Chronic acetyl-L-carnitine treatment alleviates behavioral deficits and neuroinflammation through enhancing microbiota derived-SCFA in valproate model of autism.

Autism spectrum disorder is characterized by a variety of cellular and molecular abnormalities which leads to autism-associated behaviors. Besides behavioral defects, these individuals also suffer from various associated disorders such as gastrointestinal deficit, altered gut microbiota composition and their metabolite. This study examined the effect of ALC on microbiota SCFA production and its effects on brain inflammation in VPA autism model. After prenatal exposure to valproate (600 mg/kg, i.p.) on embryonic day 12.5, followed by ALC treatment (100 mg/kg during postnatal days 23-51, p.o.), ASD-like behaviors, SCFAs amount in feces, intestine integrity (Occludin and ZO-1 tight junction proteins), systemic and brain inflammation (TNF-α and IL-1ß) were assessed. Then, Golgi-Cox staining and Western blot for Iba1 protein were utilized to identify the changes in microglia profile in cerebral cortex. In the VPA model, we found that induction of autism was associated with demoted levels of SCFAs in feces and disintegration of intestine tissue which led to elevated level of TNF-α in the plasma. Further, we characterized an increased number of microglia in our histology evaluation and Iba1 protein in cerebral cortex. We also observed elevated level of TNF-α and IL-1ß in the cerebral cortex of VPA rat. All these abnormalities were significantly alleviated by ALC treatment. Overall, our findings suggest that alleviation of behavioral abnormalities by ALC therapy in the VPA model of autism is associated with an improvement in the gut microbiota SCFAs, intestinal barrier and recovery of microglia and inflammation in the brain.

Valproate-induced murine autism spectrum disorder is associated with dysfunction of amygdala parvalbumin interneurons and downregulation of AMPK/SIRT1/PGC1α signaling.

Autism spectrum disorder (ASD) is a neurodevelopmental condition that is characterized by difficulty in social behavior and restricted behaviors. Also, in ASD, several accompanying disorders such as anxiety are observed. Considering the important role of amygdala in the pathophysiology of ASD, the present study focused on the neuronal changes and it possible signaling pathway in amygdala. After prenatal exposure to valproate (VPA; 600 mg/kg, i.p, on embryonic day 12.5), amount of ROS, MMP, caspase-3 activity, AMPK, SIRT1 and PGC1α proteins, and parvalbumin interneurons in the amygdala were assessed following evaluation of ASD and anxiety-like behaviors. Amygdala analysis revealed ROS accumulation and decreased MMP in autistic rats. In addition, caspase-3 activation elevated and immunoreactivity for parvalbumin interneurons decreased. These were accompanied by anxiety and autistic-like behaviors in open field test, elevated zero maze and U-Shaped 2 Choice Field maze. Also, our data showed that in the valproate group, protein levels of AMPK, SIRT1 and PGC1α reduced. Collectively, our results indicate that prenatal exposure to valproate leads to anxiety and autistic-like behaviors, partly through its targeting amygdala parvalbumin interneurons dysfunction and this might be affected by disturbed AMPK/SIRT1/PGC1α signaling pathway.

Ferulic Acid Attenuates Kainate-induced Neurodegeneration in a Rat Poststatus Epilepticus Model.

BACKGROUND AND AIMS: Increasing research evidence indicates that temporal lobe epilepsy (TLE) induced by kainic acid (KA) has high pathological similarities with human TLE. KA induces excitotoxicity (especially in the acute phase of the disease), which leads to neurodegeneration and epileptogenesis through oxidative stress and inflammation. Ferulic acid (FA) is one of the well-known phytochemical compounds that have shown potential antioxidant and anti-inflammatory properties and promise in treating several diseases. The current study set out to investigate the neuroprotective effects of FA in a rat model of TLE. METHODS: Thirty-six male Wistar rats were divided into four groups. Pretreatment with FA (100 mg/kg/day p.o.) started one week before the intrahippocampal injection of KA (0.8 µg/µl, 5µl). Seizures were recorded and evaluated according to Racine's scale. Oxidative stress was assessed by measuring its indicators, including malondialdehyde (MDA), nitrite, and catalase. Histopathological evaluations including Nissl staining and immunohistochemical staining of cyclooxygenase-2 (COX-2), and neural nitric oxide synthases (nNOS) were performed for the CA3 region of the hippocampus. RESULTS: Pretreatment with FA significantly attenuates the severity of the seizure and prevents neuronal loss in the CA3 region of the hippocampus in rats with KA-induced post-status epilepticus. Also, nitrite concentration and nNOS levels were markedly diminished in FA-pretreated animals compared to non-pretreated epileptic rats. CONCLUSION: Our findings indicated that neuroprotective properties of FA, therefore, could be considered a valuable therapeutic supplement in treating TLE.

