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.

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.

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.

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.

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.

Molecular Activation of the Kv11.1 Channel Reprograms EMT in Colon Cancer by Inhibiting TGFß Signaling via Activation of Calcineurin.

Control of ionic gradients is critical to maintain cellular homeostasis in both physiological and pathological conditions, but the role of ion channels in cancer cells has not been studied thoroughly. In this work we demonstrated that activity of the Kv11.1 potassium channel plays a vital role in controlling the migration of colon cancer cells by reversing the epithelial-to-mesenchymal transition (EMT) into the mesenchymal-to-epithelial transition (MET). We discovered that pharmacological stimulation of the Kv11.1 channel with the activator molecule NS1643 produces a strong inhibition of colon cancer cell motility. In agreement with the reversal of EMT, NS1643 treatment leads to a depletion of mesenchymal markers such as SNAIL1, SLUG, TWIST, ZEB, N-cadherin, and c-Myc, while the epithelial marker E-cadherin was strongly upregulated. Investigating the mechanism linking Kv11.1 activity to reversal of EMT into MET revealed that stimulation of Kv11.1 produced a strong and fast inhibition of the TGFß signaling. Application of NS1643 resulted in de-phosphorylation of the TGFß downstream effectors R-SMADs by activation of the serine/threonine phosphatase PP2B (calcineurin). Consistent with the role of TGFß in controlling cancer stemness, NS1643 also produced a strong inhibition of NANOG, SOX2, and OCT4 while arresting the cell cycle in G0/G1. Our data demonstrate that activation of the Kv11.1 channel reprograms EMT into MET by inhibiting TGFß signaling, which results in inhibition of motility in colon cancer cells.

Involvement of T-type calcium channels in the mechanism of low dose morphine-induced hyperalgesia in adult male rats.

It has been shown that systemic and local administration of ultra-low dose morphine induced a hyperalgesic response via mu-opioid receptors. However, its exact mechanism(s) has not fully been clarified. It is documented that mu-opioid receptors functionally couple to T-type voltage dependent Ca+2 channels. Here, we investigated the role of T-type calcium channels, amiloride and mibefradil, on the induction of low-dose morphine hyperalgesia in male Wistar rats. The data showed that morphine (0.01 µg i.t. and 1 µg/kg i.p.) could elicit hyperalgesia as assessed by the tail-flick test. Administration of amiloride (5 and 10 µg i.t.) and mibefradil (2.5 and 5 µg i.t.) completely blocked low-dose morphine-induced hyperalgesia in spinal dorsal horn. Amiloride at doses of 1 and 5 mg/kg (i.p.) and mibefradil (9 mg/kg ip) 10 min before morphine (1 µg/kg i.p.) inhibited morphine-induced hyperalgesia. Our results indicate a role for T-type calcium channels in low dose morphine-induced hyperalgesia in rats.

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.

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.

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.

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.

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 effect of intracerebroventricular administration of neuropeptide Y on reproductive axis function in the male Wistar rats: Involvement of hypothalamic KiSS1/GPR54 system.

Several studies have shown that neuropeptide Y (NPY) is considered to be one of the key regulators of the hypothalamic-pituitary-gonadal axis in the mammals. Also, kisspeptin is a powerful upstream regulator of gonadotropin-releasing hormone neurons in the hypothalamus. The present study aims to investigate the effects of the intracerebroventricular (ICV) injection of NPY and BIBP3226 (NPY receptor antagonist) on the reproductive axis (either hormonal or behavioral) of the male rats. Furthermore, to see whether NPY signals can be relayed through the pathway of KiSS1/GPR54, the gene expression of these peptides in the arcuate nucleus was measured. The ICV injection of NPY decreased the latencies and increased the frequencies of sexual parameters of the male rats in a significant way. Results obtained from LH and testosterone measurement showed that NPY had a significant increase in comparison with the control group. In this line, BIBP3226 antagonized the stimulative effects of NPY. Furthermore, data from real-time quantitative PCR showed that injection of NPY significantly increased the gene expression of KiSS1 and GPR54, while treatment with BIBP3226 controlled the stimulative effects of NPY on gene expression of KiSS1 and GPR54. Summing up, NPY can exert its impacts on the reproductive axis, this occurs at least partly through affecting KiSS1/GPR54 system.

