Diosmetin Mitigates Cognitive and Memory Impairment Provoked by Chronic Unpredictable Mild Stress in Mice

Background and Aim. Numerous reports have indicated that dealing with stressors in life is a main risk factor for the occurrence and progression of cognitive and memory impairment. Available treatments such as benzodiazepine and antidepressants address only certain aspects of this stress disorder and have numerous side effects. The present study was aimed at investigating the effect of diosmetin, as a flavonoid compound with potent antioxidant and anti-inflammatory effects, on cognitive impairment and chronic stress memory. Materials and Methods. In the present experimental study, male NMRI mice were exposed to chronic unpredictable mild stress (CUMS) paradigm for 35 days. Diosmetin (at doses of 10, 20, and 40 mg/kg. i.p.) or diosmetin solvent (normal saline + DMSO, 1 ml/kg; i.p.) was administered 30 min before stress induction. After 28 days, memory and cognitive performance were assessed by shuttle box and novel object recognition tests. Finally, antioxidant capacity (FRAP) and malondialdehyde (MDA) level of serum and brain, and serum corticosterone level were evaluated. Results. Behavioral tests showed that CUMS significantly reduced the secondary latency in passive avoidance memory test and diagnosis index in novel object recognition test compared to the control group (P<0.001), whereas treatment with diosmetin (20 and 40 mg/kg) significantly improved memory performance in the two tests (P<0.001). In addition, diosmetin (40 mg/kg) could pronouncedly suppress increase in serum corticosterone levels, reduction in antioxidant capacity, and production of excess MDA caused by CUMS compared to the control group (P<0.01, P<0.001, and P<0.001, respectively). Conclusion. Chronic stress can impair memory and cognition and treatment with diosmetin can partly improve this disorder in male mice by increasing the antioxidant capacity of brain tissue and serum and improving serum corticosterone levels

Late cardiac perconditioning by phenylephrine in an isolated rat heart model is mediated by mitochondrial potassium channels

The present study was designed to investigate the effect of early and late administration of phenylephrine during ischemia against regional ischemia–reperfusion injuries in an isolated rat heart model. All animals were randomly divided into experimental groups: (I) IR (Ischemic/ reperfusion): the hearts underwent 35 min of regional ischemia followed by 60 min of reperfusion; (II) 5HD-IR-0: the hearts were perfused for 5 min with 5HD (5-hydroxydecanoate, specific mKATP channel blocker, 100 µM) at the onset of regional ischemia; (III) 5HD-IR-20: the hearts were perfused for 5 min with 5HD 20 min after regional ischemia; (IV) PE-IR-10: the hearts were perfused for 5 min with phenylephrine 10 min after regional ischemia; (V) PE-IR-30: the hearts were perfused for 5 min with phenylephrine (100 µM) 30 min after regional ischemia; (VI) PE-5HD-IR-10 group: the hearts were perfused for 5 min with 5HD at the onset of regional ischemia after which phenylephrine was administrated as in group IV; and (VII) PE-5HD-IR-30: the hearts were perfused for 5 min with 5HD 20 min after the ischemia and then phenylephrine was administrated as in group V. The hemodynamic parameters were recorded throughout the experiment. Ischemia-induced arrhythmias, myocardial infarct size (IS), creatin kinase-MB isoenzyme (CK-MB), plasma lactate dehydrogenase (LDH) activities, and coronary blood flow (CBF) were measured in all animals. Perfusion of phenylephrine 30 min after the regional ischemia curtailed the myocardial infarct size, reduced CK-MB, and improved cardiac function and CBF. Administration of 5HD 30 min after the ischemia abolished cardioprotective effects of phenylephrine in the late phase. These results suggest the involvement of mKATP in the mechanism of phenylephrine-induced late preconditioning

The Role of the NMDA Receptor in the Anticonvulsant Effect of Ellagic Acid in Pentylenetetrazole-Induced Seizures in Male Mice

