Stress In Hippocampus Of Rats Research Articles

S-Ketamine Exerts Antidepressant Effects by Regulating Rac1 GTPase Mediated Synaptic Plasticity in the Hippocampus of Stressed Rats.

Clinical studies have found that ketamine has a rapid and lasting antidepressant effect, especially in the case of patients with major depressive disorder (MDD). The molecular mechanisms, however, remain unclear. In this study, we observe the effects of S-Ketamine on the expression of Rac1, neuronal morphology, and synaptic transmission function in the hippocampus of stressed rats. Chronic unpredictable mild stress (CUMS) was used to construct stressed rats. The rats were given a different regimen of ketamine (20mg/kg, i.p.) and Rac1 inhibitor NSC23766 (50µg, ICV) treatment. The depression-like behavior of rats was evaluated by sucrose preference test and open-field test. The protein expression of Rac1, GluA1, synapsin1, and PSD95 in the hippocampus was detected by Western blot. Pull-down analysis was used to examine the activity of Rac1. Golgi staining and electrophysiological study were used to observe the neuronal morphology and long-term potentiation (LTP). Our results showed that ketamine can up-regulate the expression and activity of Rac1; increase the spine density and the expression of synaptic-related proteins such as GluA1, Synapsin1, and PSD95 in the hippocampus of stressed rats; reduce the CUMS-induced LTP impairments; and consequently improve depression-like behavior. However, Rac1 inhibitor NSC23766 could have effectively reversed ketamine-mediated changes in the hippocampus of rats and counteracted its antidepressant effects. The specific mechanism of S-Ketamine's antidepressant effect may be related to the up-regulation of the expression and activity of Rac1 in the hippocampus of stressed rats, thus enhancing synaptic plasticity.

Effects of curcumin on neurobehavior and oxidative stress in hippocampus of rats exposed to manganese

Objective: To establish the animal model of subchronic manganism, and to explore the effect of manganese on neurofunction of rats and the protective effect of curcumin on neurotoxicity of manganism rats. Methods: From July to December 2019, 80 SPF male SD rats were divided into 8 groups according to body weight by random number table method, which were blank control group, low, middle and high dose manganese exposure group, low, middle and high dose curcumin antagonistic group and curcumin group, with 10 rats in each group. The low, middle and high dose manganese groups were given intraperitoneal injection of 5 mg/kg, 10 mg/kg and 15 mg/kg MnCl(2)·4H(2)O respectively. The low, middle and high dose curcumin antagonistic groups were given 100 mg/kg, 200 mg/kg and 400 mg/kg curcumin orally along with 15 mg/kg MnCl(2)·4H(2)O intraperitoneal injection. Curcumin group was given 400 mg/kg curcumin orally. The rats were exposed to 5 days a week, once a day for 16 weeks. After exposure, neurobehavioral tests (balance beam test, Morris water maze, passive avoidance test) were carried out in each group. Hippocampus tissues were taken for pathological examination and oxidative stress indexes were detected. Results: The balance beam test results showed that, compared with the blank control group, the scores of balance beam of the rats in the middle and high dose manganese exposure groups increased (P<0.05) . Compared with the high dose manganese exposure group, the balance beam scores of the low, middle and high dose curcumin antagonistic groups were decreased (P<0.05) .The results of Morris water maze showed that, compared with the blank control group, the escape latency of middle and high dose manganese exposure groups was prolonged from the third day (P<0.05) , and the average number of crossing the platform area of each manganese exposure group was decreased (P<0.05) .Compared with the high dose manganese exposure group, the escape latency of the middle and high dose curcumin antagonistic groups was shortened (P<0.05) , and the average number of crossing the original platform was increased (P<0.05) . The results of passive avoidance test show that, compared with the blank control group, the number of errors were increased in middle and high dose manganese exposure groups (P<0.05) . Compared with the high dose manganese exposure group, the number of errors in the passive avoidance test in the middle and high dose curcumin antagonistic groups were decreased (P<0.05) . Pathological examination showed that the rats treated with manganses had different degrees of degeneration and necrosis of nerve cells, and the structure of nerve cells was blurred and the number of nerve cells decreased. The above phenomena were improved after curcumin antagonism. The results of oxidative stress index showed that, compared with blank control group, the activity of superoxide dismutase (SOD) decreased and the content of malondialdehyde (MDA) increased in the hippocampus of rats exposed to middle and high dose of manganese (P<0.05) . Compared with the high dose manganese exposure group, the SOD activity increased and the MDA content decreased in the middle and high dose antagonist group (P<0.05) . Conclusion: Subchronic manganese exposure can reduce the balance function, learning and memory ability of rats, and damage the hippocampal nerve cells in oxidative stress state. Curcumin can improve the balance function and learning and memory ability of rats with manganese poisoning, improve the hippocampal nerve damage caused by manganese exposure, and has a certain protective effect on manganese induced neurotoxicity.

