memory behavior. Results: Hippocampal kindled rats showed deficits in learning and memory when passive avoidance test was performed. Application of LFS reversed the impairment in learning and memory behavior in kindled rats. At the same time, LFS markedly diminished kindling-induced neuronal loss and atrophy in the hippocampus. Conclusion: LFS may have some protection against seizure-induced cognitive damage in kindled rats.

Objective: Low-frequency stimulation (LFS) exerts suppressive effects in kindled animals. It is believed that overstimulated glutamatergic and decreased GABAergic transmission have long been associated with seizure activity. In this study, we investigated the effect of electrical LFS on different parameters of spontaneous excitatory and inhibitory post-synaptic currents (sEPSCs and sIPSCs) in hippocampal CA1 pyramidal cells in kindled animals. Materials and Methods: In this experimental study, rats were kindled by electrical stimulation of the hippocampal CA1 area in a semi-rapid manner (12 stimulations/day). The animals were considered fully kindled when they showed stage 5 seizures on three consecutive days. One group of animals received LFS 4 times at 30 seconds, 6 hours, 18 and 24 hours following the last kindling stimulation. Each LFS consisted of 4 packages at 5 minutes intervals. Each package of LFS consisted of 200 pulses at 1 Hz and each monophasic square wave pulse duration was 0.1 millisecond. At 2-3 hours post-LFS, acute hippocampal slices were prepared and a whole cell patch clamp recording was performed in all animals to measure the different parameters of sEPSCs and sIPSCs. Results: In kindled animals, the inter-event interval (as an index of occurrence) of sEPSCs decreased, whereas sIPSC increased. In addition, the decay time constant of sIPSCs as an index of the duration of its activity decreased compared to the control group. There was no significant difference in other parameters between the kindled and control groups. Application of LFS in kindled animals prevented the observed changes. There was no significant difference between the measured parameters in kindled+LFS and control groups. Conclusion: LFS application may prevent seizure-induced increase in the occurrence of sEPSCs and seizure-induced decrease in occurrence and activity duration of sIPSCs.

Glioblastoma multiforme (GBM) is a grade 4 and the most aggressive form of glioma, with a poor response to current treatments. The expression of microRNAs (miRNAs) is widely dysregulated in various cancers, including GBM. One of the overexpressed miRNAs in GBM is miR-21 which promotes proliferation, invasion and metastatic behaviors of tumor cells. With a size of 30–100 nm, the extracellular vesicles “exosomes” have emerged as a novel and powerful drug delivering systems. Recently, exosomal transfer of miRNAs or anti-miRNAs to tumor cells has introduced a new approach for therapeutic application of miRNAs to combat cancer. Here, we have tried to down-regulate miR-21 expression in glioma cell lines, U87-MG, and C6, by using engineered exosomes, packed with a miR-21-sponge construct. Our data revealed that the engineered exosomes have the potential to suppress miR-21 and consequently to upregulate miR-21 target genes, PDCD4 and RECK. Interestingly, in cells treated with miR-21-sponge exosomes we observed a decline in proliferation and also an elevation in apoptotic rates. Finally, in a rat model of glioblastoma, administrating exosomes loaded with a miR-21-sponge construct leads to a significant reduction in the volume of the tumors. In brief, our findings suggest a new therapeutic strategy to use engineered exosomes to deliver a miR-21-sponge construct to GBM cells, in order to block its malignant behavior.

Allergic rhinitis is a chronic inflammatory disease of the upper respiratory tract, which is associated with high incidence of anxiety symptom. There is evidence that medial prefrontal cortex modulates anxiety-related behaviors and receives projections from olfactory bulb. Since olfactory dysfunction has been reported in allergic rhinitis, we aimed to evaluate anxiety-like behavior and oscillations of olfactory bulb-medial prefrontal cortex circuit in an animal model of allergic rhinitis. The number of open arm entries in elevated zero maze was significantly reduced in sensitized rats exposed to intranasal ovalbumin compared to the control group, which was indicating the enhancement of anxiety-like behavior in allergic rhinitis animals. Analysis of local field potentials in olfactory bulb and medial prefrontal cortex during immobility and exploration state showed that anxiety-like behavior induced by allergic rhinitis was in association with increased activity of medial prefrontal cortex and enhancement of olfactory bulb-medial prefrontal cortex coupling in delta and theta bands. Moreover, in allergic rhinitis animals, theta strongly coordinates local gamma activity in olfactory bulb and medial prefrontal cortex, which means to have a strong local theta/gamma coupling. We suggested that disruption of olfactory bulb-medial prefrontal cortex circuit due to allergic reactions might have a governing role for inducing anxiety-like behavior in the allergic rhinitis experimental model.

