Sericin improves memory and sociability impairments evoked by transient global cerebral ischemia through suppression of hippocampal oxidative stress, inflammation, and apoptosis.

Sericin (Ser) is a natural neuroactive macromolecule with diverse pharmacological properties, and our previous findings have shown its neuroprotective potentials. This study aimed to investigate the therapeutic potential of Ser on cognitive dysfunction induced by transient global cerebral ischemia/reperfusion (tGI/R) and its mechanism of action. The tGI/R was induced in BALB/c mice by bilateral occlusion of the common carotid arteries for two 5 min followed by a 10-min reperfusion period. After 24 h, mice were treated with normal saline or different doses of Ser (100, 200, and 300 mg/kg) for 10 days. Cognitive performances were assessed using the Barnes maze and social interaction tasks. Oxidative stress markers including superoxide dismutase (SOD), glutathione peroxidase (GPx), total antioxidant capacity (TAC), and malondialdehyde (MDA) as well as pro-inflammatory cytokines (interleukin (IL)-6 and tumor necrosis factor-alpha) and anti-inflammatory cytokine (IL-10) were assessed in the hippocampus. Markers of apoptosis (pro- and cleaved caspase-9 and 3, Bax, and Bcl-2) were assessed by Western blotting. Besides, transferase-mediated dUTP nick end-labeling assay was used to detect apoptotic cell death. We show here that Ser administration improved tGI/R-induced cognitive deficits, enhanced the activity of SOD and GPx, increased TAC levels, while reduced MDA levels. Notably, Ser decreased neuronal apoptotic cell death in the hippocampal dentate gyrus (DG) region, accompanied by suppression of neuroinflammation, downregulation of pro-apoptotic proteins (caspase-9, caspases-3, and Bax), and upregulation of anti-apoptotic protein, Bcl-2. Taken together, Ser administration protected hippocampal neurons from apoptotic cell death by impeding oxidative stress and inflammatory responses and, in turn, improved cognitive function in the tGI/R mice.

Central injection of neuropeptide Y modulates sexual behavior in male rats: interaction with GnRH and kisspeptin/neurokinin B/dynorphin.

AIMS: A number of studies have shown that neuropeptide Y (NPY) is considered to be one of the key regulators of hypothalamic-pituitary-gonadal (HPG) axis in the mammals. In addition, kisspeptin (encode by Kiss1 gene), neurokinin B (encode by Tac3 gene) and dynorphin (encode by Pdyn gene) (commonly known as KNDy secreting neurons) are a powerful upstream regulators of GnRH neuron in hypothalamus. MATERIALS AND METHODS: The present study aims to investigate the effects of the intracerebroventricular (icv) injection of NPY and BIBP3226 (NPY receptor antagonist (NPYRA)) on the male sexual behavioral. Additionally, in order to see whether NPY signals can be relayed through the pathway of kisspeptin/neurokinin B/dynorphin, the gene expression of these peptides along with Gnrh1 gene in the hypothalamus were measured. RESULTS: The icv injection of NPY decreased the latencies and increase the frequencies of sexual parameters of the male rats in a significant way. In this line, NPYRA antagonized the stimulative effects of NPY. Moreover, data from real-time quantitative PCR indicated that injection of NPY significantly increased the gene expression of Gnrh1, Kiss1 and Tac3 and decrease the Pdyn while treatment with NPYRA controlled the modulative effects of NPY on these gene expression. CONCLUSIONS: In conclusion based on the results of this study, NPY can exert its impacts on the sexual behavior of male rats via modulation of the KNDy secreting neurons as an interneural pathway to GnRH neurons.

Probiotics and Nigella sativa extract supplementation improved behavioral and electrophysiological effects of PTZ-induced chemical kindling in rats.