Neurotoxic effects of high-dose piperine on hippocampal synaptic transmission and synaptic plasticity in a rat model of memory impairment.

In recent years, piperine has attracted much attention due to its various biological effects as a neuroprotective agent. Therefore, clarification of the possible side effects of piperine is important to identify its potential pharmacological action. Thus, the effects of piperine on the long-term plasticity of perforant pathway to dentate gyrus synapses were studied in hippocampus of an animal model of Alzheimer's disease (AD). Adult male rats were injected with intracerebroventricular (ICV) streptozotocin (STZ) bilaterally, on days 1 and 3 (3 mg/kg). The STZ-injected rats were treated with different doses of piperine for 4 weeks before being used in behavioral, electrophysiological and histopathological experiments. The passive-avoidance test was conducted on all animals in order to determine the cognitive performance. Rats were placed in a stereotaxic frame to implant a recording electrode in the hippocampal dentate gyrus and a stimulating electrode in the perforant path. Additionally, we assessed the density of survived neurons stained by cresyl violet. In this study, chronic administration of piperine low dose improved the ICV-STZ induced learning and long-term potentiation (LTP) impairments with no significant effect on baseline synaptic activity. In contrast, remarkable learning and long-term plasticity impairments were observed in rats treated by high dose of piperine in comparison to the other groups. Interestingly, this impaired hippocampal LTP was accompanied by an obvious alteration in baseline activity and significantly decreased neuronal numbers within the hippocampus. Therefore, our data provides a new understanding of the piperine supplementation effects on hippocampal electrophysiological profile although the consequences may be either beneficial or detrimental.

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.

Stress-Induced Spatial Memory Deficit Reversed by Basolateral Amygdala NMDA Receptor Inhibition in Male Wistar Rats.

INTRODUCTION: The present study investigated the role of the Basolateral Amygdala (BLA) N-methyl-D-aspartate (NMDA) receptors in stress-induced spatial memory disturbance among the male Wistar rats. METHODS: The male Wistar rats (Average weight =200 g) were cannulated bilaterally in the BLA, and entered the study (n=6-8) after one week. They received seven electro-foot-shock stress sessions on seven consecutive days. Memantine (0.1, 1, and 5 µg/rat) or saline (0.5 µL/ rat) was injected into the BLA, five minutes before each stress session. The control groups received the same doses of memantine and no stress. After the end of the stress sessions, blood samples were taken from all animals to evaluate their plasma corticosterone. Also, the spatial learning and memory of the study animals were evaluated using the Barnes maze method. The animals experienced five consecutive days of training on the maze for spatial learning. On the sixth day, their spatial memory was evaluated on the maze. Time, distance, the number of errors, and the taking strategy for reaching the target hole were considered as the parameters for the spatial learning and memory evaluation. RESULTS: Stress increases the plasma corticosterone level, while memantine preadministration reduces the stress effects. Besides, stress increases the time and distance to the target hole and the number of errors. Stress changed the animals' strategy from serial to random type. However, the intra-BLA memantine reversed all the disturbances induced by the stress. CONCLUSION: This study indicated that the BLA glutamate NMDA receptors modulate the effect of stress on spatial learning and memory deficit.