BACKGROUND:The precise effect of low frequency stimulation (LFS) as a newly postulated, anticonvulsant therapeutic approach on seizure-induced changes in synaptic transmission has not been completely determined. HYPOTHESIS:In this study, the LFS effect on impaired, synaptic plasticity in kindled rats was investigated. METHODS:Hippocampal kindled rats received LFS (4 trials consisting of one train of 200 monophasic square waves, 0.1 ms pulse duration, 1 Hz) on four occasions. LTP induction was evaluated using whole-cell recordings of evoked excitatory and inhibitory post-synaptic potentials (EPSPs and IPSPs respectively) in CA1 neurons in hippocampal slices. In addition, the hippocampal excitatory and inhibitory post-synaptic currents (EPSCs and IPSCs), and the gene expression of NR2A, GluR2 and γ2 were evaluated. RESULTS:LTP induction was attenuated in excitatory and inhibitory synapses in hippocampal slices of kindled rats. When LFS was applied in kindled animals, LTP was induced in EPSPs and IPSPs. Moreover, LFS increased and decreased the threshold intensities of EPSCs and IPSCs respectively. In kindled animals, NR2A gene expression increased, while γ2 gene expression decreased. GluR2 gene expression did not significantly change. Applying LFS in kindled animals mitigated these changes: No significant differences were observed in NR2A, γ2 and GluR2 gene expression in the kindled+LFS and control groups. CONCLUSION:The application of LFS in kindled animals restored LTP induction in both EPSPs and IPSPs, and returned the threshold intensity for induction of EPSCs, IPSCs and gene expression to similar levels as controls.

Objective: Hippocampal insults have been observed in multiple sclerosis (MS) patients. Fibroblast growth factor-2 (FGF2) induces neurogenesis in the hippocampus and enhances 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. Materials and Methods: In this experimental study adult male Sprague-Dawley rats received either saline or lysolecithin (LPC) injections to the right hippocampi. Animals received 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-PCR). Results: There was reduced Mbp expression at seven days after LPC injection, increased expressions of Olig2 and Nestin, and the level of Gfap did not change. FGF2 treatment reversed the expression level of Mbp to the control, significantly enhanced the levels of Olig2 and Nestin, but did not change the level of Gfap. At day-28 post- LPC, the expression level of Mbp was higher than the control in LPC-treated animals that received FGF2. The levels of Olig2, Nestin and Gfap were at the control level in the non-treated LPC group but significantly higher in the FGF2-t reated LPC group. Conclusion: FGF2 enhanced hippocampal myelination and potentiated the recruitment of OPCs and neural stem cells (NSCs) to the lesion area. Long-term application of FGF2 might also enhance astrogliosis in the lesion site.

Introduction: Following the seizure there is an inhibitory period named “post-ictal depressionperiod” which has a depressing effect on the following seizure. In this study, the role of GABAAreceptors on post-ictal depression period was investigated in amygdala kindling model of epilepsy inrat.Materials and Methods: Animals were kindled by electrical stimulation of amygdala. Then, theywere divided into four groups. Different groups of kindled animals were received a second stimulationat 10, 30, 60 and 90 min after the first stimulation and the percentage of suppression of seizureparameters after the second stimulation was calculated. In another four groups, bicucullin, a selectiveGABAA receptor antagonist (100 nM), was intra-cerebroventricularly microinjected 10 min before thesecond stimulation and its effect on the percentage of suppression induced by the first stimulation wasinvestigated. Six animals were used in each group.Results: When the second stimulation was applied at 10 and 30 min after the first stimulation asignificant reduction was observed in the seizure severity and seizure parameters were depressed afterthe second stimulation. Bicucullin microinjection significantly decreased the percentage of depressionin seizure parameters following the second stimulation compared to the animals received the solventalone (P