Prenatal and breastfeeding exposure to low dose of diethylhexyl phthalate induces behavioral deficits and exacerbates oxidative stress in rat hippocampus

Diethylhexyl phthalate (DEHP) is one of the most important derivatives of phthalate that has devastating effects on nervous system function. In this study, the effects of exposure with low doses of DEHP during pregnancy and lactation periods have been evaluated in rat's puppies. DEHP at doses 5, 40, 400 μg/kg/day and 300 mg/kg/day was given to mothers by gavage during pregnancy and lactation. The spatial and working memories were evaluated by Morris water maze test and Y maze, respectively. Oxidative stress levels were measured by biochemical tests. Histopathology of hippocampal tissue was assessed using hematoxylin and eosin, Nissl staining, and immunohistofluorescence in 60-days-old puppies. Behavioral data showed that low doses of DEHP decreased the working and spatial memories of male rats. Increased oxidative stress and decreased antioxidant activity were also observed in the hippocampus of rats which received the low doses of DEHP. However, neuronal damage, inflammation, and astrocyte activation were not significantly increased in the hippocampus of rats. Overall, exposure of mothers to low doses of DEHP during pregnancy and lactation cause behavioral deficits, especially in male newborn. The destructive effects of low doses of DEHP might be mediated through increased levels of oxidative stress in the brain.

Effects of CRMP2 DNA Methylation in the Hippocampus on Depressive-Like Behaviors and Cytoskeletal Proteins in Rats.

Chronic stress appears to alter DNA methylation and DNA methyltransferases (DNMTs) in brain regions related to emotion. Collapsin response mediator protein-2 (CRMP2) mediates the development of depression by regulating microtubule dynamics. In this study, rats were subjected to chronic unpredictable mild stress (CUMS). At the end of the CUMS procedure, normal saline or fluoxetine was administered to the rats. Moreover, normal saline or the 5-aza-2’-deoxycytidine (5-aza) was administered to the hippocampal CA1 region of the rats. Behavioral tests were performed to evaluate the depressive-like phenotypes. The CRMP2 DNA methylation levels and cytoskeletal microtubular system-related biomarkers were detected by several molecular biology techniques. The results showed that the rat model of depression was successfully established by exposure to CUMS, and fluoxetine treatment exerted an antidepressant-like effect. We observed the upregulation of DNMT1 and DNMT3a in the hippocampus of stressed rats. CUMS induced a decrease in CRMP2 expression and an increase in phosphorylated CRMP2 (pCRMP2) expression in the hippocampus of rats. The rate of DNA methylation in the CpG island of the CRMP2 promoter region in the hippocampus of stressed rats was significantly higher than that in control rats. Moreover, CUMS significantly decreased the interaction between CRMP2 and α-tubulin and decreased the microtubule dynamics. Chronic fluoxetine treatment reversed these changes. Also, hypomethylation induced by 5-aza injection into the hippocampal CA1 region caused antidepressant-like effects and increased CRMP2 expression and microtubule dynamics. These results suggested that CRMP2 DNA methylation may be involved in regulating the cytoskeletal microtubular system and mediating depressive-like behaviors.

Melatonin ameliorated CUMS-induced depression-like behavior via restoring endoplasmic reticulum stress in rat hippocampus.