Effects of intra-dentate gyrus microinjection of myokine irisin on long-term potentiation in male rats / Efeitos da microinjeção da miocina irisina no giro denteado sobre a potenciação a longo prazo em ratos machos

ABSTRACT Induction of long-term potentiation (LTP) increases the storage capacity of synapses in the hippocampal dentate gyrus (DG). Irisin is a myokine generated from FNDC5 (a gene precursor) during exercise. Although intra-cornu ammonis 1 administration of irisin fortifies LTP in mice with Alzheimer's disease, the effects of intra-DG injection of irisin on the LTP in rats remains to be elucidated in vivo. In this study, male Wistar rats were randomly divided into a control group (saline), irisin (0.5, 1, and 1.5 μg/rat), and dimethyl sulfoxide (DMSO). After treatment, the population spike (PS) amplitude and slope of excitatory postsynaptic potentials (EPSP) were measured in the DG of rats in vivo. Moreover, following completion of the experiments, the stimulating and recording sites in the hippocampus were confirmed histologically from brain sections. Furthermore, biochemical assays like malondialdehyde (MDA), total antioxidant capacity (TAC), and total oxidant status (TOS) were evaluated (the antioxidant markers were analyzed in the plasma). Our results suggest that all doses of irisin (0.5, 1, 1.5 μg/rat) caused an increase in the EPSP slope and PS amplitude when compared with the control group. In addition, the results obtained showed that irisin decreased TOS and MDA levels while increasing TAC levels as a marker of lipid peroxidation in plasma. The present report provides direct evidence that irisin affects the activity-dependent synaptic plasticity in the dentate gyrus.

RESUMO A indução de potenciação de longo prazo (LTP) aumenta a capacidade de armazenamento das sinapses no giro denteado (DG) do hipocampo. A irisina é uma miocina gerada a partir do FNDC5 (um precursor genético) durante o exercício. Embora a administração intra-Cornu Ammonis1 de irisina fortaleça a LTP em camundongos com doença de Alzheimer, os efeitos da injeção intra-denteada de irisina sobre a LTP em ratos ainda precisam ser elucidados in vivo. Neste estudo, ratos Wistar machos foram divididos aleatoriamente em um grupo controle (solução salina), irisina (0,5, 1 e 1,5 μg / rato) e dimetilsulfóxido (DMSO). Após o tratamento, a amplitude do pico populacional (PS) e a variação dos potenciais pós-sinápticos excitatórios (EPSP) foram medidos no DG de ratos in vivo. Além disso, após a conclusão das experiências, os locais de estimulação e registro no hipocampo foram confirmados histologicamente a partir de secções do cérebro. Adicionalmente, ensaios bioquímicos como malondialdeído (MDA), capacidade antioxidante total (TAC) e status oxidante total (TOS) foram avaliados (os marcadores antioxidantes foram analisados no plasma). Nossos resultados sugerem que todas as doses de irisina (0,5, 1, 1,5 μg / rato) causaram um aumento na variação da EPSP e na amplitude da PS quando comparadas com o grupo controle. Além disso, os resultados obtidos mostraram que a irisina diminuiu os níveis de TOS e MDA, enquanto aumentou os níveis de TAC como um marcador da peroxidação lipídica no plasma. O presente estudo fornece evidências diretas de que a irisina afeta a plasticidade sináptica dependente de atividade no DG.

Inhibition of Airway Contraction and Inflammation by Pomalidomide in a Male Wistar Rat Model of Ovalbumin-induced Asthma.

Asthma is a chronic inflammatory disease of the airways of the lungs. Pomalidomide (POM) a therapy for multiple myeloma has been stated to have an anti-inflammatory effect. The main goal of the present study was to assess its possible effect on airway contraction and inflammation in a rat model of ovalbumin-induced asthma. Different groups of rats received saline or pomalidomide (0.4, 0.8 mg/kg) or dexamethasone (0.6 mg/kg). The asthma was induced by ovalbumin (OVA). Trachea contraction was assayed by organ bath system. Airway histology was assessed using hematoxylin and eosin method. Serum Tumor necrosis factor alpha (TNF-α) level was analyzed by Enzyme-Linked Immunosorbent Assay and Platelet-derived growth factor (PDGFα) Gene expressions were evaluated by Real-time PCR. Pomalidomide prevented ovalbumin-induced airway contraction and histopathological damage. In addition serum, TNF-α level was significantly (p<0.05) decreased in POM treated animals compared to control (asthmatic animals that received POM vehicle). Results indicate that POM prevented the PDGF expression induced by ovalbumin. In conclusion, we found that pomalidomide ameliorated the symptoms, histopathological changes and inflammatory markers induced by ovalbumin in asthmatic rats and these effects might be related to its anti-inflammatory properties.