Preconditioning exercise reduces hippocampal neuronal damage via increasing Klotho expression in ischemic rats.

Considerable amounts of oxidants are produced in cerebral ischemia, where oxidative stress plays a key role in neuronal damage after ischemia. Klotho, an anti-aging protein, alleviates oxidative stress by activating the transcription of an important antioxidant enzyme, manganese superoxide dismutase (MnSOD), in the nervous system. Thus, increased Klotho expression level could lead to a reduction in neuronal damages after brain ischemia via lowering oxidative stress. It is known that physical activity increases Klotho expressions. In this study, we assessed neuroprotective effects of preconditioning exercise in rats (treadmill running at a speed of 20 m/min,30 min/day, six days/week, for3 weeks) on hippocampal Klotho and MnSOD expression in the brain using an animal model of stroke, middle cerebral artery occlusion (MCAO). Our study revealed a reduction in hippocampal Klotho and MnSOD expression as well as CA1 neuronal activity in MCAO compared to the sham group. Exercise prevented the ischemia-induced decline in Klotho and MnSOD expression levels as well as CA1 neuronal activity in Exercise + MCAO compared to the MCAO group. Also, exercise significantly improved the neurological scores and reduced brain infarction area in Exercise + MCAO in comparison to MCAO group. There was a post-ischemia deficit in the working memory, as measured by spontaneous alternation percentage using Y-maze test, in MCAO compared to the sham group. The latter effect was not observed in the Exercise + MCAO group, which could be related to an increase in the antioxidant capacity as exhibited by Klotho and MnSOD up-regulation. The results were confirmed with a positive correlation between Klotho expression and MnSOD expression which allows proposing Klotho as a potential neuroprotective protein in ischemic stroke with respect to antioxidant defense. In general, the present study suggested that preconditioning exercise induced upregulation of Klotho and MnSOD, as well as attenuated the post-ischemic injuries. The upregulation of Klotho might be an underlying mechanism by which preconditioning exercise plays as a neuroprotective factor against post-ischemic neural injuries in ischemic rats.

The potential neuroprotective roles of olive leaf extract in an epilepsy rat model induced by kainic acid.

BACKGROUND AND PURPOSE: Epilepsy is recognized as a chronic neurologic disease. Increasing evidence has addressed the antioxidant and anti-inflammatory roles of olive leaf extract (OLE) in neurodegenerative diseases. So, the current study aimed to investigate the neuroprotective roles of OLE in epilepsy. EXPERIMENTAL APPROACH: Forty rats were divided into 4 groups including a control group, sham group, kainic acid (KA) group, and KA + OLE group. KA (4 µg/rat) was injected intrahippocampal, and OLE (300 mg/kg) was orally administrated for 4 weeks. Animals were sacrificed, and their hippocampi were isolated. KA- induced seizure activity was recorded. Oxidative stress index was assessed by measuring its indicators including malondialdehyde (MDA), nitrite, nitrate, and glutathione (GSH) as well as the catalase (CAT) activity. The supernatant concentration of tumor necrosis factor-α (TNF-α) and the apoptosis rate in neurons were measured. FINDINGS/RESULTS: Treatment with OLE significantly reduced the seizure score. OLE decreased oxidative stress index by reducing the concentration of MDA, nitrite, and nitrate as well as increasing the level of GSH. OLE had a significant anti-apoptotic effect on neurons. However, CAT activity and the level of TNF-α were not affected. CONCLUSION AND IMPLICATIONS: Our findings indicated neuroprotective properties of OLE, which is mainly mediated by its antioxidant and anti-apoptotic effects, therefore, could be considered as a valuable therapeutic supplement for epilepsy.