Background and Aim. Epilepsy is the most common neurological disorder after stroke. Ellagic acid (EA) has been shown to possess neuroprotective effects. The N-methyl-D-aspartate receptor (NMDA-R) is involved in the pathophysiology of seizure. We aimed to evaluate the possible involvement of NMDA-R in the anticonvulsant effect of EA in pentylenetetrazole- (PTZ-) induced seizures in male mice. Methods. In this experimental study, 64 mice were divided into 8 groups and received the following: normal saline; EA at doses of 6.25, 12.5, and 25 mg/kg; NMDA agonist at a dose of 75 mg/kg; NMDA antagonist (ketamine) at a dose of 0.5 mg/kg; an effective dose of EA plus NMDA agonist; and a subeffective dose of EA plus ketamine. We induced seizure using intravenous administration of PTZ. 60 minutes before induction of seizure, drugs were administrated. Duration lasts to seizure-induced was measured. Finally, the gene expression of NMDA receptor subunits (Nr2a and Nr2b) was assessed in the prefrontal cortex. Results. Results showed that EA increased the seizure threshold and decreased the expression of Nr2a and Nr2b. We determined that ketamine potentiated and NMDA attenuated the effects of subeffective and effective doses of EA. Conclusion. EA probably via attenuation of the NMDA-R pathway possesses an anticonvulsant effect in PTZ-induced seizure in mice

Evaluation of the anticonvulsant effect of carvacrol in Pentylenetetrazole (PTZ)-induced seizures in male mice: N-Methyl-D-Aspartic Acid receptor role

Background. Epilepsy is one of the most common neurological disorders after stroke. Due to the side effects and poor response of conventional anticonvulsant drugs, researchers have turned their attention to find new drugs. Carvacrol is a phenolic compound with neuroprotective, anti-inflammatory, antioxidant and anticonvulsant effects. The aim of the study was to investigate the anticonvulsant effects of carvacrol in PTZ-induced seizures in male mice and to investigate the role of N-Methyl-D- Aspartic Acid (NMDA) receptor. Methods. In the present experimental study, 90 mice were randomly divided into 9 groups (n=10). Drugs were injected intraperitoneally 30 minutes before PTZ injection. Then, seizure onset time, serum and brain antioxidant capacity (TAC) and malondialdehyde (MDA) and NMDA receptor gene expression in the hippocampus were examined. Results. Seizure onset time in the group received carvacrol (20 and 40 mg/kg) was significantly longer than the PTZ group (P<0.05). Treatment with carvacrol (20 and 40 mg/kg) significantly increased serum and brain antioxidant capacity and reduced serum and brain MDA compared to the PTZ group (at doses of 5, 10, 20 and 40 mg/kg). The expression of NR2A and NR2B subunits of hippocampal NMDA receptors in carvacrol-received mice was significantly lower than the PTZ group. Conclusion. Carvacrol has anticonvulsant effects, possibly by inhibiting oxidative stress and reducing the expression of subunits of NMDA receptor

Rutin via Increase in the CA3 Diameter of the Hippocampus Exerted Antidepressant-Like Effect in Mouse Model of Maternal Separation Stress: Possible Involvement of NMDA Receptors

Background and Aim. Rutin is a flavonol with neuroprotective activity. The aim of the present study is to investigate the role of the glutamatergic system in the antidepressant-like effect of rutin in a mouse model of maternal separation (MS) stress focusing on histological changes in the CA3 area of the hippocampus. Methods. Mouse neonates were exposed to MS paradigm 3 hours daily from postnatal days (PND) 2 to 14. The control and MS mice were divided separately into 16 groups (n=8) (8 groups for each set) including mice that received normal saline, mice that received rutin at doses of 10, 50, and 100 mg/kg, mice that received NMDA at a dose of 150 mg/kg, mice that received ketamine (NMDA antagonist) at a dose of 0.25 mg/kg, mice that received NMDA antagonist plus a subeffective dose of rutin, and mice that received NMDA plus an effective dose of rutin. Forced swimming test (FST) was performed. Afterwards, the hippocampus was evaluated in cases of histopathological changes as well as expression of NR2A and NR2B genes. Results. Rutin significantly reduced immobility time in the FST. The expression of NR2A and NR2B subunits of NMDA receptor in MS mice was significantly higher than that in the control group. Rutin significantly decreased the expression of NR2B and NR2A subunits in the hippocampus. The CA3 diameter and percentage of dark neurons in the hippocampus of MS mice significantly decreased and increased, respectively, which partially reversed following rutin administration. Conclusion. Rutin, partially, through a neuroprotective effect on the hippocampus exerted antidepressant-like effect. We concluded that NMDA receptors, at least in part, mediated the beneficial effect of rutin