INTRODUCTION: Epilepsy is a most common neurological disorder that has negative effects on cognition. In the present study, we investigated the protective effect of Nigella sativa (NS) and probiotics on seizure activity, cognitive performance, and synaptic plasticity in pentylenetetrazole (PTZ) kindling model of epilepsy. METHODS: One hundred and forty-four rats were divided into 2 experiments: In experiment 1, animals were grouped and treated as follows: 1) control (PTZ + saline), 2) NS treatment, 3) probiotic treatment, and 4) NS and probiotic treatment. Six weeks after the treatment, PTZ kindling were performed, and 48 h after kindling, spatial learning and memory were measured in Morris water maze (MWM) test. Animals in experiment 2 received the same treatment as experiment 1: in control nonkindled groups, control animals were treated with probiotics, NS, and probiotics + NS. Six weeks after the treatment, PTZ kindling were performed, and 48 h after kindling, field potentials were recorded from the dentate gyrus area of the hippocampus; synaptic transmission and long-term potentiation (LTP) was measured. RESULTS: The results showed that the probiotic and NS supplementation significantly reduces kindling development so that animals in PTZ + NS + probiotic did not show full kindling. In MWM test, the escape latency and traveled path in the kindled group were significantly higher than the control group. In PTZ + NS + probiotics, these parameters were significantly lower than those in the PTZ + saline group. Adding probiotic and NS supplementation significantly reduced population spike (PS)-LTP as compared with the PTZ + saline group. CONCLUSION: Probiotic and NS supplementation have some protection against seizure, seizure-induced cognitive impairment, and hippocampal LTP in kindled rats.

Intranasal insulin treatment restores cognitive deficits and insulin signaling impairment induced by repeated methamphetamine exposure.

Long-term use of methamphetamine (MA) causes a broad range of cognitive deficits. Recently, it has been reported insulin signaling and mitochondrial biogenesis are involved in cognitive processes. This study aimed to examine whether MA induces cognitive deficits concomitant with insulin signaling impairment and mitochondrial dysfunctions and also intranasal (IN) insulin treatment can reverse cognitive deficits caused by MA. Rats were repeatedly treated with increasing doses of MA (1-10 mg/kg) twice a day for 10 days, and their cognitive functions were assessed using Y-maze, novel object recognition and passive avoidance tasks. The expression of components involved in insulin signaling (IR/IRS2/PI3K/Akt/GSK3ß) and mitochondrial biogenesis (PGC-1α, NRF1, and TFAM) was measured in the hippocampus. Therapeutic effects of IN insulin delivery (0.5- IU/day, for 7 days after MA discontinuation) were also investigated in MA-treated animals. Our results showed that repeated MA exposure induced cognitive deficits, and led to insulin signaling impairment and mitochondrial dysfunction. Interestingly, IN insulin treatment reduced MA-induced cognitive impairments possibly through activating insulin signaling, particularly PI3K/Akt/GSK3ß pathway, and mitochondrial biogenesis. Thus, insulin and insulin signaling pathway can be considered as useful targets for the treatment of abnormalities associated with MA abuse.

Blockade of prelimbic glutamate receptor reduces the reinforcing effect of morphine.

The prelimbic cortex (PrL) as a part of the medial prefrontal cortex (mPFC) plays a crucial role in drug addiction. Previous studies have shown that glutamatergic transmission through the NMDA and AMPA receptors plays an important role in morphine rewarding properties. In this study, we evaluated the effect of glutamate receptors blockade within the PrL on morphine self-administration. Male Wistar rats were randomly selected and divided into 7 groups. Trained rats were placed in self-administration apparatus, where they pressed an active lever for receiving morphine (5 mg/mL) in test groups and saline in saline group during 11 consecutive days for 2 h per session. The effects of intra-prelimbic AMPA receptor antagonist (CNQX; 0.5 and 2.5 µg/0.5 µL) and the NMDA antagonist (AP5; 0.1 and 1 µg/0.5 µL) on self-administration were tested. Our results demonstrated that intra-prelimbic injection of different doses of CNQX and AP5, and co-administration of these 2 drugs before self-administration significantly decreased active lever pressing compared with morphine group (p < 0.001). Also, the number of self-infusion significantly decreased in test groups compared with morphine group (p < 0.001). These findings suggest that a reduction in PrL glutamatergic output can modulate morphine reinforcement.