A literature overview on epilepsy and inflammasome activation.

Epilepsy is one of the most prevalent serious brain disorders worldwide. Accumulating evidence has suggested that inflammation participates in the progression and pathogenesis of epilepsy. During inflammation, a cytosolic multimolecular complex called the "inflammasome" is activated, driving the innate immune response. This inflammatory pathway by sensing various pathogens and molecules from damaged cells and then activation of caspase-1 enzyme initiates inflammatory responses. Activated caspase-1 leads to the proteolytic cleavage of the pro-inflammatory cytokines, interleukin-1ß (IL-1ß) and interleukin-18 (IL-18), and also induction of an inflammatory programmed cell death termed pyroptosis. NLR family pyrin domain-containing 1 (NLRP1) and NLRP3 are the two best-characterized inflammasome members, and both basic and clinical research has reported their activation during epilepsy. This overview is intended to summarize the current literature concerning NLRP1 and NLRP3 inflammasome activation and epilepsy.

Deep Brain Stimulation of the Lateral Hypothalamus Facilitates Extinction and Prevents Reinstatement of Morphine Place Preference in Rats.

OBJECTIVES: We have previously shown that high-frequency (HF) deep brain stimulation (DBS) of the lateral hypothalamus (LH) during the acquisition phase of morphine-induced conditioned place preference (CPP) abolished the development of morphine reward. In the present study, we investigated the effect of DBS in the LH during the extinction phase of morphine CPP. MATERIALS AND METHODS: Rats were implanted with electrodes in the LH and went through conditioning trials for morphine CPP (40 min each, for three days), followed by extinction trials (20 min, for nine days). DBS-like stimulation (square pulses at 13 or 130 Hz, 200 µA, 100 µsec) was applied during the extinction trials. RESULTS: Rats that received HF-DBS (130 Hz) accomplished extinction of morphine place preference by day 5 of the phase, whereas those in sham-stimulation or low-frequency-DBS (LF-DBS, 13 Hz) groups reached the criterion for extinction at day 8. One day later, rats received a priming injection of morphine (2 mg/kg) to reinstate the extinguished preference. While rats in the sham-DBS and LF-DBS relapsed into the state of preferring morphine-associated context, those in the HF-DBS group did not show such preference. Rats were then proceeded into an additional phase of extinction training (20 min, once daily, three to five days) with DBS, followed by restraint stress-induced reinstatement test. Again, sham-DBS and LF-DBS had no effect on relapse to the morphine place preferring state, but HF-DBS completely prevented the relapse. CONCLUSION: HF-DBS facilitated extinction of morphine place preference and disrupted drug priming- and stress-induced renewal of morphine place preference.

Inhibition of brain 17ß-estradiol synthesis by letrozole induces cognitive decline in male and female rats.

BACKGROUND: Hippocampal aromatase is responsible for local synthesis of 17ß-estradiol (E2) that has much higher concentrations than serum levels in males and females. Letrozole, an aromatase inhibitor, passes through the brain barriers, distributes to the brain, and affects local E2 synthesis. Here, the effects of intra-cerebroventricular (ICV) letrozole administration in the presence and absence of gonads were examined on the cognitive abilities of male and female rats. METHOD: Animals received intra-ICV injection of letrozole or vehicle for 14 consecutive days. Spatial working memory, novel object recognition memory, and anxiety-related behavior, were evaluated using Y-maze, object recognition test, and elevated plus maze, respectively. The E2 levels in the serum and hippocampal tissue were measured by the ELISA technique. RT-PCR was performed to assess the hippocampal estrogen receptors (ER) expression. Moreover, letrozole effect on neuronal activity of CA1 pyramidal neurons was studied by in vivo single-unit recording. RESULTS: Letrozole (0.2, 0.4, and 0.8 µg) significantly decreased the hippocampal E2 levels compared to the vehicle group. Letrozole caused cognitive impairments in a dose-dependent manner in male and female rats in the presence or absence of gonads. Dose-response analysis revealed that the minimum effective dose of letrozole on the behavioral measures was 0.4 µg. Letrozole also caused an up-regulation of ERα and ERß and a down-regulation of GPR30 gene expression. The firing rate of pyramidal neurons was reduced by letrozole in gonadal-intact animals. CONCLUSION: The detrimental effects of letrozole treatment on cognitive abilities in the presence and absence of gonads indicate that local E2 synthesis in the hippocampus is a crucial factor in normal cognitive performance. The suppressive effect of letrozole on hippocampal neuronal firing might alter synaptic plasticity that is critical for memory formation. These data potentially suggest that memory deficits following letrozole administration should be monitored.