Melatonin is a hormone synthesized and secreted by the pineal gland with the effect of regulating sleep rhythm. Circadian and sleep disturbances may be central for understanding the pathophysiology and treatment of depression. Recently, the melatonergic system has been implicated in the pathophysiology and treatment of depression. In this study, we observed the effects of melatonin on depression-like behavior induced by chronic unpredictable mild stress (CUMS) in rats, and its molecular mechanism was explored. Adult male Sprague-Dawley rats were exposed to CUMS for 4 weeks. Melatonin or saline was injected intraperitoneally. Behavioral changes of Sprague-Dawley rats were detected by the open field test, sugar preference test, elevated O maze test and forced swimming test. In addition, the plasma corticosterone level and the expression of endoplasmic reticulum stress-related protein in the hippocampus of rats were measured. Compared with the control group, the CUMS-exposed Sprague-Dawley rats showed depression-like behavior, which was significantly improved by melatonin treatment. Moreover, CUMS induced endoplasmic reticulum stress and JNK phosphorylation in the hippocampus. Melatonin treatment could significantly reverse the endoplasmic reticulum stress and JNK phosphorylation induced by CUMS. These results suggest that melatonin improves depression-like behavior by inhibiting endoplasmic reticulum stress induced by CUMS. This study demonstrates that melatonin can improve depression-like behavior induced by CUMS, which may be related to the inhibition of endoplasmic reticulum stress and JNK phosphorylation in rat hippocampus.

Anti-Lingo-1 antibody ameliorates spatial memory and synapse loss induced by chronic stress.

Chronic stress can induce cognitive impairment, and synapse number was significantly decreased in the hippocampus of rats suffering from chronic stress. Lingo-1 is a potent negative regulator of axonal outgrowth and synaptic plasticity. In the current study, the effects of anti-Lingo-1 antibody on the spatial learning and memory abilities and hippocampal synapses of stressed rats were investigated. After 4 weeks of stress exposure, the model group was randomly divided into a chronic stress group and an anti-Lingo-1 group. Then, the anti-Lingo-1 group rats were treated with anti-Lingo-1 antibody (8 mg/kg) for 3 weeks. The effects of anti-Lingo-1 antibody on the spatial learning and memory abilities were investigated with the Morris water maze test. Immunohistological staining and an unbiased stereological method were used to estimate the total number of dendritic spine synapses in the hippocampus. At the behavioral level, after 3 weeks of treatment, the anti-Lingo-1 group rats displayed significantly more platform location crossings in the Morris water maze test than the chronic stress group rats. Anti-Lingo-1 significantly prevented the declines in dendritic spine synapses and postsynaptic density protein-95 (PSD-95) expression in the dentate gyrus and the CA1 and CA3 regions of the hippocampus. The present results indicated that anti-Lingo-1 antibody may be a safe and effective drug for alleviating memory impairment in rats after chronic stress and protecting synapses in the hippocampus of stressed rats.

Spinacia oleracea L. extract attenuates hippocampal expression of TNF-α and IL-1β in rats exposed to chronic restraint stress.

Background: Restraint stress causes inflammation in nervous system that leads to emersion of neurodegenerative diseases. Spinach (Spinacia oleracea L.) contains different agents with antioxidant, antiapoptosis, and hepatoprotective properties. This study examined the effect of spinach hydroalcoholic extract (SHE) on TNF-α and IL-1β expression in hippocampus of male Wistar rats exposed to chronic restraint stress. Methods: Rats were divided into 6 groups of 5: (1) control (intact); (2) nS-S200; (3) nS-S400; (4) stress; (5) stress-S200; (6) stressS400. Groups 2 and 3 and groups 5 and 6 received S. oleracea leaf hydroalcoholic extract in 200 and 400 mg/kg doses for 21 consecutive days by gavage. Groups 4, 5 and 6 were put in a restrainer 6 hours per day for 21 consecutive days. Then, the expression of IL-1β and TNF-α mRNAs and neuronal death in the hippocampus of rats were assessed by real time PCR and Nissl staining, respectively. Oneway analysis of variance was used for data analysis, and p<0.05 was considered statistically significant. Results: The results showed that the expression of IL-1β and TNF-α was increased in hippocampus of rats exposed to stress compared to control groups (p<0.001). Furthermore, the expression of these proinflammatory cytokines was decreased in the stress-S200 and stress-S400 groups when compared to stress group (p<0.001). Immobility also caused neuronal death in CA1 region of hippocampus, and SHE reduced damage in CA1 pyramidal neurons layer in stressed rats. Conclusion: Spinach decreases neuroinflammation in hippocampus of stressed rats, which may be due to its abundant antiinflammatory and antioxidant phytochemicals. The results of this study suggest that spinach may be effective in the prevention and treatment of neurodegenerative diseases.