Effects of cannabinoid and vanilloid receptor agonists and their interaction on learning and memory in rats.

Despite previous findings on the effects of cannabinoid and vanilloid systems on learning and memory, the effects of the combined stimulation of these 2 systems on learning and memory have not been studied. Therefore, in this study, we tested the interactive effects of cannabinoid and vanilloid systems on learning and memory in rats by using passive avoidance learning (PAL) tests. Forty male Wistar rats were divided into the following 4 groups: (1) control (DMSO+saline), (2) WIN55,212-2, (3) capsaicin, and (4) WIN55,212-2 + capsaicin. On test day, capsaicin, a vanilloid receptor type 1 (TRPV1) agonist, or WIN55,212-2, a cannabinoid receptor (CB1/CB2) agonist, or both substances were injected intraperitoneally. Compared to the control group, the group treated with capsaicin (TRPV1 agonist) had better scores in the PAL acquisition and retention test, whereas treatment with WIN55,212-2 (CB1/CB2 agonist) decreased the test scores. Capsaicin partly reduced the effects of WIN55,212-2 on PAL and memory. We conclude that the acute administration of a TRPV1 agonist improves the rats' cognitive performance in PAL tasks and that a vanilloid-related mechanism may underlie the agonistic effect of WIN55,212-2 on learning and memory.

Alpha-Tocopherol Reduces Brain Edema and Protects Blood-Brain Barrier Integrity following Focal Cerebral Ischemia in Rats.

OBJECTIVE: This study was conducted to examine the neuroprotective effects of α-tocopherol against edema formation and disruption of the blood-brain barrier (BBB) following transient focal cerebral ischemia in rats. MATERIALS AND METHODS: Ninety-six male Sprague-Dawley rats were divided into 3 major groups (n = 32 in each), namely the sham, and control and α-tocopherol-treated (30 mg/kg) ischemic groups. Transient focal cerebral ischemia (90 min) was induced by occlusion of the left middle cerebral artery. At the end of the 24-hour reperfusion period, the animals were randomly selected and used for 4 investigations (n = 8) in each of the 3 main groups: (a) assessment of neurological score and measurement of infarct size, (b) detection of brain edema formation by the wet/dry method, (c) evaluation of BBB permeability using the Evans blue (EB) extravasation technique, and (d) assessment of the malondialdehyde (MDA) and reduced glutathione (GSH) concentrations using high-performance liquid chromatography methods. RESULTS: Induction of cerebral ischemia in the control group produced extensive brain edema (brain water content 83.8 ± 0.11%) and EB leakage into brain parenchyma (14.58 ± 1.29 µg/g) in conjunction with reduced GSH and elevated MDA levels (5.86 ± 0.31 mmol/mg and 63.57 ± 5.42 nmol/mg, respectively). Treatment with α-tocopherol significantly lowered brain edema formation and reduced EB leakage compared with the control group (p < 0.001, 80.1 ± 0.32% and 6.66 ± 0.87 µg/g, respectively). Meanwhile, treatment with α-tocopherol retained tissue GSH levels and led to a lower MDA level (p < 0.01, 10.17 ± 0.83 mmol/mg, and p < 0.001, 26.84 ± 4.79 nmol/mg, respectively). CONCLUSION: Treatment with α-tocopherol reduced ischemic edema formation and produced protective effects on BBB function following ischemic stroke occurrence. This effect could be through increasing antioxidant activity.

Complexity of Compensatory Effects in Nrf1 Knockdown: Linking Undeveloped Anxiety-Like Behavior to Prevented Mitochondrial Dysfunction and Oxidative Stress.

