S-3,4-DCPG, a potent orthosteric agonist for the mGlu8 receptor, facilitates extinction and inhibits the reinstatement of morphine-induced conditioned place preference in male rats.

The limbic system, particularly the NAc, shows a high concentration of metabotropic glutamate receptors (mGluRs). Recent evidence suggests the significant involvement of mGluRs in mental disorders, including substance abuse and addiction. The objective of this study was to examine the involvement of mGlu8 receptors in the NAc in the mechanisms underlying the extinction and reinstatement of conditioned place preference (CPP) induced by morphine. Male Wistar rats underwent surgical implantation of bilateral cannulas in the NAc and were assessed in a CPP protocol. In study 1 at the same time as the extinction phase, the rats were given varying doses of S-3,4-DCPG (0.03, 0.3, and 3 µg/0.5 µl). In study 2, rats that had undergone CPP extinction were given S-3,4-DCPG (0.03, 0.3, and 3 µg/0.5 µl) five minutes prior to receiving a subthreshold dose of morphine (1 mg/kg) in order to reactivate the previously extinguished morphine response. The findings demonstrated that administering S-3,4-DCPG directly into the accumbens nucleus resulted in a decrease in the duration of the CPP extinction phase. Moreover, dose-dependent administration of S-3,4-DCPG into the NAc inhibited CPP reinstatement. The observations imply that microinjection of S-3,4-DCPG as a potent orthosteric agonist with high selectivity for the mGlu8 receptor into the NAc promotes the process of extinction while concurrently exerting inhibitory effects on the reinstatement of morphine-induced CPP. This effect may be associated with the modulation of glutamate engagement within the NAc and the plasticity of reward pathways at the synaptic level.

Vitamin D Protects Against Cardiac Hypertrophy Through the Regulation of Mitochondrial Function in Aging Rats.

Cardiac aging is defined as mitochondrial dysfunction of the heart. Vitamin D (VitD) is an effective agent in ameliorating cardiovascular disorders. In this study, we indicated the protective effects of VitD against cardiac aging. Male Wistar rats were randomly divided into four groups: control (CONT), D-galactose (D-GAL): aged rats induced by D-GAL, D-GAL + Ethanol: aged rats treated with ethanol, and D-GAL + VitD aged rats treated with VitD. Aging was induced by D-GAL at 150 mg/kg via intraperitoneal injection for 8 weeks. Aged rats were treated with VitD (D-GAL + VitD) by gavage for 8 weeks. The serum samples were used to evaluate biochemical factors, and heart tissues were assessed to determine oxidative stress and gene expression. The D-GAL rats exhibited cardiac hypertrophy, which was associated with decreased antioxidant enzyme activity, enhanced oxidative marker, and changes in the expression of mitochondrial genes in comparison with the control rats. Co-treatment with VitD ameliorated all these changes. In conclusion, VitD could protect the heart against D-GAL-induced aging via enhancing antioxidant effects, and the expression of mitochondrial genes.

Underlying mechanisms behind the neuroprotective effect of vanillic acid against diabetes-associated cognitive decline: An in vivo study in a rat model.

Hippocampal synaptic dysfunction, oxidative stress, neuroinflammation, and neuronal loss play critical roles in the pathophysiology of diabetes-associated cognitive decline (DACD). The study aimed to investigate the effects of vanillic acid (VA), a phenolic compound, against DACD and explore the potential underlying mechanisms. Following confirmation of diabetes, rats were treated with VA (50 mg/kg/day; P.O.) or insulin (6 IU/rat/day; S.C.) for 8 consecutive weeks. The cognitive performance of the rats was evaluated using passive-avoidance and water-maze tasks. Long-term potentiation (LTP) was induced at hippocampal dentate gyrus (DG) synapses in response to high-frequency stimulation (HFS) applied to the perforant pathway (PP) to evaluate synaptic plasticity. Oxidative stress factors, inflammatory markers, and histological changes were evaluated in the rat hippocampus. This study showed that streptozotocin (STZ)-induced diabetes caused cognitive decline that was associated with inhibition of LTP induction, suppression of enzymatic antioxidant activities, enhanced lipid peroxidation, elevated levels of inflammatory proteins, and neuronal loss. Interestingly, chronic treatment with VA alleviated blood glucose levels, improved cognitive decline, ameliorated LTP impairment, modulated oxidative-antioxidative status, inhibited inflammatory response, and prevented neuronal loss in diabetic rats at a level comparable to insulin therapy. The results suggest that the antihyperglycemic, antioxidative, anti-inflammatory, and neuroplastic properties of VA may be the mechanisms behind its neuroprotective effect against DACD.