Administration of Vitamin D3 and E supplements reduces neuronal loss and oxidative stress in a model of rats with Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is the most common neurodegenerative disease across the world. The major cause of AD is extensive oxidative stress and inflammation in central nervous system (CNS). Vitamin D3 and E are the most known vitamins that control oxidative stress and mitochondrial respiratory function. They may prevent neuronal loss in AD. Few studies have been conducted to assess the effect of vitamins on AD. Therefore, the aim of this study was to assess the effect of vitamin D3 and E on AD. Methods: In this study, 60 rats were randomly divided into six groups (n = 10) namely the control group, sham group, AD group with intra-hippocampal Aß1-40 injection, AD+vitamin D3 group, AD+vitamin E group and AD+vitamin D3 and E group. Memory and learning were measured by the Novel Object Recognition (NOR) test. Neuronal survival was assessed by H&E and cresyl violet staining, and oxidative stress was measured by malondialdehyde (MDA) level and superoxide dismutase (SOD) activity. In vitamin-treated groups, learning and memory, which were measured by NOR, improved significantly. Vitamin D3 and E administration decreased neuronal loss in AD brain rats. Results: Results showed that MDA decreased and SOD increased in treatment groups; but, a combination of vitamin D3 and E was more effective in decreasing oxidative stress in AD compared to other treatment groups. Conclusion: The present study indicated that vitamin D3 and E and their combination can improve memory and learning deficit, and decrease neuronal loss and oxidative stress in Alzheimer's model.

The Effect of Rosmarinic Acid on Apoptosis and nNOS Immunoreactivity Following Intrahippocampal Kainic Acid Injections in Rats.

INTRODUCTION: Kainic Acid (KA) is an ionotropic glutamate receptor agonist. KA can induce neuronal overactivity and excitotoxicity. Rosmarinic Acid (RA) is a natural polyphenolic compound with antioxidant, anti-apoptotic, anti-neurodegenerative, and anti-inflammatory properties. This study aimed to assess the effect of RA on apoptosis, nNOS-positive neurons number, as well as Mitogen-Activated Protein Kinase (MAPK) and Cyclooxygenase-2 (COX-2) immunoreactivity, following intrahippocampal Kainic acid injection in rats. METHODS: The study rats were randomly assigned to three groups of sham, KA (KA was injected into the right side of the hippocampus) and KA+RA (a dose of 10 mg/kg/day through a gavage needle for one week before KA injection). Then, histopathological changes, including apoptosis [Terminal Deoxynucleotidyl Transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay], nNOS-positive neurons number, as well as COX-2 and MAPK immunoreactivity were evaluated in the hippocampus. RESULTS: In the RA pretreated group, nNOS-positive neurons and TUNEL-positive cells were significantly reduced compared to the KA group (P<0.05). COX-2and MAPK immunoreactivity demonstrated no significant changes compared to the KA group. They indicated a significant higher reactivity for COX-2 (P<0.01) and MAPK (P<0.005) versus the sham group. CONCLUSION: RA had neuroprotective effects, compared to KA, through reduced apoptosis and nNOS-positive neurons, but not MAPK and COX-2.