Anxiety-related disorders are complex illnesses that underlying molecular mechanisms need to be understood. Mitochondria stand as an important link between energy metabolism, oxidative stress, and anxiety. The nuclear factor, erythroid-derived 2,-like 1(Nrf1) is a member of the cap "n" collar subfamily of basic region leucine zipper transcription factors and plays the major role in regulating the adaptive response to oxidants and electrophiles within the cell. Here, we injected small interfering RNA (siRNA) targeting Nrf1 in dorsal third ventricle of adult male albino Wistar rats and subsequently examined the effect of this silencing on anxiety-related behavior. We also evaluated apoptotic markers and mitochondrial biogenesis factors, along with electron transport chain activity in three brain regions: hippocampus, amygdala, and prefrontal cortex. Our data revealed that in the group that received Nrf1-siRNA, anxiety-related behavior did not show any significant changes compared to the control group. Caspase-3 did not increase in Nrf1-siRNA-injected rats even though Bax/Bcl2 ratio markedly elevated in Nrf1-knockdown rats in all three mentioned regions compared to control rats. Also, Nrf1 silencing of complex I and II-III did not alter, generally. In addition, Nrf1-knockdown affected mitochondrial biogenesis markers. The level of peroxisome proliferator-activated receptor gamma coactivator-1α and cytochrome-c increased, which indicates a possible role for mitochondrial biogenesis in anxiety.

Effect of nucleus accumbens shell 5-HT4 receptors on the impairment of ACPA-induced emotional memory consolidation in male Wistar rats.

The present study investigates the effects of 5-HT4 receptors of the nucleus accumbens (NAc) shell on the impairment of emotional memory consolidation induced by cannabinoid CB1 receptor stimulation. The elevated plus maze test-retest paradigm was used to assess memory in adult male Wistar rats. Intra-NAc shell administration of ACPA (selective cannabinoid CB1 receptor agonist 0.006 µg/rat) and RS23597 (5-HT4 receptor antagonist 0.01 µg/rat), immediately after training, decreased emotional memory consolidation, suggesting a drug-induced amnesia, whereas post-training intra-NAc shell microinjections of RS67333 (5-HT4 receptor agonist 0.016 µg/rat) increased emotional memory consolidation. Interestingly, RS67333 exerted a dual effect on ACPA-induced behaviors, potentiating and restoring amnesia caused by the subthreshold and effective doses of ACPA, respectively. However, neither RS23597 nor AM251 (CB1 receptor antagonist 30, 60 and 120 ng/rat) affected emotional memory consolidation. Nonetheless, a subthreshold dose of AM251 (120 ng/rat) reversed the amnesia induced by ACPA (0.006 µg/rat) and RS23597 (0.01 µg/rat). None of the above doses altered the locomotor activity. In conclusion, our results suggest that the NAc-shell 5-HT4 receptors are involved in the modulation of ACPA-induced amnesia.

Antinociceptive and anti-inflammatory effects of the aerial parts of Artemisia dracunculus in mice.

CONTEXT: Tarragon (Artemisia dracunculus L., Asteraceae) is an ancient herb, which is widely used as a medicine, flavoring, or fragrance. OBJECTIVE: To determine the antinociceptive and anti-inflammatory effects of aerial parts of tarragon, we investigated the effects of ethanolic extract of the plant in adult male Balb/c mice. MATERIALS AND METHODS: Antinociceptive activity was determined using formalin, hot-plate, and writhing tests. The effect of the ethanolic extract on acute inflammation was evaluated by xylene-induced ear edema in mice. The ethanolic extract was administered at doses of 5, 10, 50, and 100 mg/kg, i.p. The control group received saline as vehicle of ethanolic extract. RESULTS: Our results showed that the ethanolic extract (50 and 100 mg/kg) decreased both phases of pain in the formalin test (ED50 = 109.66 and 87.13 mg/kg, respectively). In the hot-plate test, the extract (50 and 100 mg/kg) increased pain threshold during 60 min (ED50 = 81.03 mg/kg). The extract (50 and 100 mg/kg) exhibited antinociceptive activity against acetic acid-induced writhing (ED50 = 66.99 mg/kg). The extract (50 and 100 mg/kg) showed significant activity in the xylene ear edema test (ED50 = 78.20 mg/kg). Pretreatment of the animals with naloxone decreased the analgesia induced by the extract in hot-plate and formalin tests; therefore, opioid receptors may be involved, at least partly, in the analgesic effect of tarragon extract. DISCUSSION AND CONCLUSION: The results suggested that tarragon have significant analgesic and anti-inflammatory effects in mice, and, therefore, further studies are required to evaluate these effects and additional potential of the plant.