Parkinson's disease tremor prediction using EEG data analysis-A preliminary and feasibility study.

PURPOSE: Tremor is one of the hallmarks of Parkinson's disease (PD) that does not respond effectively to conventional medications. In this regard, as a complementary solution, methods such as deep brain stimulation have been proposed. To apply the intervention with minimal side effects, it is necessary to predict tremor initiation. The purpose of the current study was to propose a novel methodology for predicting resting tremors using analysis of EEG time-series. METHODS: A modified algorithm for tremor onset detection from accelerometer data was proposed. Furthermore, a machine learning methodology for predicting PD hand tremors from EEG time-series was proposed. The most discriminative features extracted from EEG data based on statistical analyses and post-hoc tests were used to train the classifier for distinguishing pre-tremor conditions. RESULTS: Statistical analyses with post-hoc tests showed that features such as form factor and statistical features were the most discriminative features. Furthermore, limited numbers of EEG channels (F3, F7, P4, CP2, FC6, and C4) and EEG bands (Delta and Gamma) were sufficient for an accurate tremor prediction based on EEG data. Based on the selected feature set, a KNN classifier obtained the best pre-tremor prediction performance with an accuracy of 73.67%. CONCLUSION: This feasibility study was the first attempt to show the predicting ability of EEG time-series for PD hand tremor prediction. Considering the limitations of this study, future research with longer data, and different brain dynamics are needed for clinical applications.

Effect of vitamin D on cardiac hypertrophy in D-galactose-induced aging model through cardiac mitophagy.

BACKGROUND: Cardiac apoptosis plays a key role in increased morbidity associated with aging-induced-cardiac disorder. Mitochondria play an important role in cardiac apoptosis, and dynamin-related protein 1 (Drp1), as a main mediator of mitochondrial fission, can trigger the mitophagy process to sustain the mitochondrial quality. The present study was done to determine the effect of vitamin D (VitD) treatment on cardiac hypertrophy through mitophagy regulation in aged animals induced by D-galactose (D-GAL). METHODS AND RESULTS: Male Wistar rats were randomly divided into four groups: control, D-GAL (aging group), D-GAL co-injected with VitD (D-GAL ± VitD), and D-GAL plus ethanol (D-GAL ± Ethanol). Aging was induced by an intraperitoneal (i.p.) administration of D-GAL at 150 mg/kg daily for eight weeks and also VitD (400 IU/kg) or ethanol was injected (i.p.) into aging rats. Then, the levels of cardiac mitophagy and cardiac apoptosis were determined by measuring the expression of tensin homologue (PTEN)-induced putative kinase 1 (PINK1), Drp1, Bcl2-Associated X (Bax), and B-cell lymphoma 2 (Bcl2) genes. Aging in rats was associated with a reduction in mitophagy and also an increase in apoptosis of the heart through down-regulation of Drp1, PINK1, and Bcl2 genes and also up-regulation of Bax. However, VitD improved cardiac hypertrophy through cardiac mitophagy in D-GAL-induced aging rats. CONCLUSION: VitD can inhibit cardiac hypertrophy by an increase in mitophagy and a decrease in apoptosis in the aging heart. The illustration of the suggested mechanism underlying of Vitamin D in cardiac hypertrophy induced by aging.

Modulation of GPC-4 and GPLD1 serum levels by improving glycemic indices in type 2 diabetes: Resistance training and hawthorn extract intervention.