Inhibitory factors have been implicated in the failure of remyelination in demyelinating diseases. Myelin associated inhibitors act through a common receptor called Nogo receptor (NgR) that plays critical inhibitory roles in CNS plasticity. Here we investigated the effects of abrogating NgR inhibition in a non-immune model of focal demyelination in adult mouse optic chiasm.A focal area of demyelination was induced in adult mouse optic chiasm by microinjection of lysolecithin. To knock down NgR levels, siRNAs against NgR were intracerebroventricularly administered via a permanent cannula over 14 days, Functional changes were monitored by electrophysiological recording of latency of visual evoked potentials (VEPs). Histological analysis was carried out 3, 7 and 14 days post demyelination lesion. To assess the effect of NgR inhibition on precursor cell repopulation, BrdU was administered to the animals prior to the demyelination induction. Inhibition of NgR significantly restored VEPs responses following optic chiasm demyelination. These findings were confirmed histologically by myelin specific staining. siNgR application resulted in a smaller lesion size compared to control. NgR inhibition significantly increased the numbers of BrdU+/Olig2+ progenitor cells in the lesioned area and in the neurogenic zone of the third ventricle. These progenitor cells (Olig2+ or GFAP+) migrated away from this area as a function of time.Our results show that inhibition of NgR facilitate myelin repair in the demyelinated chiasm, with enhanced recruitment of proliferating cells to the lesion site. Thus, antagonizing NgR function could have therapeutic potential for demyelinating disorders such as Multiple Sclerosis.

BACKGROUND: Degeneration of retinal ganglion cells (RGCs) is a common occurrence in several eye diseases. This study examined the functional improvement and protection of host RGCs in addition to the survival, integration and neuronal differentiation capabilities of anterior specified neural progenitors (NPs) following intravitreal transplantation. METHODOLOGY/PRINCIPAL FINDINGS: NPs were produced under defined conditions from human induced pluripotent stem cells (hiPSCs) and transplanted into rats whose optic nerves have been crushed (ONC). hiPSCs were induced to differentiate into anterior specified NPs by the use of Noggin and retinoic acid. The hiPSC-NPs were labeled by green fluorescent protein or a fluorescent tracer 1,1' -dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) and injected two days after induction of ONC in hooded rats. Functional analysis according to visual evoked potential recordings showed significant amplitude recovery in animals transplanted with hiPSC-NPs. Retrograde labeling by an intra-collicular DiI injection showed significantly higher numbers of RGCs and spared axons in ONC rats treated with hiPSC-NPs or their conditioned medium (CM). The analysis of CM of hiPSC-NPs showed the secretion of ciliary neurotrophic factor, basic fibroblast growth factor, and insulin-like growth factor. Optic nerve of cell transplanted groups also had increased GAP43 immunoreactivity and myelin staining by FluoroMyelin™ which imply for protection of axons and myelin. At 60 days post-transplantation hiPSC-NPs were integrated into the ganglion cell layer of the retina and expressed neuronal markers. CONCLUSIONS/SIGNIFICANCE: The transplantation of anterior specified NPs may improve optic nerve injury through neuroprotection and differentiation into neuronal lineages. These NPs possibly provide a promising new therapeutic approach for traumatic optic nerve injuries and loss of RGCs caused by other diseases.

Introduction & Objective: In the CNS, adenosine is known to suppress repetitive neuronal Firing, suggesting a role as an endogenous modifier of seizures. Indeed, intracerebral adenosine concentrations rise acutely during seizure activity and are thought to be responsible for terminating seizures and establishing a period of post-ictal refractoriness. However, it is unclear whether this suppression results from a general depression of brain excitability or through action on particular sites critical for the control of after discharge generation and/or seizure development and propagation. In this regard, comparison of the effects of adenosine A1 receptors of CA1 (region of the ‎hippocampus) on entorhinal cortex and amygdala kindled seizures was ‎investigated in this study. Materials & Methods: In this experimental study, Animals were kindled by daily electrical stimulation of amygdale (group A) or entorhinal cortex (group B). In the fully kindled animals, N6-‎cyclohexyladenosine (CHA1 and 10 mM a selective adenosine A1 receptor ‎agonist) and 1,3-dimethyl-8-cyclohexylxanthine(CPT1 ‎µ‎M a selective ‎adenosine A1 receptors antagonist ) were microinfused bilaterally into the CA1 ‎region of hippocampus (1ml/2min ) and animals were stimulated at 5 and 15 minutes after drug ‎injection. All animals were received artificial cerebrospinal fluid, 24 h before ‎each drug injection and this result were used as control. Results: The seizure parameters were measured at 5 and 15min post injection. Obtained data showed that CHA at concentrations of 10 ‎µ‎M reduced ‎entorhinal cortex and amygdala after discharge and stage5 seizure durations and ‎increased stage4 latency. CHA at concentration 1‎µ‎M significantly alters ‎seizure parameters of group A but not effect on group B. Intrahippocampal (CA1 region) pretreatment of CPT (1 ‎µ‎M) before CHA abolished the effects of CHA on seizure parameters. Conclusion: It ‎may be suggested that hippocampal CA1 region plays an important role in ‎seizure propagation from entorhinal cortex and amygdala to other brain ‎region/s and activation of adenosine A1 receptors in this region have ‎anticonvulsant effects on amygdala rather than entorhinal cortex kindled ‎seizures.