Nanoselenium attenuates renal ischemia-reperfusion injury in rats.

Using selenium (Se) nanoparticles has received attention in recent years because of their therapeutic benefits due to their anticancer, antioxidant, anti-inflammatory, and anti-diabetic effects. This research was conducted to evaluate the possible protective impact of nano-Se on renal unilateral ischemia/reperfusion injury (uIRI) in adult male Wistar rats. Using clamping of the left renal pedicle within 45 min uIRI was induced. The animals were randomly divided into nine groups of control, nano-Se (0.25, 0.5, and 1 mg/kg bw/day) alone, uIRI control, and uIRI rats administrated with nano-Se. At 30 days after treatment, the animals were sacrificed to be assessed biochemically and histopathologically. Nano-Se in uIRI groups have significantly decreased serum creatinine, urea levels, renal histological damage, and increased antioxidant status. Also, our findings demonstrated that the administration of nano-Se caused a significant decrease in the immunoreactivity level of the epidermal growth factor (EGF) and EGFR expression (EGF receptor) in the renal tissue of the uIRI rats. Therefore, nano-Se possesses renoprotective effects, and this effect might be attributable to its antioxidant and free radical scavenger effects. These renoprotective effects may depend on the decreased EGF immunoreactivity level and EGFR expression in the kidney tissue and improve the structure of the kidney tissue. Thus, our research provided biochemical and histological data supporting the potential clinical use of nano-Se for the treatment of certain kidney disorders.

The therapeutic potential of Melissa officinalis L. hydroalcoholic extract and rosmarinic acid in a rat asthmatic model: A study on anti-inflammatory and antioxidant effects.

Objective: The article studies how Melissa officinalis L. extract and rosmarinic acid (RA) affect lung inflammation, pathology, and oxidative stress in rats with ovalbumin-induced asthma. Materials and Methods: Asthma was induced in rats using ovalbumin injection and inhalation. The study assessed lung inflammation, pathological changes, and oxidative stress in control, untreated asthmatic rats and three treatment groups. These groups received M. officinalis extract (50, 100, 200 mg/kg), RA (0.5, 1, 2 mg/kg), or dexamethasone (Dex) 1 mg/kg. Results: In the sensitized group, white blood cell counts, malondialdehyde, and nitrite levels increased significantly, while thiol levels and the activity of superoxide dismutase and catalase decreased (p<0.001). However, all treatment groups with the extract, RA, and Dex showed a significant reduction in total white blood cells, eosinophils, monocytes, malondialdehyde, and nitrite levels compared to the asthma group (p<0.001 in all groups). Thiol levels and catalase and superoxide dismutase activity were significantly higher in all treated groups with RA and high extract doses (p<0.001). Lung pathological changes were also significantly less severe in the treated groups with dexamethasone, plant extract, and RA compared to the asthma group (p<0.05 to p<0.001). Conclusion: This study showed that M. officinalis and RA have antioxidant and anti-inflammatory effects in an animal asthma model, suggesting their potential for treating asthma symptoms.

Effect of low frequency electrical stimulation on spike and wave discharges of perioral somatosensory cortex in WAG/Rij rats.

Low frequency electrical stimulation has been revealed that as a potential cure in patient with drug resistant to epilepsy. This study tries to evaluate the effect of low frequency electrical stimulation (LFS) on absence seizure of perioral region primary somatosensory cortex (S1po). Eighteen male WAG/Rij rats were received LFS (3Hz, square wave, monophasic, 200µs, and 400µA) for 25min into S1po for a period of five days. There is 6 animals per group .The stimulating electrodes were implanted according to stereotaxic landmarks and EEG recording was obtained 30min before and after LFS to analyse frequency, number and duration of spike-wave discharges (SWD). The results showed that in animals with unilateral stimulating electrodes (Exp1) in first and second days and also in animals with bilateral stimulating electrodes (Exp2) in days 3rd and 4th. LFS had significant decrease effects (p<0.05) on mean number of SWD between pre-LFS. In comparison pre-LFS to post-LFS, mean of duration in Exp2 decreased significantly. In continuous application of LFS (5 days) only the data of first day was differently significant (p<0.05) but data of other days had no difference. Comparison of data between Exp1, Exp2 and control groups showed that the mean number of Exp1 was significantly different (p<0.05) and mean pick frequency in Exp2 was significantly decreased in comparison with Exp1 group (p<0.05). The LFS of S1po produces significant antiepileptic effect on absence seizure but it was not persistent till the next day and shows a short time effect.