Aims: This study was designed to investigate the effects of resistance training (RT) and hawthorn extract (Ha) on Glypican-4 (GPC-4) and Insulin-regulated glycosylphosphatidylinositol-specific phospholipase D (GPLD1) serum levels in T2DM and to examine the relationship of these variables with glycemic indexes. Method: 40 male Wistar rats were divided into five equal groups: Healthy Control (H-C), Diabetes Control (D-C), Diabetes Resistance training (D-RT), Diabetes Hawthorn (D-Ha), and Diabetes Resistance training Hawthorn (D-RT-Ha). T2DM was induced with a 4-week high-fat diet (HFD) and one dose of STZ intraperitoneal injection (35 mg/kg). 1-week after the injection, RT (with a range of 50%-100%1RM/3 day/week) and gavage of Ha extract (100 mg/kg/day) was performed for 12 weeks. Results: The glycemic indices improvement (reducing blood glucose and increasing serum insulin level) caused by RT and/or Ha increased GPC-4 and decreased GPLD1 in the T2DM rats, but these positive changes were more effective in the combination of RT + Ha. A strong correlation was also observed between GPC-4 and GPLD1 with blood glucose and insulin. Conclusion: The increase in serum GPC-4 levels was probably due to the direct effect of RT + Ha, and the improvement of glycemic indexes after RT and Ha. The double effect of RT + Ha can be a regulatory mechanism for GPC-4 and its related factors in controlling T2DM complications.

Regulatory effects of trimetazidine in cardiac ischemia/reperfusion injury.

Ischemia/reperfusion (I/R) injury is a tissue damage during reperfusion after an ischemic condition. I/R injury is induced by pathological cases including stroke, myocardial infarction, circulatory arrest, sickle cell disease, acute kidney injury, trauma, and sleep apnea. It can lead to increased morbidity and mortality in the context of these processes. Mitochondrial dysfunction is one of the hallmarks of I/R insult, which is induced via reactive oxygen species (ROS) production, apoptosis, and autophagy. MicroRNAs (miRNAs, miRs) are non-coding RNAs that play a main regulatory role in gene expression. Recently, there are evidence, which miRNAs are the major modulators of cardiovascular diseases, especially myocardial I/R injury. Cardiovascular miRNAs, specifically miR-21, and probably miR-24 and miR-126 have protective effects on myocardial I/R injury. Trimetazidine (TMZ) is a new class of metabolic agents with an anti-ischemic activity. It has beneficial effects on chronic stable angina by suppressing mitochondrial permeability transition pore (mPTP) opening. The present review study addressed the different mechanistic effects of TMZ on cardiac I/R injury. Online databases including Scopus, PubMed, Web of Science, and Cochrane library were assessed for published studies between 1986 and 2021. TMZ, an antioxidant and metabolic agent, prevents the cardiac reperfusion injury by regulating AMP-activated protein kinase (AMPK), cystathionine-γ-lyase enzyme (CSE)/hydrogen sulfide (H2S), and miR-21. Therefore, TMZ protects the heart against I/R injury by inducing key regulators such as AMPK, CSE/H2S, and miR-21.

The role of hippocampal 5-HT1D and 5-HT1F receptors on learning and memory in rats.

Serotonin is a neurotransmitter, which is involved in memory via its receptors. The 5-HT1D and 5-HT1F receptors mainly exist in the hippocampus, which plays an important role in memory processing. However, few studies have assessed the effect of these serotonin receptors on memory. We evaluated the effect of a 5-HT1D receptor agonist, PNU142633, 5-HT1D receptor antagonist, BRL15572 hydrochloride, and 5-HT1F receptor agonist, LY344864, on the recognition and avoidance memory in the hippocampus area. Fifty adult male Wistar rats weighing 200-250 g were divided into the control, sham-operated, PNU, BRL, and LY groups (n=10 per group). Bilateral guide cannulas were implanted into the dentate gyrus area of the hippocampus. The drugs were administered at the dose of 1 µg/µl before the novel object recognition (NOR) and passive avoidance learning (PAL) tests. The results showed that in the NOR test, the administration of PNU and LY had no significant effect on recognition index; however, the recognition index was increased by BRL. In the PAL test, the administration of PNU had no significant effect on recognition index, but the administration of BRL and LY increased the time spent in the dark compartment of the apparatus and decreased the step-through latency into the dark compartment apparatus. It can be concluded that the inhibition of the hippocampal 5-HT1D receptor improved cognition memory but impaired avoidance memory. Activation of the hippocampal 5-HT1F receptor had no effect on cognitive memory but impaired avoidance memory.

Royal jelly improves learning and memory deficits in an amyloid ß-induced model of Alzheimer's disease in male rats: Involvement of oxidative stress.