Cannabinoid receptor type 1 modulates the effects of polyunsaturated fatty acids on memory of stressed rats

ABSTRACT Memory and GABAergic activity in the hippocampus of stressed rats improve after n-3 polyunsaturated fatty acid (PUFA) supplementation. On the other hand, cannabinoid receptor type 1 (CB1) strongly regulates inhibitory neurotransmission in the hippocampus. Speculation about a possible relation between stress, endocannabinoids, and PUFAs. Here, we examined whether the effects of PUFAs on memory of chronically stressed rats depends on pharmacological manipulation of CB1 receptors. Male Sprague-Dawley rats were orally supplemented with n-3 (fish oil) or n-6 (primrose oil) PUFAs during chronic restraint stress (CRS) protocol (6 h/day; 21 days). First, we studied if the expression of CB1 receptors in the hippocampus may be affected by CRS and PUFAs supplementation by real-time PCR and immunofluorescence. CRS up-regulated the CB1 expression compared with the non-stressed rats, while only n-3 PUFAs countered this effect. Memory was evaluated in the Morris water maze. Stressed rats were co-treated with PUFAs and/or modulators of CB1 receptor (AM251, antagonist, 0.3 mg/kg/day; WIN55,212-2, agonist, 0.5 mg/kg/day) by intraperitoneal injections. Memory improved in the stressed rats that were treated with AM251 and/or n-3 PUFAs. Supplementation with n-6 PUFAs did not affect memory of stressed rats, but co-treatment with AM251 improved it, while co-treatment with WIN55,212-2 did not affect memory. Our results demonstrate that activity of the CB1 receptors may modulate the effects of PUFAs on memory of stressed rats. This study suggests that endocannabinoids and PUFAs can both become a singular system by being self-regulated in limbic areas, so they control the effects of stress on the brain.

Ketamine ameliorates depressive-like behaviors by tPA-mediated conversion of proBDNF to mBDNF in the hippocampus of stressed rats

Some studies have indicated that ketamine has a rapid antidepressant effects, but the underlying molecular mechanism is still unclear. Researchers have found that mature brain-derived neurotrophic factor (mBDNF) and its precursor proBDNF are related to depression; they elicit opposite effects on cellular functions. It is clear that tissue plasminogen activator (tPA) is a key regulatory element in the conversion of proBDNF to mBDNF. The chronic unpredicted mild stress (CUMS) procedure is a classical and reliable method to establish the model of depression. This study found that sucrose preference and locomotor activity were both reduced in CUMS-treated rats while were increased in those who were injected with ketamine. The hippocampal proBDNF/mBDNF ratio was downregulated after ketamine treatment in those rats, together with an increased level of tPA in the hippocampus. However, tPA activity was unaltered after ketamine intraperitoneal injection. Intrahippocampal injection of active plasminogen activator inhibitor-1 (inhibitor of tPA) before ketamine treatment reversed the antidepressant effects and upregulated the proBDNF/mBDNF ratio. The results of this study suggest that the antidepressant action induced by ketamine may be related to tPA-mediated conversion of proBDNF to mBDNF in the hippocampus.

