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

Anticonvulsant effect of minocycline on pentylenetetrazole-induced seizure in mice: involvement of nitric oxide and N-methyl-D-aspartate receptor

Anticonvulsant effects of minocycline have been explored recently. This study was designed to examine the anticonvulsant effect of acute administration of minocycline on pentylenetetrazole-induced seizures in mouse considering the possible role of the nitric oxide/N-methyl-D-aspartate (NMDA) pathway. We induced seizure using intravenous administration of pentylenetetrazole. Our results showed that acute administration of minocycline increased the seizure threshold. Furthermore, co-administration of subeffective doses of the nonselective nitric oxide synthase (NOS) inhibitor NG-L-arginine methyl ester (10 mg/kg) and the neuronal NOS inhibitor 7-nitroindazole (40 mg/kg) enhanced the anticonvulsant effect of subeffective doses of minocycline (40 mg/kg). We found that inducible NOS inhibitor aminoguanidine (100 mg/kg) had no effect on the antiseizure effect of minocycline. Moreover, L-arginine (60 mg/kg), as a NOS substrate, reduced the anticonvulsant effect of minocycline. We also demonstrated that pretreatment with the NMDAreceptor antagonists ketamine (0.5 mg/kg) and MK-801 (0.05 mg/kg) increased the anticonvulsant effect of subeffective doses of minocycline. Results showed that minocycline significantly decreased the hippocampal nitrite level. Furthermore, co-administration of a neuronal NOS inhibitor like NMDA receptor antagonists augmented the effect of minocycline on the hippocampal nitrite level. In conclusion, we revealed that anticonvulsant effect of minocycline might be, at least in part, due to a decline in constitutive hippocampal nitric oxide activity as well as inhibition of NMDA receptors

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

Radiological and histological comparison between nano-bioglass and commercial bioglass in bone healing in a rabbit model

Fracture healing is a complex physiological process. It involves the coordination of several different types of cells, proteins, and expression of various genes. Bone healing is very essential for fracture management, malfusion, osteomyelitis, removal of bone tumors, joint attachment, and also in joint prothesis. Diverse synthetic and biological grafts are used in bone healing. In this study, we evaluated and compared the effects of nano-bioglass and commercial bioglass on healing of experimental tibial defects in ten white New Zealand rabbits. Three round holes were created in tibial bone with orthopedic drill. One of the hole was left empty as control while the other two holes were filled by experimental grafts. Radiografts were taken after 2 and 6 weeks whereas pathological slides were prepared only after 6 weeks. Radiological and histological evaluation was performed blindly, and the results score were analyzed statistically. The data showed that nano-bioglass is superior to commercial bioglass in bone healing whereas commercial bioglass is better than control

Ferulic acid through mitigation of NMDA receptor pathway exerts anxiolytic-like effect in mouse model of maternal separation stress

Experiencing early-life stress plays an important role in the pathophysiology of anxiety disorders. Ferulic acid is a phenolic compound found in some plants which has several pharmacological properties. N-methyl-D-aspartate (NMDA) receptors are involved in the pathophysiology of mood disorders. In this study we aimed to assess the anxiolytic-like effect of ferulic acid in a mouse model of maternal separation (MS) stress by focusing on the possible involvement of NMDA receptors. Mice were treated with ferulic acid (5 and 40 mg/kg) alone and in combination with NMDA receptor agonist/antagonist. Valid behavioral tests were performed, including open field test (OFT) and elevated plus maze test (EPM), while quantitative real time polymerase chain reaction (qRT-PCR) was used to evaluate gene expression of NMDA subunits (GluN2A and GluN2B) in the hippocampus. Findings showed that treatment of MS mice with ferulic acid increased the time spent in the central zone of the OFT and increased both open arm time and the percent of open arm entries in the EPM. Ferulic acid reduced the expression of NMDA receptor subunit genes. We showed that administration of NMDA receptor agonist (NMDA) and antagonist (ketamine) exerted anxiogenic and anxiolytic-like effects, correspondingly. Results showed that co-administration of a sub-effective dose of ferulic acid plus ketamine potentiated the anxiolytic-like effect of ferulic acid. Furthermore, co-administration of an effective dose of ferulic acid plus NMDA receptor agonist (NMDA) attenuated the anxiolytic-like effect of ferulic acid. In deduction, our findings showed that NMDA, partially at least, is involved in the anxiolytic-like effect of ferulic acid in the OFT and EPM tests

Ferulic acid through mitigation of NMDA receptor pathway exerts anxiolytic-like effect in mouse model of maternal separation stress