Blockade of the orexin receptors in the ventral tegmental area could attenuate the stress-induced analgesia: A behavioral and molecular study.

Exposure to stressful stimuli induces various physiological and behavioral responses, affects pain perception, and alters gene expression. Stress elicits an analgesic effect in laboratory animals, termed the "stress-induced analgesia" (SIA). Orexin neuropeptides, processed from pre-pro-orexin in the hypothalamus, release during stress and are known to be antinociceptive. The current study examined the modulatory role of the ventral tegmental area (VTA) orexinergic system in the restraint SIA and extracellular signal-regulated kinase (ERK) activation in the nucleus accumbens (NAc). Adult male Wistar rats were subjected to intra-VTA injection of orexin-1 and -2 receptor antagonists (SB334867 and TCS OX2 29; 1, 3, 10, and 30 nmol/0.3 µl, respectively) five min before a 3-h period of exposure to restraint stress (RS). Western blot analysis was also used to assess the levels of ERK and phosphorylated ERK (p-ERK) in the NAc tissues. RS exposure produced an analgesic response to the thermal pain model (Tail-flick test). RS-induced antinociception was inhibited by intra-VTA administration of SB334867 and TCS OX2 29. Moreover, in the molecular study, exposure to forced swim stress (FSS) and RS significantly enhanced the p-ERK/ERK ratio. Blockade of both orexin receptors diminished the p-ERK/ERK ratio, but this decrease was significant only in the FSS group of animals that received TCS OX2 29. Collectively, the present findings suggested the functional roles of intra-VTA orexin receptors and ERK signaling in the SIA.

Comparing the synaptic potentiation in schaffer collateral-CA1 synapses in dorsal and intermediate regions of the hippocampus in normal and kindled rats.

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.

Downregulation of Bax/Bcl-2 Expression During Apoptosis in the Hippocampus of Diabetic Male Wistar Rats: Ameliorative Effects of Peganum harmala Seed Extract.

Background: Apoptosis is proposed as a possible mechanism for diabetes-induced hippocampal neuronal cell death. Numerous studies have suggested that the therapeutic properties of plants, such as antioxidant and anti-apoptotic, are effective in improving the complications of diabetes in the hippocampus. Objectives: This study aimed to evaluate the anti-apoptotic properties of Peganum harmala (P. harmala) in the brain hippocampal cells of diabetic rats. Methods: In this experimental study, 48 male Wistar rats were divided into six groups (n = 8) as follows: Control (C), diabetic (D), harmine (H), diabetic plus harmine (DH), seed extract (S), and diabetic plus seed extract (DS). A single dose of streptozotocin (STZ) (60 mg/kg) was enough to cause diabetes. Seed extract and harmine were given at 150 mg/kg and 6.5 mg/kg, respectively (daily by oral gavage for 28 days). The glucose levels in the blood were measured, and the histological staining of the hippocampus was examined. Percentages of apoptotic hippocampal cells were identified with flow cytometry. Bax and Bcl-2 expression was assayed via Real time- polymerase chain reaction (PCR) and Western blot. Results: In DH (P = 0.001) and DS (P = 0.01) rats, the mean fasting blood glucose level significantly reduced compared with the D group. Bax and Bcl-2 expression at both mRNA and protein levels significantly differed between the D group and other groups (P = 0.01). Harmine and the seed extract considerably reduced the Bax/Bcl-2 ratio in the hippocampal cells compared to the D group (P = 0.001). Conclusions: Streptozotocin-induced apoptosis in the hippocampus of diabetic rats was reduced by administering the seed extract of Peganum harmala. The P. harmala seed extract and its active ingredient, harmine, could be used as anti-apoptotic drugs.