The anxiolytic effects of atorvastatin and simvastatin on dietary-induced increase in homocysteine levels in rats

The aim of this study was to evaluate the effects of atorvastatin and simvastatin on behavioral manifestations that followed hyperhomocysteinemia induced by special dietary protocols enriched in methionine and deficient in B vitamins (B6, B9, B12) by means of alterations in anxiety levels in rats. Simultaneously, we investigated the alterations of oxidative stress markers in rat hippocampus induced by applied dietary protocols. Furthermore, considering the well-known antioxidant properties of statins, we attempted to assess their impact on major markers of oxidative stress and their possible beneficial role on anxiety-like behavior effect in rats. The 4-week-old male Wistar albino rats were divided (eight per group) according to basic dietary protocols: standard chow, methionine-enriched, and methionine-enriched vitamins B (B6, B9, B12) deficient. Each dietary protocol (30days) included groups with atorvastatin (3mg/kg/day i.p.) and simvastatin (5mg/kg/day i.p.). The behavioral testing was performed in the open field and elevated plus maze tests. Parameters of oxidative stress (index of lipid peroxidation, superoxide dismutase, catalase activity, glutathione) were determined in hippocampal tissue samples following decapitation after anesthesia. Methionine-load dietary protocols induced increased oxidative stress in rat hippocampus, which was accompanied by anxiogenic behavioral manifestations. The methionine-enriched diet with restricted vitamins B intake induced more pronounced anxiogenic effect, as well as increased oxidative stress compared to the methionine-load diet with normal vitamins B content. Simultaneous administration of statins showed beneficial effects by means of both decreased parameters of oxidative stress and attenuation of anxiety. The results obtained with simvastatin were more convincible compared to atorvastatin.

The Neuroprotective Efficacy of Lagenaria vulgaris Extract against Oxidative Stress in Rat Hippocampus

The neuroprotective potential of ethanolic extract of Lagenaria vulgaris EELV seeds against Oxidative Stress in Rat Hippocampus was evaluated to ascertain the validity of folkloric claims The neuroprotective potential was evaluated through oxidative stress induced by sodium azide in the hippocampus of rats Brain homogenates were pre incubated for minutes with mg mL EELV and then incubated for minutes with mM sodium azide and were examined for oxidative markers viz thiobarbituric acid reactive substances TBARS catalase CAT superoxide dismutase SOD since their levels are altered on exposure to sodium azide The results indicated that the levels of TBARS CAT activity were enhanced and SOD activity was reduced by sodium azide EELV prohibited the changes in TBARS CAT and SOD Cell viability was evaluated by the dimethylthiazol yl diphenyl tetrazolium bromide MTT and it rsquo s showed no change in MTT reduction by Sodium azide However EELV increased MTT reduction in the presence or absence of sodium azide Hence it can be concluded that EELV has potential antioxidant and neuroprotective activity in the rat hippocampal homogenate which may be due to the presence of flavonoids

Early adolescent stress-induced changes in prefrontal cortex miRNA-135a and hippocampal miRNA-16 in male rats.

Early-life stress increases susceptibility to post-traumatic stress disorders (PTSD), in which the dysfunction of 5-hydroxytryptamine plays an important role. miRNA-135a in the prefrontal cortex (PFC) and miRNA-16 in the hippocampus (HIP) are closely related to the 5-HT neurotransmitter system. Here, we investigated behavior, miRNA-135a in the PFC, miRNA-16 in the HIP, and 5-HT1AR expression in both brain regions in adolescent and adult rats that were exposed to inescapable stress during their adolescence. Paroxetine hydrochloride and corticotropin-releasing factor antagonist (CP-154,526) were used as intervening measures. Our study demonstrated that early adolescent stress induced anxiety-like behaviors and spatial memory damage, a reduction in miRNA-135a expression was associated with increased 5-HT1AR expression in PFC, and increased miRNA-16 expression in the HIP of stressed rats. Drug treatments alleviated behaviors and reversed the miRNA-135a, miRNA-16, and 5-HT1AR expression in stressed rats.

Metformin Alleviated the Neuronal Oxidative Stress in Hippocampus of Rats under Single Prolonged Stress.