Possible involvement of NMDA receptor in the anxiolytic-like effect of caffeic acid in mice model of maternal separation stress

Background and aim: Anxiety disorders are one of the most common psychiatric disorders worldwide. Common anti-anxiety medications are associated with several side effects. Caffeic acid (CA) is a phenolic compound with several pharmacological effects. The aim of this study was to investigate the anxiolytic-like effect of CA in maternally separated (MS) mice focusing on the possible involvement of the NMDA receptor. Materials and methods: In this study, we used the MS paradigm (as a valid animal model of anxiety) in male mice and examined their anxiety-like behavior in postnatal day (PND) 45. The animals were divided into 12 experimental groups. Mice treated with CA alone and in combination with the NMDA receptor agonist/antagonist and then using open field (OFT) and elevated plus maze (EPM) anxiety-like behavior was assessed. Finally, the expression of NMDA receptor subtypes was assessed in the hippocampus using RT-PCR. Results: Finding showed that CA exerted anxiolytic-like effects in the OFT and EPM tests. We showed that administration of effective dose of NMDA significantly reversed the anxiolytic-like effect of effective dose of CA and co-administration of ketamine (a NMDA receptor antagonist) significantly potentiated the effect of sub-effective dose of CA. Furthermore, ketamine enhanced the CA-reducing effect on NMDA receptors in the MS mice. Conclusion: Our finding demonstrated that, probably at least, NMDA receptors are involved in the anxiety-like properties of CA in MS mice. Keywords:Maternal separation; Mice; Anxiety; Caffeic acid; Neuroscience; Pharmaceutical science; Molecular biology; Developmental biolog

Possible involvement of l-arginine-nitric oxide pathway in the antidepressant activity of Auraptene in mice

Background: Depression is one of the most common mental illnesses worldwide. Nitric oxide (NO) is involved in the pathophysiology of depression. Auraptene (a coumarin derivative) has been shown to possess pharmacological effects on neurological diseases. Purpose: The present study aimed to investigate the possible role of the NO pathway in Auraptene antidepressant effects in male mice. Methods: Behavioral tests were used to assess depression-like behaviors. The mice received Auraptene at 10, 30, and 100 mg/kg, the combination of the sub-effective (ineffective) dose of Auraptene (10 mg/kg) and L-NAME, and the combination of the effective dose of Auraptene (30 mg/kg) and L-arginine. Finally, OFT, TST, FST, brain, serum MDA level, antioxidant capacity, hippocampus, and serum NO level were measured. Results: The data analysis showed that Auraptene (30 mg/kg) improved depression-like behaviors. Auraptene (30 mg/kg) also significantly reduced serum NO levels (P < 0.05) and significantly increased serum MDA (10 mg/kg, P < 0.05). Auraptene at 30 mg/kg also increased serum antioxidant capacity (P < 0.01). Co-administration of L-NAME and the sub-effective dose of Auraptene enhanced the effects of Auraptene. However, co-administration of the effective dose of Auraptene and L-arginine reduced the impacts of Auraptene. Conclusions: The results showed that Auraptene causes antidepressant effects in a dose-dependent manner and acts as a prooxidant at 100 mg/kg, and exacerbates oxidative stress. The antidepressant effects of this active molecule are exerted by reducing the NO level in the hippocampus and serum, increasing the antioxidant capacity, and reducing the MDA level in the serum

NMDA Receptor Mediates the Anticonvulsant Effect of Hydroalcoholic Extract of Artemisia persica in PTZ-Induced Seizure in Mice