Background Experiencing early-life stress plays an important role in the pathophysiology of anxiety disorders. Ferulic acid is a phenolic compound found in some plants which has several pharmacological properties. N-methyl-D-aspartate (NMDA) receptors are involved in the pathophysiology of mood disorders. In this study we aimed to assess the anxiolytic-like effect of ferulic acid in a mouse model of maternal separation (MS) stress by focusing on the possible involvement of NMDA receptors. Methods Mice were treated with ferulic acid (5 and 40 mg/kg) alone and in combination with NMDA receptor agonist/antagonist. Valid behavioral tests were performed, including open field test (OFT) and elevated plus maze test (EPM), while quantitative real time polymerase chain reaction (qRT-PCR) was used to evaluate gene expression of NMDA subunits (GluN2A and GluN2B) in the hippocampus. Results Findings showed that treatment of MS mice with ferulic acid increased the time spent in the central zone of the OFT and increased both open arm time and the percent of open arm entries in the EPM. Ferulic acid reduced the expression of NMDA receptor subunit genes. We showed that administration of NMDA receptor agonist (NMDA) and antagonist (ketamine) exerted anxiogenic and anxiolytic-like effects, correspondingly. Results showed that co-administration of a sub-effective dose of ferulic acid plus ketamine potentiated the anxiolytic-like effect of ferulic acid. Furthermore, co-administration of an effective dose of ferulic acid plus NMDA receptor agonist (NMDA) attenuated the anxiolytic-like effect of ferulic acid. Conclusions In deduction, our findings showed that NMDA, partially at least, is involved in the anxiolytic-like effect of ferulic acid in the OFT and EPM tests. Keywords: NMDA; anxiety; ferulic acid; maternal separation stress; mice

Adenylyl Cyclase (AC) Mediates the Antidepressant-Like Effects of Tropisetron on a Mouse Model of Maternal Separation Stress

The adenylyl cyclase (AC) pathway is involved in the pathophysiology of depression. Finding new antidepressants with high medicinal properties and low side effects is warranted. Therefore, this study was designed to determine the antidepressant-like effect of tropisetron on a maternal separation (MS) model in mice, considering the possible role of AC. NMRI male mice were divided into eleven groups. The control group was treated with saline and MS groups were treated with saline, tropisetron (a 5-HT3 receptor antagonist) at doses of 1, 3, and 5 mg/kg; forskolin (an activator of AC) at doses of 5, 10, and 25 mg/kg; a subeffective dose of forskolin with a subeffective dose of tropisetron; and an effective dose of tropisetron plus an effective dose of NB001 (3 mg/kg) (an AC inhibitor). After treatment, animals were subjected to behavioral tests including the forced swimming test (FST), splash test, and open field test (OFT). We showed that MS caused depressive-like behaviors determined as an increase in the immobility time in the forced swimming test (FST) and decreased grooming time in the splash test. Our results showed that administration of tropisetron, as well as forskolin, mitigated the depressive-like behaviors in MS mice. We found that coadministration of a subeffective dose of tropisetron plus a subeffective dose of forskolin potentiated the antidepressant-like effect of tropisetron. However, coadministration of an effective dose of NB001 with an effective dose of tropisetron did not significantly affect the antidepressant-like effect of tropisetron. We concluded that the antidepressant-like effects of tropisetron on MS mice are partially mediated through the adenylyl cyclase pathway

On the role of corticosterone in behavioral disorders, microbiota composition alteration and neuroimmune response in adult male mice subjected to maternal separation stress

Experiencing psychosocial adversities in early life such as maternal separation (MS) increases the risk of psychiatric disorders. Immune-inflammatory responses have imperative roles in the pathophysiology of psychiatric disorders. MS relatively changes the composition of intestinal microbiota leading to an overactivation of the hypothalamic–pituitary–adrenal (HPA) axis, and subsequently increases the corticosterone level. In this study, we aimed to evaluate the role of corticosterone in behavioral changes and microbiota modifications in a mouse model of MS afflicted neuroinflammatory response in the hippocampus. For this purpose, 180 min of MS stress was applied to mice at postnatal day (PND) 2–14 followed by behavioral tests including forced swimming test (FST), splash test, open field test (OFT) and elevated plus maze (EPM) at PND 50–52. For evaluating the role of corticosterone, mice were subjected to adrenalectomy. Using real-time RT-PCR, the expression of inflammatory genes was determined in the hippocampus and colon tissues. We found that MS provoked depressive- and anxiety-like behaviors in adult male mice. In addition, MS was able to active a neuroimmune response in the hippocampus, motivate inflammation and histopathologic changes in the colon tissue and modify the composition of gut microbiota as well. Interestingly, our findings showed that adrenalectomy (decline in the corticosterone level), could modulate the above-mentioned negative effects of MS. In conclusion, our results demonstrated that overactivation of HPA axis and the subsequent increased level of corticosterone could act, possibly, as the deleterious effects of MS on behavior, microbiota composition changes and activation of neuroimmune response