In an animal model of post-traumatic stress disorder (PTSD), our previous studies showed mitochondrial stress-induced apoptosis in the hippocampus. Metformin, the most commonly prescribed anti-diabetic drug, exerts its effects through 5'-adenosine monophosphate-activated protein kinase (AMPK) activation. It was shown that a neuroprotective role was gradually established against stroke, spinal cord injury and Parkinson's disease. The aim of this study was to explore the role of the AMPK pathway in neuronal apoptosis in the hippocampus using a rat model of PTSD. The model PTSD rats received acute exposure to prolonged stress (single prolonged stress, SPS), followed by examination of the effects of genes and/or proteins related to the AMPK and oxidative stress pathways in the hippocampus with or without metformin preconditioning. The results indicated that the level of phosphorylated AMPK was markedly increased after SPS. Metformin protected the hippocampus as evidenced by abolishing down-regulation of the AMPK pathway and up-regulating expression of oxidative stress-related genes. These results indicated that metformin attenuated oxidative stress in the hippocampus in rats under SPS. AMPK pathway activation may be a novel therapeutic protocol for PTSD patients.

N-3 Polyunsaturated fatty acid supplementation restored impaired memory and GABAergic synaptic efficacy in the hippocampus of stressed rats

While chronic stress induces dendritic atrophy in the hippocampus and impairs learning and memory, supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) is known to improve learning and memory of control rats. Whether n-3 PUFA supplementation improves dendritic morphology, synaptic transmission, and memory of chronically stressed rats remains unknown. In this work, we randomly assigned male Sprague-Dawley rats in four experimental groups: two unsupplemented groups, control and stress, and two supplemented groups with n-3 PUFA (DHA and EPA mix), control + n-3 PUFA and stress + n-3 PUFA. Dendritic morphology and synaptic transmission in the hippocampus were evaluated by Golgi stain and patch-clamp tools, respectively. The Y-maze and Morris water maze were used to analyze the effects of chronic stress on memory. Supplementation with n-3 PUFA improved dendritic architecture and restored the frequency of inhibitory post-synaptic currents of hippocampal pyramidal neurons of rats from stress group. In addition, n-3 PUFA supplementation improved spatial memory. Our results demonstrate that n-3 PUFA supplementation had three beneficial effects on stressed rats: prevented or compensated dendritic atrophy in CA3; restored the probability of GABA release in CA1; and improved spatial memory. We argue that n-3 PUFA supplementation can be used in treating stress-related psychiatric disorders such as depression and anxiety.

The Synergy Effect of Low-Intensity Exercise Training and Caloric Restriction on BDNF in Rat Hippocampus

PURPOSE: Recent studies have suggested that exercise training and caloric restriction have beneficial effects on brain function, including the improvements of cognitive function by the promotion of brain-derived neurotrophic factor (BDNF) expression in the hippocampus. In addition, the level of oxidative stress might be involved in the mechanism to explain these effects. The purpose of this study was to investigate the synergy effects between 12-week low-intensity exercise training and caloric restriction on BDNF expression and the level of oxidative stress in rat hippocampus. METHODS: Twenty-six, 7 week-old male Wistar rats were randomly divided into the following 4 groups: 1) sedentary control (Con, n=7); 2) exercise (Ex, n=6); 3) caloric restriction (CR, n=7); and 4) exercise training and caloric restriction (ExCR, n=6). Ex and ExCR underwent treadmill running at 10 m/min, 5° slope, 30 min/day, 5 days/week. Although Con and Ex were fed ad libitum over time, CR and ExCR consumed 40 % less food compared with Con. Forty-eight hours after the termination of the 12-week intervention, rats were sacrificed and the hippocampus was quickly dissected for measurement of BDNF and 4-hydroxy-2-nonenal (4-HNE) contents, and serum total antioxidant capacity (TAC) were also assessed. RESULTS: 4-HNE contents in Ex and CR were significantly increased compared with Con (p<0.05, respectively). However, these elevation was not observed in ExCR. On the other hand, no changes were observed in the alteration of serum TAC among 4 groups. Hippocampal BDNF contents was significantly increased in Ex compared with Con (p<0.05), whereas the exercise-induced elevation in BDNF was completely suppressed by a combination with caloric restriction. Furthermore, we found a significant relationship between hippocampal BDNF and 4-HNE contents (p<0.05), suggesting the hypothesis that oxidative stress is essential for the expression of BDNF in the hippocampus. CONCLUSION: Our findings indicate that optimal stimulus of oxidative stress induced by low-intensity exercise training contributes to BDNF expression in hippocampus. However, it is conceivable that exercise training combined with caloric restriction might not have a synergy effect on hippocampal BDNF expression.