The functional effects of piperine and piperine plus donepezil on hippocampal synaptic plasticity impairment in rat model of Alzheimer's disease.

AIMS: The modulatory effects of piperine on drug metabolizing enzymes play an important role in the control of pharmacokinetic and the bioavailability properties of the administered drugs. The present study investigated the effect of piperine and piperine-donepezil co-administration on cognitive functions and synaptic plasticity at hippocampal perforant pathway (PP) to dentate gyrus (DG) synapses in an experimental model of Alzheimer's disease (AD). MATERIALS AND METHODS: Intracerebroventricularly (ICV) streptozotocin (STZ) injected rats were treated once daily with piperine, donepezil and piperine combined with donepezil for 4 weeks. Cognitive performance was evaluated using passive avoidance and Morris water maze performance tasks. Analysis of evoked field potentials was done to explore possible effects on input/output response, paired-pulse facilitation and long-term synaptic plasticity (LTP) at PP to DG synapses of hippocampus. KEY FINDINGS: Rats subjected to ICV injection of STZ exhibited cognitive deficit associated with a hippocampal oxidative stress, effects that were reversed by chronic treatment with piperine or donepezil and or piperine combined with donepezil. Chronic treatment with piperine or donepezil restored the disruptive effects of STZ on LTP without altering basal synaptic transmission. SIGNIFICANCE: We found that optimal hippocampal function is dependent on tissue redox homeostasis. Piperine might reduce the synaptotoxic effects of STZ on hippocampal synaptic neurotransmission and correspondently is a good potential for neuroprotection against oxidative damage from ICV injection of STZ. These results suggest that piperine or donepezil significantly ameliorate cognitive deficit and LTP induction by attenuating oxidative status.

The neuroprotective effect of MicroRNA-149-5p and coenzymeQ10 by reducing levels of inflammatory cytokines and metalloproteinases following focal brain ischemia in rats.

The increase in some factors following cerebral ischemia, especially Matrix metalloproteinase (MMPs) and inflammatory factors lead to blood-brain barrier (BBB) damages, edema and neuronal death. Previous studies have shown that these molecules are miRNA-149-5p (miR-149) and Coenzyme (Co) Q10 targets. Therefore, in this study, the effect of mimic of miRNA-149-5p (mimic miR) and CoQ10 on the expression of metalloproteinase 1 and 2 and inflammatory cytokines following injury caused by cerebral ischemia is investigated. Cerebral ischemia was modeled by Middle Cerebral Artery Occlusion (MCAO). Male Wistar rats were randomly divided into 6 groups: sham (without surgery and treatment), control (MCAO), negative control (NC): MCAO + scrambled miR, vehicle: MCAO + Ethanole, first treatment: MCAO + mimic miR, second treatment: MCAO + Q10. Each group was divided into 6 subgroups to evaluate neurological defects, the volume of tissue damage using 2,3,5-triphenyl tetrazolium chloride (TTC) staining, blood-brain barrier permeability using cerebral Evans Blue (EB) staining, edema by measuring the percentage of brain water, MMP-2,9 mRNA and miR-149-5p levels using Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and the levels of IL-6 and TNF-α proteins using ELISA. The data obtained from this study showed that the use of mimic miR and Q10 increased the level of miR-149, decreased the extent of neurological defects and tissue damage, increased BBB integrity, decreased brain water percentage and also decreased the level of inflammatory cytokines and MMPs. It seems that the use mimic of miRNA-149-5p and Q10 can have a protective effect on the brain by reducing MMPs and inflammatory factors following cerebral ischemia and this could lead to a new treatment strategy to reduce the complications of cerebral ischemia.

Modulatory role of the orexin system in stress-induced analgesia: Involvement of the ventral tegmental area.