Assessment of Probiotics Mixture on Memory Function, Inflammation Markers, and Oxidative Stress in an Alzheimer's Disease Model of Rats.

Background: The most important cause of neurodegeneration in Alzheimer's disease (AD) is associated with inflammation and oxidative stress. Probiotics are microorganisms that are believed to be beneficial to human and animals. Probiotics reduce oxidative stress and inflammation in some cases. Therefore, this study determined the effects of probiotics mixture on the biomarkers of oxidative stress and inflammation in an AD model of rats. Methods: In this study, 50 rats were allocated to five groups, namely control, sham, and AD groups with Aß1-40 intra-hippocampal injection, as well as AD + rivastigmine and AD + probiotics groups with Aß1-40 intra-hippocampal injection and 2 ml (1010 CFU) of probiotics (Lactobacillus reuteri, Lactobacillus rhamnosus, and Bifidobacterium infantis) orally once a day for 10 weeks. MWM was used to assess memory and learning. To detect Aß plaque, Congo red staining was used. Oxidative stress was monitored by measuring the MDA level and SOD activity, and to assess inflammation markers (IL-1ß and TNF-α) in the hippocampus, ELISA method was employed.. Results: Spatial memory improved significantly in treatment group as measured by MWM. Probiotics administration reduced Aß plaques in AD rats. MDA decreased and SOD increased in the treatment group. Besides, probiotics reduced IL-1ß and TNF-α as inflammation markers in the AD model of rats. Conclusion: Our data revealed that probiotics are helpful in attenuating inflammation and oxidative stress in AD.

Deep brain stimulation of the orbitofrontal cortex prevents the development and reinstatement of morphine place preference.

The orbitofrontal cortex (OFC) is involved in compulsive drug seeking and drug relapse. Its involvement in cue-, context-, and stress-induced reinstatement of drug seeking has also been confirmed in animal models. Deep brain stimulation (DBS) was proposed to be an effective intervention for patients with treatment-refractory addiction. Therefore, in the present study, we investigated the potential efficacy of DBS in the OFC for controlling addictive-like behaviors in rats. Rats were bilaterally implanted with electrodes in the OFC and trained to the morphine conditioned place preference (CPP; 3, 5, and 7 mg/kg). High-frequency (HF; 130 Hz) or low-frequency (LF; 13 Hz) DBS-like stimulation was applied during the conditioning (40 minutes, once daily, 3 days) or extinction (20 minutes, once daily, 6-10 days) trials. Following the extinction, morphine preference was reinstated by a priming dose of morphine (2 mg/kg). When applied during the conditioning phase, HF-DBS significantly decreased preference for the morphine-associated context. HF-DBS during the extinction phase of morphine CPP reduced the number of days to full extinction of morphine preference and prevented morphine priming-induced recurrence of morphine preference. LF-DBS did not change any of these addictive behaviors. HF-DBS had no significant effect on novel object recognition memory. In conclusion, HF-DBS of the OFC prevented morphine preference, facilitated extinction of morphine preference, and blocked drug priming-induced reinstatement of morphine seeking. These findings may indicate a potential applicability of DBS in the treatment of relapse to drug use. Further studies will be necessary to assess the translatability of these findings to the clinic.

Hypoxic-conditioned medium from adipose tissue mesenchymal stem cells improved neuroinflammation through alternation of toll like receptor (TLR) 2 and TLR4 expression in model of Alzheimer's disease rats.