Mauritia flexuosa L. protects against deficits in memory acquisition and oxidative stress in rat hippocampus induced by methylmercury exposure

Objective: Methylmercury (MeHg) is the most toxic form of mercury that can affect humans through the food chain by bioaccumulation. Human organism is capable of triggering visual and cognitive disorders, neurodegeneration, as well as increased production of reactive species of O2 and depletion of natural anti-oxidant agents. In this context, Mauritia flexuosa L., a fruit rich in compounds with anti-oxidant properties, emerged as an important strategy to prevent the MeHg damages. So, this work has aimed to elucidate the protective effect of Mauritia flexuosa L. on the damage caused by the exposure of rats to MeHg.Methods: In order to evaluate the effect of MeHg on rat aversive memory acquisition and panic-like behavior, we have used elevated T-maze apparatus and after behavioral test, the hippocampus was removed to perfom lipid peroxidation.Results: Our results demonstrated that the exposure to MeHg caused deficits in inhibitory avoidance acquisition (aversive conditioning) and in the learning process, and increased levels of lipid peroxidation in hippocampus tissue. However, the pretreatment with feed enriched with Mauritia flexuosa L. showed a protective effect against cognitive deficits caused by MeHg and also prevented the occurrence of cytoplasmic membrane damage induced by lipid peroxidation in the hippocampal region.Discussion: Therefore, this study suggests that Mauritia flexuosa L. represents an important strategy to prevent neurocytotoxics and behavioral effects of MeHg.

Effects of RAGE-Specific Inhibitor FPS-ZM1 on Amyloid-β Metabolism and AGEs-Induced Inflammation and Oxidative Stress in Rat Hippocampus.

An increased level of advanced glycation end products (AGEs) is observed in brains of patients with Alzheimer's disease (AD). AGEs and receptor for AGEs (RAGE) play important roles in the pathogenesis of AD. FPS-ZM1 is a high-affinity RAGE-specific blocker that inhibits amyloid-β binding to RAGE, neurological damage and inflammation in the APP(sw/0) transgenic mouse model of AD. FPS-ZM1 is not toxic to mice and can easily cross the blood-brain barrier. In this study, an AGEs-RAGE-activated rat model were established by intrahippocampal injection of AGEs, then these rats were treated with intraperitoneal administration of FPS-ZM1 and the possible neuroprotective effects were investigated. We found that AGEs administration induced an-regulation of Abeta production, inflammation, and oxidative stress, and an increased escape latency of rats in the Morris water maze test, all of these are significantly reduced by FPS-ZM1 treatment. Our results suggest that the AGEs-RAGE pathway is responsible for cognitive deficits, and therefore may be a potential treatment target. FPS-ZM1 might be a novel therapeutic agent to treat AD patients.

The effects of hydroalcoholic extract of Nigella sativa seed on oxidative stress in hippocampus of STZ-induced diabetic rats.