Alzheimer's disease (AD) as the commonest type of dementia is associated with the cognitive function failure. Oxidative stress performs an essential role in the progression of AD. Royal jelly (RJ) is a natural product of bees with antioxidant and anti-inflammatory properties. The present research aimed to investigate the possible protective effect of RJ on learning and memory in a rat model of Aß-induced AD. Forty male adult Wistar rats were equally distributed into five groups: control, sham-operated, Aß (receiving intracerebroventricular (ICV) injection of amyloid beta (Aß1-40)), Aß + RJ 50 mg/kg, and Aß + RJ 100 mg/kg. RJ was administered daily post-surgery by oral gavage for four weeks. Behavioral learning and memory were examined using the novel object recognition (NOR) and passive avoidance learning (PAL) tests. Also, oxidative stress markers, such as malondialdehyde (MDA), total oxidant status (TOS) and total antioxidant capacity (TAC), were assessed in the hippocampus. Aß reduced step-through latency (STLr) and increased time spent in the dark compartment (TDC) in the PAL task and also decreased discrimination index in the NOR test. Administration of RJ ameliorated the Aß-related memory impairment in both NOR and PAL tasks. Aß decreased TAC and increased MDA and TOS levels in the hippocampus, whereas RJ administration reversed these Aß-induced alterations. Our results indicated that RJ has the potential to ameliorate learning and memory impairment in the Aß model of AD via attenuating oxidative stress.

Association of vitamin A and its organic compounds with stroke - a systematic review and meta-analysis.

PURPOSE: The main purpose of this systematic review was to evaluate the association between the stroke (risk of stroke and the mortality due to stroke) and vitamin A, its organic compounds and its provitamins. METHOD: Major databases including PubMed, Scopus, and Web of Science were searched. Studies with human samples were included for risk assessment. The association was assessed using odds ratio (log(OR)) and a random-effect model. I2 statistic, variance (tau2) and prediction interval were used for heterogeneity assessment. The funnel plot was used for publication bias. RESULTS: Twenty-one studies including 5789 stroke patients were retrieved. Twenty studies had sufficient information for quantitative analyses. The pooled effect showed an inverse association between vitamin A and its organic compound with the risk of stroke (log(OR) = -0.46 95%CI (-0.81;-0.12)) and with the risk of mortality due to stroke (log(OR) = -0.39 95%CI (-0.74;-0.04)). However, according to subgroup analyses, the association was dependent on the compound in a way that retinol and beta-carotene were the most effective compounds. The effects of several confounding factors and the threshold levels for vitamin A and its organic compound on the effectiveness were discussed. CONCLUSION: Insufficiency of retinol and beta-carotene significantly increased the risk of stroke; however, due to heterogeneity between studies more studies are needed for evaluating clinical significance of this outcome.

Bioflavonoid exerts analgesic and anti-inflammatory effects via transient receptor potential 1 channel in a rat model.

BACKGROUND: Pain is an uncomfortable sensation in the body. Kaempferol is a flavonoid with antinociceptive effects. Transient receptor potential (TRP) channels have been characterized in the sensory system. OBJECTIVE: This study evaluated the central antinociceptive effect of Kaempferol and possible mechanisms of action of transient receptor potential cation channel subfamily V member 1 (TRPV1). METHODS: Capsaicin as a TRPV agonist (5 µg/µL, intracerebroventricular [ICV]) and capsazepine as its antagonist (10 µg/µL, icv) were used to test the analgesic effect of kaempferol (1.5 mg, ICV). Morphine (10 µg, ICV) was used as a positive control. The other groups were treated with a combination of kaempferol and capsaicin, kaempferol and capsazepine, and capsaicin and capsazepine. The cannula was implanted in the cerebroventricular area. The tail-flick, acetic acid, and formalin tests were used to assess analgesic activity. For evaluation of antiinflammatory effect, the formalin-induced rat paw edema was used. RESULTS: Kaempferol significantly decreased pain in the acute pain models, including the tail-flick and the first phase of the formalin test. In the late phase of the formalin test, as a valid model of nociception, capsazepine inhibited the antinociceptive effect of kaempferol. CONCLUSIONS: Kaempferol has an analgesic effect in the acute pain model and can affect inflammatory pain. Also, the TRPV1 channel plays a role in the antinociceptive activity of kaempferol.