Microglia have a pivotal role to initiate immune responses in AD brains through toll-like receptors and induce neuroinflammation. Adipose tissue mesenchymal stem cells (ATSCs) secret many neurotrophic and anti-inflammatory factors called conditioned medium (CM). Many studies have demonstrated that CM of mesenchymal stem cells facilitate regeneration and attenuates inflammation in many disorders. To this purpose, the effect of ATSCs-conditioned medium (ATSC-CM) on brain inflammation and the role of toll-like receptors were investigated in this study. Seventy-two rats were randomly divided into 6 groups: control, sham, sham+ATSC-CM: 200µl ATSC-CM once a day intraperitoneally for 8 days, AD group injected the Aß1-40 intra-hippocampal, AD+ASC-CM, which was injected Aß1-40 intra-hippocampal and 200µl ATSC-CM once a day intraperitoneally for 8 days and AD+ rivastigmine: was injected Aß1-40 intra-hippocampal and received rivastigmine (0.6 mg/kg) orally once a day for 2 weeks. Memory and learning were measured by Morris water maze and novel object recognition tests. For detection of beta-amyloid plaque, Congo red staining was used, and neuronal survival was assessed by Nissl staining. Expression of TLR2 and TLR4 was measured by real-time PCR, and finally, to assess inflammation markers (IL-1ß and TNF-α) in the hippocampus, ELISA kits were used. In treatment group spatial and recognition memory significantly was improved. ATSC-CM administration decreased beta amyloid plaques and enhanced neuronal survival in AD brain rats. In addition, TLR2 and TLR4 expression decreased in treatment group. Results also showed that ATSC-CM reduced IL-1ß and TNF-α as inflammation markers. ATSC-CM improved memory deficit, decreased beta amyloids formation, increased neuron survival, and attenuated inflammation by reducing the expression of TLRs.

Saffron (Crocus sativus) aqueous extract reverses the hypothalamus-pituitary-adrenal axis activity in rat model of post-traumatic stress disorder

Abstract Crocus sativus L., Iridaceae, has been used worldwide in traditional medicinefor treatment ofsome neurological disorderssuch as depression. Post-traumatic stress disorder is a mental disorder developed in peoplewho experience stressful events. Since stress has been proposed tocause thehypothalamic-pituitary-adrenal axis malfunction in post-traumatic stress disorder patients, this study aimed at investigating the effect of saffron aqueous extract on hypothalamic-pituitary-adrenal axis activity in rats of post-traumatic stress disorder model. Here, Post-traumatic stress disorder animals received an acute electro foot shock; however, 5 min before the stress session, these animals received an intra-cerebral-ventricular (10 µg/rat) infusion of either saffron aqueous extract or saline. Twenty one days later, they were re-exposedto the stress box withoutinducing stress, andthen were examined for their freezing behavior. The impact of stress and saffron aqueous extract on serum corticosterone, corticotrophin releasing hormone gene expression in hypothalamus and glucocorticoid receptor gene expression in pituitary gland werethen evaluated on day 28. Intra-cerebral-ventricular injection of saffron aqueous extract resulted in an increase in serum corticosterone level and reduced symptoms of freezing behavior, and corticotrophin releasing hormone and glucocorticoid receptor gene expression in post-traumatic stress disorder groups.Saffron administration could improve the symptoms of stress-induced post-traumatic stress disorder, possiblythrough the adjustment ofhypothalamic-pituitary-adrenal axis function.

Assessment of the protective effect of KN-93 drug in systemic epilepsy disorders induced by pilocarpine in male rat.

BACKGROUND AND AIMS: Epileptic seizures occur as a consequence of a sudden imbalance between the stimuli and inhibitors within the network of cortical neurons in favor of the stimulus. One of the drugs that induce epilepsy is pilocarpine. Systemic injection of pilocarpine affects on muscarinic receptors. Increasing evidence has addressed the implication of KN-93 by blocking Ca2+ /calmodulin-dependent protein kinase II (CaMKII), suppressing oxidative stress and inflammation, and also reducing neuron decay. So, we aimed to evaluate the potential preventive effects of KN-93 in systemic epilepsy disorders induced by pilocarpine. MATERIALS AND METHODS: In this animal study, male rats were divided into five groups including treatment group (KN-93 with the dose of 5 mM/10 µL dimethyl sulfoxide (DMSO) before inducing epilepsy by 380 mg/kg pilocarpine) KN-93 group (received 5 mM KN-93), control group, epilepsy group (received 380 mg/kg pilocarpine Intraperitoneal), and sham group (received 10 µL DMSO). Oxidative stress was assessed by measuring its indicators including the concentration of malondialdehyde (MDA), nitrite, glutathione (GSH), as well as the antioxidant activity of catalase. In addition, serum levels of proinflammatory mediators including tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were determined. RESULTS: Pretreatment with KN-93 significantly reduced oxidative stress index by reducing the concentration of MDA, nitrite, and increasing the level of GSH. In addition, low concentrations of TNF-α and IL-1ß were observed in hippocampus supernatant of KN-93 pretreated rats in comparison with the pilocarpine groups. Moreover, administration of KN-93 improved neuronal density and attenuated the seizure activity and behavior. CONCLUSIONS: Overall, our findings suggest that KN-93 can effectively suppress oxidative stress and inflammation. Furthermore, KN-93 is able to attenuate seizure behaviors by preventing its effects on neuron loss, so, it is valuable for the treatment of epileptic seizures.