It is necessary to seek more effective sources to design new drug against epilepsy. This study aimed to evaluate the effect of hydroalcoholic extract of Artemisia persica on pentylenetetrazole-(PTZ-) induced seizure in male mice by investigating the possible role of the NMDA receptor and antioxidative stress effect. The phenolic profile of A. persica extract was determined by HPLC-DAD analysis. Mice were treated with normal saline or A. persica extract or pentobarbital or a subeffective dose of extract plus ketamine (NMDA receptor antagonist) and/or effective dose of extract plus NMDA. PTZ (90 mg/kg) was injected intravenously for induction of seizure. The seizure threshold was measured. Then mice were euthanized and the antioxidant capacity and the level of malondialdehyde (MDA) of the prefrontal cortex and serum were measured. The gene expression of NMDA receptor subunits (Nr2a and Nr2b) was determined by real-Time PCR. Findings showed that A. persica extract increased the seizure threshold, increased antioxidant capacity, and decreased MDA levels in the serum and brain samples. A. persica extract reduced the expression of NMDA receptor subunits. The result showed that ketamine potentiated the effect of the subeffective dose of extract. HPLC analysis showed that quercetin had the highest flavonoid content and also caffeic acid had the highest content of the phenolic acids. A. persica extract probably via NMDA receptor exerts anticonvulsant properties

Diosgenin via NMDA Receptor Exerted Anxiolytic-like Effect in Maternally Separated Mice

Background and aim: Anxiety is one of the most common psychiatric disorders that lead to disruption of daily and quality of life. Routine medications have many side effects and cause physical dependence and psychosocial addiction. Diosgenin is a phytosteroid found in a number of herbs. The aim of present study was to investigate the anxiolytic-like effect of diosgenin in the maternal separation model in male mice focusing on the role of NMDA receptors. Material and methods: Maternal separation (MS) paradigm was performed daily (3 h) from postnatal day (PND) 2-14. Male mice were treated with different dose of diosgenin to find effective and sub-effective doses. In the next step, mice were treated with effective dose of diosgenin plus NMDA and or sub-effective dose of diosgenin plus ketamine (NMDA antagonist). Valid behavioral test for evaluation of anxiety-like behavior were performed. Then, mice were killed, hippocampus dissected out and gene expression of NMDA receptors (NR2a and NR2b subunits) was assessed. Results: MS provokes anxiety-like behaviors in the open field test (OFT) and elevated plus maze (EPM). Diosgenin significantly mitigated negative effects of MS. Co-administration of NMDA attenuated anxiolytic-like effect of effective dose of diosgenin while ketamine potentiated the anxiolytic effect of sub-effective dose of diosgenin. Furthermore, MS increased the expression of NMDA receptor in the hippocampus which to some extent modulated with diosgenin. Conclusion: Diosignin has anxiolytic-like effect in MS mice which at least, in part, mediated through NMDA receptors. Keywords: Anxiety; Diosignin; Maternal separation; NMDA receptor; mice

Diosgenin via NMDA Receptor Exerted Anxiolytic-like Effect on Maternally Separated Mice

Background and aim: Anxiety is one of the most common psychiatric disorders that lead to the disruption of daily life and also the quality of life. Routine medications have many side effects and cause physical dependence and psychosocial addiction. Diosgenin is a phytosteroid found in a number of herbs. The present study aimed to investigate the anxiolytic-like effect of diosgenin in the maternal separation model in male mice focusing on the role of NMDA receptors. Materials and Methods: Maternal separation (MS) paradigm was performed daily (3 h) from postnatal day (PND) 2-14. Male mice were treated with different doses of diosgenin to find effective and sub-effective doses. In the next step, mice were treated with an effective dose of diosgenin plus NMDA and or a sub-effective dose of diosgenin plus ketamine (NMDA antagonist). Valid behavioral tests for the evaluation of anxiety-like behavior were performed. Then, mice were euthanized, the hippocampus was dissected out and gene expression of NMDA receptors (NR2a and NR2b subunits) was assessed. Results: MS provokes anxiety-like behaviors in the open field test (OFT) and elevated plus maze (EPM) test. Diosgenin significantly mitigated the negative effects of MS. Co-administration of NMDA attenuated anxiolytic-like effect of the effective dose of diosgenin, while ketamine potentiated the anxiolytic effect of sub-effective dose of diosgenin. Furthermore, MS increased the expression of the NMDA receptor in the hippocampus which to some extent modulated with diosgenin. Conclusion: Diosignin has an anxiolytic-like effect on MS mice which at least, in part, mediated through NMDA receptors