ANTECEDENTES: A dor é uma sensação desconfortável no corpo. Kaempferol é um flavonoide com efeitos antinociceptivos. Canais receptores de potencial transitório têm sido caracterizados no sistema sensorial. OBJETIVO: Este estudo avaliou o efeito antinociceptivo central do kaempferol e os possíveis mecanismos de ação do TRPV1. MéTODOS: Capsaicina como agonista de TRPV (5 µg/µL, intracerebroventricular [ICV]) e capsazepina como seu antagonista (10 µg/µL, icv) foram usados para testar o efeito analgésico do kaempferol (1,5 mg, ICV). A morfina (10 µg, ICV) foi usada como controle positivo. Os outros grupos foram tratados com uma combinação de kaempferol e capsaicina, kaempferol e capsazepina e capsaicina e capsazepina. A cânula foi implantada na área cerebroventricular. Os testes de movimento de cauda, ácido acético e formalina foram usados para avaliar a atividade analgésica. Para avaliação do efeito anti-inflamatório, foi utilizado o edema de pata de rato induzido por formalina. RESULTADOS: Kaempferol diminuiu significativamente a dor nos modelos de dor aguda, incluindo o movimento da cauda e a primeira fase do teste de formalina. Na fase tardia do teste da formalina, como modelo válido de nocicepção, a capsazepina inibiu o efeito antinociceptivo do kaempferol. CONCLUSõES: Kaempferol tem efeito analgésico no modelo de dor aguda e pode afetar a dor inflamatória. Além disso, o canal TRPV1 desempenha um papel na atividade antinociceptiva do kaempferol.

The effects of polyvinyl alcohol-coated selenium nanoparticles on memory impairment in rats.

Some mineral elements exert beneficial neuroprotection, especially in the form of nanoparticles. The aim of the present study was to evaluate the effects of selenium nanoparticles (SeNPs) and polyvinyl alcohol (PVA)-coated SeNPs (PVA-SeNPs) on Alzheimer's disease (AD) in a rat model of AD. Twenty-eight rats were randomly divided into four groups of seven rats: control, Alz, Alz + Se, and Alz + Se-PV groups. PVA-SeNPs and SeNPs were chemically synthesized and orally administrated (0.4 mg/kg) to the AD rats for one month. AD was induced by an intracerebroventricular (ICV) injection of streptozotocin (STZ). The memory function was assessed by the novel object recognition (NOR) and passive avoidance learning (PAL) tests. The expression of hippocampal brain-derived neurotrophic factor (BDNF) and stress oxidative markers (MDA and TAC), and the number of amyloid-beta (Aß) plaques were assessed using ELISA kits, biochemical methods, and Congo red staining, respectively. The results of the behavioral tests showed that the discrimination index in the NOR test increased in the Alz + PVA-SeNPs group compared to the Alz group. Memory performance in the PAL task improved in the PVA-SeNPs and SeNPs groups compared to the Alz group. The level of the BDNF in both of the Alz treatment groups (PVA-SeNPs and SeNPs) showed a significant increase compared to the Alz group. MDA levels and Aß plaques decreased in both NPs-treated Alz groups, while TAC levels decreased in all Alz groups. PVA-SeNPs were more effective than SeNPs in the improvement of the cognition deficit. The results suggest that PVA-SeNPs improve the cognition and memory deficit induced by an ICV injection of STZ through a decrease in the number of Aß plaques and malondialdehyde levels and an increase in the BDNF levels.

Bioflavonoid exerts analgesic and antiinflammatory effects via transient receptor potential 1 channel in a rat model / Bioflavonoide exerce efeitos analgésicos e antiinflamatórios via canal receptor do potencial transitório 1 em um modelo de rato

Abstract Background Pain is an uncomfortable sensation in the body. Kaempferol is a flavonoid with antinociceptive effects. Transient receptor potential (TRP) channels have been characterized in the sensory system. Objective This study evaluated the central antinociceptive effect of Kaempferol and possible mechanisms of action of transient receptor potential cation channel subfamily V member 1 (TRPV1). Methods Capsaicin as a TRPV agonist (5 μg/μL, intracerebroventricular [ICV]) and capsazepine as its antagonist (10 μg/μL, icv) were used to test the analgesic effect of kaempferol (1.5 mg, ICV). Morphine (10 μg, ICV) was used as a positive control. The other groups were treated with a combination of kaempferol and capsaicin, kaempferol and capsazepine, and capsaicin and capsazepine. The cannula was implanted in the cerebroventricular area. The tail-flick, acetic acid, and formalin tests were used to assess analgesic activity.For evaluation of antiinflammatory effect, the formalin-induced rat pawedema was used. Results Kaempferol significantly decreased pain in the acute pain models, including the tail-flick and the first phase of the formalin test. In the late phase of the formalin test, as a valid model of nociception, capsazepine inhibited the antinociceptive effect of kaempferol. Conclusions Kaempferol has an analgesic effect in the acute pain model and can affect inflammatory pain. Also, the TRPV1 channel plays a role in the antinociceptive activity of kaempferol.