Curcumin nanoparticles incorporated collagen-chitosan scaffold promotes cutaneous wound healing through regulation of TGF-ß1/Smad7 gene expression.

Wound healing is a tissue regeneration process which is regulated by a complex interaction of multiple growth factors, primarily transforming growth factor-ß1 (TGF-ß1). The natural antagonist of transforming growth factor-ß (TGF-ß) signaling is Smad7. It has been shown that curcumin (an antioxidant) and some biocompatible polymers like collagen and chitosan enhance cutaneous wound healing. In this study, three scaffolds made with curcumin-nanoparticles (CNs) and using collagen and chitosan with various ratios of collagen and chitosan were used for evaluation of wound healing activity on full thickness punch wound model using male Wistar rats. The wound healing in terms of histology and morphology was assessed at different time points post-wounding and the expression pattern of TGF-ß1 and Smad7 was studied. CNs incorporated collagen-chitosan scaffolds significantly accelerated the healing of the wounds, as revealed by a significant change in the wound area, the epidermal thickness, the density of granulation tissue, the number of new vessels and a higher collagen content compared to the control group. However, blank collagen-chitosan scaffolds did not cause any significant change in the above parameters, except for epidermal thickness compared to the control group. Incorporation of CNs into collagen-chitosan scaffold changed expression of TGF-ß1 and Smad7 mRNAs in the healing wounds compared to the control group. Indeed, blank collagen-chitosan scaffold did not cause any significant up-regulation either in TGF-ß1 mRNA expression or in Smad7 mRNA expression (except for day 3 post-wounding), compared to the control group. This study indicates that topical application of CNs-incorporated collagen-chitosan scaffold promotes wound healing via a regulatory effect on the expression of TGF-ß1 and Smad7 mRNA in the cutaneous wound-healing model.

Clinical and metabolic response to probiotic administration in people with Parkinson's disease: A randomized, double-blind, placebo-controlled trial.

BACKGROUND & AIMS: The investigation was done to assess the impacts of probiotic supplementation on movement and metabolic parameters in individuals with Parkinson's disease (PD). METHODS: The study is randomized, double-blind, placebo-controlled clinical trial, which was done in sixty people with PD. Individuals were randomly divided into two groups in order to take either 8 × 109 CFU/day probiotic or placebo (n = 30 each group) that lasted 12 weeks. The Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) was recorded at pre- and post-intervention. RESULTS: Compared with the placebo, consuming probiotic decreased MDS-UPDRS (-4.8 ± 12.5 vs. +3.8 ± 13.0, P = 0.01). Probiotic supplementation also reduced high-sensitivity C-reactive protein (-1.6 ± 2.5 vs. +0.1 ± 0.3 mg/L, P < 0.001) and malondialdehyde (-0.2 ± 0.3 vs. +0.1 ± 0.3 µmol/L, P = 0.006), and enhanced glutathione levels (+40.1 ± 81.5 vs. -12.1 ± 41.7 µmol/L, P = 0.03) in comparison with the placebo. Additionally, probiotic consumption resulted in a statistically significant reduction in insulin levels (-2.1 ± 3.4 vs. +1.5 ± 5.1 µIU/mL, P = 0.002) and insulin resistance (-0.5 ± 0.9 vs. +0.4 ± 1.2, P = 0.002), and a statistically significant rise in insulin sensitivity (+0.01 ± 0.02 vs. -0.006 ± 0.02, P = 0.01) in comparison with the placebo. Probiotic intake had no any significant impact on other metabolic profiles. CONCLUSIONS: Our study evidenced that 12 weeks of probiotic consumption by individuals with PD had useful impacts on MDS-UPDRS and few metabolic profiles. Registered under ClinicalTrials.gov Identifier no. http://www.irct.ir: IRCT2017082434497N4.