Objective: Temporal lobe epilepsy is the most common type of epilepsy in adult humans, which is characterized clinically by a progressive development of spontaneous recurrent seizures of temporal lobe origin. Because of the side effects of current treatment protocols, the resistance to pharmacological therapy in this investigation, bone marrow stromal cells were used to evaluate the recovery of epileptic rats induced by pilocarpine. Materials & Methods: In this randomized experimental research, the rats were divided into five groups, controls (untreated), three treated groups (12, 24 and 36 hours) and a group treated with the vehicle only. The animals in chronic phase were monitored via video monitoring system for three weeks (day & night). For assessment of the response for the treatment of epileptic’s rat using BMSCs therapy, Racine scale was used as a behavioral test. BMSCs (2 – 3 million cells) were labeled with BrdU and were injected via tail vein rat 12, 24, 36 hours after first seizure. After 6 week all rats sacrificed and processed for paraffin, sectioned and for Cresyl violet staining. Data were analyzed by use of Wilcoxon signed Ranks test and Tukey’s test. Results: The result of the study showed that the behavioral test in three week as follows: in control group (untreated), number of seizure is 6.25±1.3 in vehicle group, number of seizure was 6.2±0.8 the group which received BMSCs 12 h after seizure all rats died the group which received BMSCs (24 h after seizure), the number was 2±0.4 and the group which received BMSCs (36 h after seizure), the number of seizure was 2.25±0.47. There was significant difference between treated (2 and 36 hours) groups and other groups in number of seizure (P

Introduction: Neural stimulation is a promising new technology for the treatment of medically-intractable seizures. Transcranial Magnetic Stimulation (TMS) is a simple, non-invasive, low cost technique which is widely used in neurophysiology. In a few studies that have been performed at different frequencies the therapeutic effects of this technique were not obvious. Repetition of low frequencies TMS (≤1 Hz) has inhibitory and quenching effects on neuron activities and it decreases the excitability of the cortex. In epilepsy, as a disease of the central nervous system, the excitability of the cortex increases. It seems that such a technique at its optimum frequencies has therapeutic potential in epilepsy. Materials and Methods: In this study, the effect of 0.1, 0.5, 1 and 2 Hz repetitive Transcranial Magnetic Stimulation (rTMS) at an intensity of 80% Resting Motor Threshold (RMT) and at 1 Hz with an intensity of 90 and 100% RMT on Amygdala-kindling model in rats in optimum spatial coordinate was investigated. The procedure includes delivering a daily 5 minute rTMS stimulus using a butterfly figure coil having 25 mm in diameter and the coordinate which induces the maximum electrical field in Amygdala area. The stimulus was given within five minutes after the electrical kindling stimulus was delivered. The number of days to reach stage 1, 2, 3, 4 and 5 of kindling model After Discharge Duration (ADD) in each day and the percentage of cumulative ADD between the treated and the control group was statistically compared. Two groups were used to investigate the effect of the intensity of the magnetic field. A frequency of 1 Hz rTMS at an intensity of 90% and 100% RMT was delivered with the same physical parameters as before. Results: Using a frequency of 1 Hz rTMS at an intensity of 80% and RMT of 90% showed a significant inhibitory effect on the spread of seizure into other areas of brain in comparison to the control group. Increasing the intensity of the magnetic field from 80 to 90% RMT increased the inhibitory effect of this technique. However, the quenching effect was significantly decreased when the intensity of the magnetic field was increased to 100% RMT. Discussion and Conclusion: It seems that the frequency of rTMS and Motor Threshold of subject are important factors in causing physiological effects. This study showed that rTMS technique at some frequencies and intensities may have therapeutic effect on epilepsy.