Resumo Antecedentes A dor é uma sensação desconfortável no corpo. Kaempferol é um flavonoide com efeitos antinociceptivos. Canais receptores de potencial transitório têm sido caracterizados no sistema sensorial. Objetivo Este estudo avaliou o efeito antinociceptivo central do kaempferol e os possíveis mecanismos de ação do TRPV1. Métodos Capsaicina como agonista de TRPV (5 μg/μL, intracerebroventricular [ICV]) e capsazepina como seu antagonista (10 μg/μL, icv) foram usados para testar o efeito analgésico do kaempferol (1,5 mg, ICV). A morfina (10 μg, ICV) foi usada como controle positivo. Os outros grupos foram tratados com uma combinação de kaempferol e capsaicina, kaempferol e capsazepina e capsaicina e capsazepina. A cânula foi implantada na área cerebroventricular. Os testes de movimento de cauda, ácido acético e formalina foram usados para avaliar a atividade analgésica. Para avaliação do efeito anti-inflamatório, foi utilizado o edema de pata de rato induzido por formalina. Resultados Kaempferol diminuiu significativamente a dor nos modelos de dor aguda, incluindo o movimento da cauda e a primeira fase do teste de formalina. Na fase tardia do teste da formalina, como modelo válido de nocicepção, a capsazepina inibiu o efeito antinociceptivo do kaempferol. Conclusões Kaempferol tem efeito analgésico no modelo de dor aguda e pode afetar a dor inflamatória. Além disso, o canal TRPV1 desempenha um papel na atividade antinociceptiva do kaempferol.

The comparison of omega-3 and flaxseed oil on serum lipids and lipoproteins in hyperlipidemic male rats.

Hyperlipidemia affects a significant number of patients despite treatment with cholesterol-lowering drugs. Due to the low efficacy of synthetic drugs, there is a need for new agents with low side effects. Therefore, the effects of flaxseeds oil and animal omega-3 on the hyperlipidemic rats were investigated. Forty male Wistar rats were assigned to four groups (n = 10): 1) control group that was fed with a standard diet (pallets). 2) high-fat diet (HFD) control group that was fed with high-fat food for 42 days, 3) Omega-3 group that received HFD for 21 days, followed by HFD + omega-3 capsule (600 mg/kg; 21 days/gavage), and 4) flaxseed oil group that received HFD for 21 days, followed by HFD + flaxseed oil (10 ml/kg; 21 days/gavage). Blood samples were collected three times and at the stages one to third of the experiment from the rats' tail. The results showed that high levels of fat significantly increased cholesterol, triglyceride (TG), and low-density lipoprotein (LDL) in the flaxseed, HFD control, and omega-3 groups in the second stages of the experiment. Inverse, omega-3 or flaxseed oil supplementation decreased cholesterol, TG, and LDL levels and increased high-density lipoprotein (HDL) level in comparison with the HFD control group in the third stages of the experiment. There was no significant difference in the studied parameters between the flaxseed- and omega-3-treated groups. It can be concluded that flaxseed oil similar to omega-3 is effective in the treatment of hyperlipidemia.

Combined Effect of Co-administration of Stromal Cell-Derived Factor-1 and Granulocyte-Colony Stimulating Factor on Rat Model of Alzheimer's Disease.