Protective properties of the aqueous extract of saffron (Crocus sativus L.) in ischemic stroke, randomized clinical trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Crocus sativus L. has been used throughout the world in traditional medicine as a treatment for neurological disorders such as depression. Growing attention is currently being paid to the use of neuroprotective agents in ischemic strokes. AIM OF THE STUDY: This study assed the effect of saffron as a neuroprotective natural product in cerebral ischemia in human. STUDY DESIGN: Patients with acute ischemic stroke were randomly allocated to receive either routine stroke care (control group, n = 20) or routine care plus aqueous extract of saffron capsule (200 mg/day) (saffron-treated group, n = 19). Both groups were monitored during their four-day hospital stay and the three-month follow-up period. The groups were compared in terms of short- and long-term effects of saffron capsules using the National Institute of Health Stoke Scale (NIHSS), Barthel Scale, and serum neuron specific enolase (NSE), Brain-derived neurotrophic factor (BDNF), S100 levels. RESULTS: Based on the NIHSS, the severity of stroke during the first four days was significantly lower in the saffron-treated group than in the control group (P < 0.05). Compared to the levels on the first day, serum NSE and s100 levels were significantly decreased and BDNF concentration was increased in the saffron-treated group on the fourth day. Also, our results showed there was a negative significant non-linear cubic regression between BDNF concentration and score of NIHSS. At the end of the three-month follow-up period, the mean Barthel index was significantly higher in the saffron-treated group than in the control group (P < 0.001). CONCLUSION: The results of this study confirmed the short and long-term neuroprotective effects of aqueous extract of saffron on ischemic stroke in humans.

Huperzine A ameliorates cognitive dysfunction and neuroinflammation in kainic acid-induced epileptic rats by antioxidant activity and NLRP3/caspase-1 pathway inhibition.

Temporal lobe epilepsy (TLE) is one of the most prevalent types of epilepsy in human. Huperzine A (Hup-A) has been reported to possess antioxidative and anti-inflammatory properties; however, its role in TLE induced by kainic acid has not been determined. The current study investigated the protective effects of Hup-A (0.1 mg/kg) in kainic acid-induced model of TLE in the rat. In the current study, it was found that Hup-A significantly prevented the seizure intensity and learning and memory deterioration which was assessed by Morris water maze (MWM) and novel object recognition task (NOR). Additionally, Hup-A inhibited oxidative stress, inflammation, and acetylcholinesterase activity (AChE). In addition, catalase and superoxide dismutase (SOD) activities increased after Hup-A treatment, while malondialdehyde (MDA) and nitrite levels significantly reduced. Regarding inflammation, this drug decreased kainic acid-induced NLRP3 expression in microglial cells and caspase-1 activity in hippocampal tissue, possibly through diminishing oxidative stress. Taken together, our data showed that Hup-A could be a potential protective substance to ameliorate seizure severity and some memory deficits related to epilepsy via attenuating neuroinflammation and protection of neurons.

Bone marrow-derived mesenchymal stem cell and simvastatin treatment leads to improved functional recovery and modified c-Fos expression levels in the brain following ischemic stroke.