BACKGROUND: Exposure to stressful experiences is often accompanied by suppressing pain perception, referred to as stress-induced analgesia. The neuropeptides orexins are essential in regulating the mechanism that responds to stressful and painful stimuli. Meanwhile, the ventral tegmental area (VTA), as a part of descending pain inhibitory system, responds to noxious stimuli. This study aimed to investigate the role of intra-VTA administration of orexin receptor antagonists on stress-induced antinociceptive responses in the animal model of acute pain. METHOD: Ninety-three adult Wistar rats weighing 230-250 g were unilaterally implanted by a cannulae above the VTA. Animals were pretreated with different doses (1, 3, 10 and 30 nM/0.3 µl) of SB334867 as the orexin-1 receptor antagonist and TCS OX2 29 as the orexin-2 receptor antagonist into the VTA, just 5 min before 6 min exposure to forced swim stress (FSS). Nociceptive threshold was measured using the tail-flick test as a model of acute pain. RESULTS: The results showed that exposure to FSS could significantly increase analgesic responses. Moreover, intra-VTA administration of SB334768 and TCS OX2 29 blocked the antinociceptive effect of FSS in the tail-flick test. CONCLUSION: The findings suggest that OX1 and OX2 receptors in the VTA might modulate the antinociceptive behaviours induced by FSS in part. SIGNIFICANCE: Acute exposure to physical stress suppresses pain-related behaviors in the animal model of acute pain. Blockade of the OX1 and OX2 receptors in the VTA attenuates antinociceptive responses induced by FSS. The contribution of the OX2 receptors in the VTA is more predominant than OX1 receptors in stress-induced analgesia.

Minocycline Enhance the Restorative Ability of Olfactory Ensheathing Cells by the Upregulation of BDNF and GDNF Expression After Spinal Cord Injury.

Introduction: Spinal Cord Injury (SCI) is a global public health issue that results in extensive neuronal degeneration, axonal and myelin loss, and severe functional deficits. Neurotrophic factors are a potential treatment for reducing secondary damage, promoting axon growth; they are responsible for inducing myelination after injury. Olfactory Ensheathing Cells (OECs) and minocycline have promoted locomotor function after SCI. The present study investigated the neuroprotective effects of combined treatment with minocycline and OECs on spinal cord injury related to Brain-Derived Neurotrophic Factor (BDNF) and Glial Derived Neurotrophic Factor (GDNF) expressions after SCI. Methods: Adult female rats were used to experimental SCI by weight compression method. Rats received an intraperitoneal minocycline injection (90 mg/kg) immediately after SCI and 24 h after injury. OECs were transplanted one week after the injury. The hindlimb function was assessed using Basso Beattie Bresnahan (BBB) locomotor rating scale and Electromyography (EMG). After 5 weeks, the spinal cord segment centered at the injury site was removed for histopathological analysis. Immunohistological and western blot assays were performed to observe the expression of NeuN, BDNF, GDNF, and Myelin Basic Protein (MBP). Results: SCI induced the loss of locomotor function with decreased BDNF and GDNF expressions in the injury site. Minocycline+OECs increased the score of the BBB locomotor scale and increased spared tissue in the injury site. Immunohistochemical results suggested that NeuN expression significantly increased in the minocycline+OECs group than other groups. Moreover, electromyography amplitude in treated rats was increased compared to the control group. BDNF, GDNF, and MBP expressions and the number of ventral motor neurons increased further by minocycline+OECs in SCI rats. Conclusion: The present study provides evidence that minocycline may facilitate recovery of locomotor function by OECs by increasing BDNF and GDNF expressions following SCI. Highlights: Combined treatment with Minocycline and OECs increased the locomotor function.The results showed that BDNF and GDNF expression increased by combined treatment with minocycline and OECs. Plain Language Summary: This study examined the effect of combined treatment with minocycline and olfactory ensheathing cell on the BDNF and GDNF expression after spinal cord injury model in rat. The results showed that injection of minocycline before transplantation of OECs enhances expression of neurotrophic factors that lead to an appropriate environment for transplanted OECs and increases neuronal survival that promotes tissue sparing and functional recovery.