Introduction: Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by amyloid plaque deposits, neuronal cell loss, and memory impairment. Granulocyte-colony stimulating factor (G-CSF) is a growth factor associated with AD improvement. Stromal cell-derived factor-1 (SDF-1) mediates therapeutic effects of G-CSF. This study investigated the effect of combination treatment of G-CSF and SDF-1 on amyloid plaque deposits, apoptosis, and behavior of AD rats. Methods: Intracerebroventricular amyloid-beta [Aß(1-42)] peptide was used to induce AD in Aß rats. There were six groups including naive control, sham-operated, Aß, Aß + G-CSF, Aß + SDF-1, and Aß + G-CSF + SDF-1. SDF-1 intra-cerebroventricular (ICV), G-CSF Subcutaneous (SC), or a combination of them were administered to Aß rats weekly for 2 months. The cognition and memory were assessed using the novel object recognition, passive avoidance, and Morris water maze tests. Next, rat brains were removed and the amyloid plaque and apoptosis were detected in the brain and hippocampus using immunohistochemistry and TUNEL assay, respectively. Results: The amyloid-beta and apoptotic cell levels dropped in groups receiving SDF-1 and G-CSF combination compared to the Aß group. Also, number of microglial cells increased significantly in the combination group compared to other treatment groups. Moreover, learning and memory were significantly improved in the combination group compared to the Aß groups (P < 0.05). Conclusion: SDF-1 and G-CSF combination therapy can offer a promising strategy for AD.

Electrophysiological study of the interactive role of the cannabinoid breakdown inhibitors and L-type calcium channels on granular neurons in the hippocampal dentate gyrus in rats.

The interaction between L-type voltage-dependent Ca2+ channels and the endocannabinoid system (eCs) in synaptic plasticity is controversial. In the present research, the impact of acute administration of URB597, as an endocannabinoid breakdown inhibitor, was evaluated after chronic injection of verapamil, as a Ca2+ channels blocker, on inducing long-term potentiation (LTP) in the rat's hippocampal dentate gyrus (DG). Treatment of male Wistar rats was done using intraperitoneal(i.p) injection of verapamil hydrochloride (n = 8) and saline (n = 10), as the solvent of verapamil once a day within 13 days. Anesthetization was done by i.p injection of urethane and the rats were located in the stereotaxic apparatus for surgery, electrode implantation, and field potential recording. After observing a steady-state baseline response, saline or URB597 were injected (n = 9). Measurement of the population spike (PS) amplitude and slope of field excitatory postsynaptic potentials (fEPSPs) in the DG region was performed as a result of perforant pathway (PP) stimulation. Our treatments could inhibit LTP. Our results indicated that the chronic administration of verapamil produced a significant decrease in the slope of fEPSP and PS amplitude. Also, acute URB597 administration decreased the slope of fEPSP and PS amplitude compared to the saline group. Moreover, URB597 administration in combination with chronic administration of verapamil produced a greater decrease in fEPSP slope and PS amplitude than the saline group. These findings indicated that verapamil and URB597 disrupted LTP induction in the DG. Moreover, an interaction was observed between Ca2+ channels and eCs. Therefore, the eCs possibly play a selective role in synaptic plasticity.

The interactive effects of verapamil and CB1 cannabinoid receptor antagonist/inverse agonist, AM251 on passive avoidance learning and memory in rat.

There are reports regarding the effects of intracellular Ca2+ and synthesis and release of endocannabinoids. The secretion of endocannabinoids depends on the L-type calcium channel. The present study evaluated the involvement of the cannabinoid CB1 receptors in the effect of L-type calcium channel blocker verapamil on passive avoidance learning (PAL) in adult male rats. In this study, we examined the effects of an acute administration of the cannabinoid CB1 receptors antagonist/inverse agonist AM251 following a chronic administration of the Ca2+ channel blocker verapamil on PAL. Male Wistar rats were administered verapamil (10, 25 and 50 mg/kg) or saline intraperitoneally (i.p) daily for 13 days (n = 10/group). After this treatment period, a learning test (acquisition) was performed, and a retrieval test was performed the following day. The results indicated that chronic systemic administration of verapamil (in a dose-dependent manner) impaired memory acquisition and retrieval. Pre-training acute administration of a selective CB1 antagonist/inverse agonist, AM251 (5 mg/kg, i.p.) did not change memory acquisition and retrieval. Co-administration of the verapamil and AM251 significantly reversed verapamil-induced amnesia, suggesting a functional interaction between AM251 and verapamil. The results indicated the interactive effects of cannabinoid CB1 receptors and L-type calcium channel in passive avoidance learning and AM251 can counter the effects of verapamil on memory.