OBJECTIVES: The beneficial outcomes of bone marrow-derived mesenchymal stem cell (BMSC) treatment on functional recovery following stroke has been well established. Furthermore, 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors have also been shown to increase neuronal survival and promote the movement of BMSCs towards the sites of inflammation. However, the precise mechanisms mediating the improved neurological functional recovery in stoke models following a combination treatment of Simvastatin and BMSCs still remained poorly understood. MATERIALS AND METHODS: Here, an embolic stroke model was used to experimentally induce a focal ischemic brain injury by inserting a preformed clot into the middle cerebral artery (MCA). Following stroke, animals were treated either with an intraperitoneal injection of Simvastatin, an intravenous injection of 3 ×106 BMSCs, or a combination of these two treatments. RESULTS: Seven days after ischemia, the combination of Simvastatin and BMSCs led to a significant increase in BMSC relocation, endogenous neurogenesis, arteriogenesis and astrocyte activation while also reducing neuronal damage when compared to BMSC treatment alone (P<0.001 for all). In addition, based on western blot analysis, following stroke there was a significant decrease in c-Fos expression (P<0.001) in the combination treatment group. CONCLUSION: These results further demonstrate the synergistic benefits of a combination treatment and help to improve our understanding of the underlying mechanisms mediating this beneficial effect.

Descriptive epidemiology: prevalence, incidence, sociodemographic factors, socioeconomic domains, and quality of life of epilepsy: an update and systematic review.

INTRODUCTION: The purpose of this study was to investigate the contributions of quality of life (QOL), sociodemographic factors (age, sex, etc.), residential areas, general attitudes toward epilepsy, socioeconomic domains, prevalence and incidence in epileptic patients from Iran. MATERIAL AND METHODS: A systematic literature search was conducted, including database searches in PubMed, Medline, Embase, ScienceDirect, Scopus, ISC, Health, Web of Science, and the Cochrane Library Database of relevant articles, personal files and systematic reviews to identify studies examining risk factors in epilepsy. RESULTS: This review article shows that certain socio-demographic and socio-economic factors, geographic variation in epidemiologic patterns of epilepsy as well as clinical factors may be crucial in determining QOL in epilepsy patients and provides further evidence supporting the validity of the scale in QOL based on consideration of different target groups in different areas. CONCLUSIONS: Prevalence of epilepsy appears to be correlated with socioeconomic status in the lower socioeconomic groups. Also demographic characteristics, socio-economic factors and clinical presentation are linked to different QOL of these patients among nations. The educational program has a beneficial effect on self-management behaviors in patients with epilepsy. More work needs to be done to improve tools that help to evaluate efficiently the health-related quality of life of people with epilepsy.

Deep brain stimulation in a rat model of post-traumatic stress disorder modifies forebrain neuronal activity and serum corticosterone.

OBJECTIVES: Post-traumatic stress disorder (PTSD), one of the most devastating kinds of anxiety disorders, is the consequence of a traumatic event followed by intense fear. In rats with contextual fear conditioning (CFC), a model of PTSD caused by CFC (electrical foot shock chamber), deep brain stimulation (DBS) alleviates CFC abnormalities. MATERIALS AND METHODS: Forty Male Wistar rats (220-250 g) were divided into 5 groups (n=8) and underwent stereotactic surgery to implant electrodes in the right basolateral nucleus of the amygdala (BLn). After 7 days, some animals received a foot shock, followed by another 7-day treatment schedule (DBS treatment). Next, freezing behavior was measured as a predicted response in the absence of the foot shock (re-exposure time). Blood serum corticosterone levels and amygdala c-Fos protein expression were assessed using Enzyme-linked immunosorbent assay (ELISA) and Western blot, respectively. Furthermore, freezing behaviors by re-exposure time test and general anxiety by elevated plus-maze (EPM) were evaluated. RESULTS: PTSD decreased serum corticosterone levels and increased both amygdala c-Fos expression and freezing behaviors. Therefore, DBS treatment significantly (P<0.001) enhanced serum corticosterone levels and could significantly (P<0.001) reduce both c-Fos protein expression and freezing behaviors' duration. However, DBS treatment has no effect on the general anxiety in PTSD rats. CONCLUSION: We argue that these outcomes might demonstrate the mechanism of DBS treatment, a complete therapeutic strategy, in PTSD patients.