Oxidative stress plays an important role in the etiology of diabetic complications. Diabetes impairs hippocampus neurogenesis, synaptic plasticity, and learning. The aim of this study was to investigate the effects of hydroalcoholic extract of Nigella sativa seed on oxidative stress in STZ-induced diabetic rats' hippocampus. Diabetes induced by 60 mg/kg STZ, i.p, and the rats were divided into five experimental groups (n=8-10 in each group) including control (received 0.5 ml normal saline), untreated STZ-diabetic (received 0.5 ml normal saline), and treated rats received Nigella sativa extract (200 and 400 mg/kg) or metformin (300 mg/kg) by gavage for 42 days. Serum glucose concentration and body weight as well as hippocampus tissue malondialdehyde and thiol levels were determined by calorimetric assay. Serum glucose level in the diabetic rats treated with 200 mg/kg Nigella sativa extract at the days 24 and 45 decreased in comparison to untreated diabetic group (p<0.05, p<0.01, respectively). Weight loss was significantly different between metformin and Nigella sativa extract at the dose of 200 and 400 mg/kg (p<0.05). Thiol content of hippocampus increased by 200 mg/kg Nigella sativa extract in comparison to untreated diabetic group (p<0.05). Malondialdehyde content of hippocampus reduced by Nigella sativa extract, 200 mg/kg (p<0.001), 400 mg/kg (p<0.05), and metformin (p<0.05) in comparison to the untreated diabetic group. The results of the present study showed that hydroalcoholic extract of the Nigella sativa decreased oxidative stress in hippocampus of the STZ-induced diabetic rats. Nigella sativa at the dose of 200 mg/kg was more effective to reduce oxidative stress in hippocampus of rats.

Age-related dysfunctions of the autophagy lysosomal pathway in hippocampal pyramidal neurons under proteasome stress

Autophagy plays a key role in the maintenance of cellular homeostasis, and autophagy deregulation gives rise to severe disorders. Many of the signaling pathways regulating autophagy under stress conditions are still poorly understood. Using a model of proteasome stress in rat hippocampus, we have characterized the functional crosstalk between the ubiquitin proteasome system and the autophagy-lysosome pathway, identifying also age-related modifications in the crosstalk between both proteolytic systems. Under proteasome inhibition, both autophagy activation and resolution were efficiently induced in young but not in aged rats, leading to restoration of protein homeostasis only in young pyramidal neurons. Importantly, proteasome stress inhibited glycogen synthase kinase-3β in young but activated in aged rats. This age-related difference could be because of a dysfunction in the signaling pathway of the insulin growth factor-1 under stress situations. Present data highlight the potential role of glycogen synthase kinase-3β in the coordination of both proteolytic systems under stress situation, representing a key molecular target to sort out this deleterious effect.

Cinnamic aldehyde treatment alleviates chronic unexpected stress-induced depressive-like behaviors via targeting cyclooxygenase-2 in mid-aged rats

Ethnopharmacological relevanceCOX-2 has been considered as a potent molecular target for prevention and therapy of depression. However, a recent study showed that COX-2 inhibitor does not improve depressive symptoms in persons aged 70 and over. Therefore, whether treatments targeting COX-2 have a clinical efficacy in depression, especially elderly individuals, remains unclear. Cinnamic aldehyde is a major constituent of Cinnamomum cassia, which has exhibited excellent anti-inflammatory activities as a COX-2 inhibitor. To investigate the potential antidepressant effect of cinnamic aldehyde in mid-aged rats. Materials and methodsThe depressive-like behaviors were measured after the rats exposed to chronic unexpected mild stress (CUMS). Cinnamic aldehyde was administrated by oral gavage to stressed rats (22.5, 45, 90mg/kg, respectively) for 21 days. The mRNA, protein expression and activity of cyclooxygenase-2 (COX-2), as well as prostaglandin E2 (PGE2) levels were measured in the frontal cortex and hippocampus of stressed animals. ResultsWe found that CUMS procedure not only decreased the sucrose preference, but also elevated the COX-2 activity, mRNA and protein levels, and increased PGE2 concentration in rat brain regions. Treatment with high doses of cinnamic aldehyde (45, 90mg/kg) reversed the behavioral abnormalities, and decreased the COX-2 protein and activity (but not COX-2 mRNA expression) and PGE2 concentration in frontal cortex and hippocampus of stressed rats. ConclusionCinnamic aldehyde exerted antidepressant-like effects in stressed mid-aged rats, and its mechanism of action appears to decrease COX-2 protein and activity. The current findings suggest that targeting COX-2 system might be benefit to the depression, especially elderly individuals and cinnamic aldehyde might be a promising medicine to treat the subjects in the depression.