Sex differences in spatial learning and memory and hippocampal long-term potentiation at perforant pathway-dentate gyrus (PP-DG) synapses in Wistar rats.

BACKGROUND: Recent studies show that gender may have a significant impact on brain functions. However, the reports of sex effects on spatial ability and synaptic plasticity in rodents are divergent and controversial. Here spatial learning and memory was measured in male and female rats by using Morris water maze (MWM) task. Moreover, to assess sex difference in hippocampal synaptic plasticity we examined hippocampal long-term potentiation (LTP) at perforant pathway-dentate gyrus (PP-DG) synapses. RESULTS: In MWM task, male rats outperformed female rats, as they had significantly shorter swim distance and escape latency to find the hidden platform during training days. During spatial reference memory test, female rats spent less time and traveled less distance in the target zone. Male rats also had larger LTP at PP-DG synapses, which was evident in the high magnitude of population spike (PS) potentiation and the field excitatory post synaptic potentials (fEPSP) slope. CONCLUSIONS: Taken together, our results suggest that sex differences in the LTP at PP-DG synapses, possibly contribute to the observed sex difference in spatial learning and memory.

Deferoxamine preconditioning enhances the protective effects of stem cells in streptozotocin-induced Alzheimer's disease.

AIMS: Stem cell-based therapy is one of the promising strategies in the treatment of Alzheimer's disease (AD), but the short lifespan and low homing of transplanted cells continue to be a major obstacle in this method. Preconditioning of stem cells before transplantation could increase cell therapy efficiency. Herein, we examined whether the treatment of stem cells with deferoxamine (DEF) prior to graft could enhance the neuroprotective effects of stem cells in the streptozotocin (STZ)-treated male rats. MATERIALS AND METHODS: After induction of the AD model, the rats were transplanted with DEF-preconditioned Adipose-derived mesenchymal stem cells (AMSCs) or untreated cells. Memory function, antioxidant capacity, cell density, and homing of transplanted cells were assessed using Morris water maze and shuttle box tasks as well as biochemical and histochemical methods. KEY FINDINGS: Transplantation of AMSCs caused a memory improvement when compared to the AD model. The injection of DEF-preconditioned AMSCs was more effective in improving learning and memory than the untreated cells through an increase in the antioxidant capacity. Moreover, the homing of transplanted cells was higher in the rats that received the preconditioned cells than that of the naïve cell-injected group. SIGNIFICANCE: It seems that the transplantation of DEF-treated cells may increase the efficiency of stem cells via an increase in the antioxidant capacity.

Chronic stimulation of the serotonergic 5-HT4 receptor modulates amyloid-beta-related impairments in synaptic plasticity and memory deficits in male rats.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory decline and impaired hippocampal synaptic plasticity. The serotonin 5-HT4 receptor is involved in learning and memory processes. This study explored the effects of chronic stimulation of 5-HT4R on cognition, memory, long-term potentiation (LTP), paired-pulse ratio (PPR), and neuronal apoptosis in a rat model of amyloid-beta (Aß)-induced AD. Thirty-five male Wistar rats were randomly divided into three groups as follows: the sham, Aß, and Aß + BIMU8 groups. Aß (6 µg/µl) was administrated by intracerebroventricular (icv) injection. The animals were treated with BIMU8 (1 µg/µL, ICV) as a 5-HT4R agonist for 30 days. Memory and behavioral changes were assessed by the passive avoidance learning, novel object recognition, open field, and elevated plus maze tests. Hippocampal synaptic plasticity was evaluated in the dentate gyrus (DG) in response to the stimulation applied to the perforant pathway. Furthermore, neuronal apoptosis was measured in the hippocampus. Data were analyzed by SPSS version 19 using one-way ANOVA, followed by Tukey's post hoc test. Aß induced memory deficits and neuronal loss and inhibited LTP induction. Aß also increased the normalized PPR. BIMU8 enhanced the slope of the field excitatory postsynaptic potential in LTP and improved cognition behavior. Paired-pulse inhibition or facilitation was not affected by LTP induction in Aß animals receiving the BIMU8. It can be concluded that the stimulation of the 5-HT4 receptor modulated the Aß-induced cognition and memory deficits, probably via a decrease in the hippocampal apoptotic neurons and an improvement in the hippocampal synaptic functions without involving its inhibitory interneurons.