Ulcerative colitis is chronic and recurrent disease of the gastrointestinal tract with uncertain etiology and incomplete treatment options. N-methyl-d-aspartate (NMDA) receptor suppression has shown anti-inflammatory effects in-vitro and in-vivo. The aim of present study was to evaluate the role of dizocilpine (MK-801), a noncompetitive NMDA receptor antagonist, on TNBS (trinitrobenzene sulfonic acid)-induced murine model of colitis. Dizocilpine (0. 1, 1 and 5 mg/kg) was given to mice intraperitoneally from 24 h before induction of colitis and daily thereafter for 4 days. Dexamethasone (1 mg/kg) was used as the reference drug. Colitis was induced by intracolonic administration of TNBS/Ethanol (50/50 v/v, 40mg/kg). Animals were sacrificed 5 days after colitis induction and distal colons were examined macroscopically and microscopically. The colonic tissue level of pro-inflammatory cytokines including interleukin 1β (IL-1β ), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α ) were assessed by ELISA. Myeloperoxidase (MPO) level was also measured in colon. Dizocilpine, particularly with intermediate dose of 1mg/kg significantly improved animal’ s weight loss as well as macroscopic and microscopic signs of colitis, reduced colonic levels of IL-1β , IL-6, TNF-α and MPO activity. Hence, dizocilpine has significant protective effects in TNBS-induced colitis and NMDA suppression may be a new and effective therapeutic strategy in ulcerative colitis via decreasing in pro-inflammatory cytokine production.

Introduction: Exploratory behaviors in rodents are an indicator of anxiety behaviors. In the present study, the combined effect of aerobic exercise with different intensities and inhibition of the glutamate system on exploratory behavior in rats was investigated. Materials and Methods: In this experimental study, 80 male Wistar rats were randomly divided into 10 groups including control, diazepam (0. 6 mg/kg), two doses of MK-801 (0. 1 and 0. 05 mg/kg), two groups of acute aerobic exercise (low and moderate intensity), two acute aerobic exercise groups (low and moderate intensity) + dose 0. 1 MK801, the two groups performing acute aerobic exercise (low and moderate intensity) + dose 0. 05 MK-801. On the test day, immediately after exerciseو drugs were injected, and 30 minutes later, exploratory behaviors were assessed by an open field. Results: Low and moderate-intensity exercise with MK-801 at a dose of 0. 05 mg/kg significantly increased the frequency of rearing and decreased the number of grooming, and frequency of defecation compared to control and MK-801 groups (P<0. 01, P<0. 01 and P<0. 05, respectively). In addition, performing low and medium intensity exercise with MK-801 at a dose of 0. 1 mg/kg significantly increased the number of rearing and decreased the number of grooming, and frequency of defecation compared to control and MK-801 groups (P<0. 001, P<0. 001 and P<0. 05, respectively). Conclusion: The results of the present study suggest that the use of exercise in combination with NMDA inhibition can be effective on anxiety-induced exploratory behaviors in animals.

Purpose: Memantine is an approved drug for the treatment of Alzheimer’ s disease (AD). Autophagy, lysosome dysfunction, and sigma receptors have possible roles in the pathophysiology of AD. Therefore, we aimed to investigate the contribution of sigma receptors and lysosome inhibition to the neuroprotective effects of memantine against amyloid-beta (Aβ )-induced neurotoxicity in SH-SY5Y cells. Methods: We determined the neuroprotective effects of memantine (2. 5 μ M), dizocilpine (MK801, as a selective N-methyl-D-aspartate (NMDA) receptor antagonist) (5 μ M) against Aβ 25– 35 (2 μ g/μ L)-induced neurotoxicity. We used chloroquine (10, 20, and 40 μ M) as a lysosome inhibitor and BD-1063 (1, 10, and 30 μ M) as a selective sigma receptor antagonist. The MTT assay was used to measure the neurotoxicity in the SH-SY5Y cells. Data were analyzed using the one-way ANOVA. Results: Memantine (2. 5 μ M), dizocilpine (5 μ M), chloroquine (10 and 20 μ M) and BD-1063 (1, 10 and 30 μ M) decreased the neurotoxic effects of Aβ on the SH-SY5Y cells. However, chloroquine (40 μ M) increased the neurotoxic effects of Aβ . Cell viability in the cells treated with memantine + Aβ + chloroquine (10, 20, and 40 μ M) was significantly lower than the memantine + Aβ-treated group. Moreover, cell viability in the memantine + Aβ group was higher than the memantine + Aβ + BD-1063 (10 and 30 μ M) groups. Conclusion: The lysosomal and sigma receptors may contribute to the neuroprotective mechanism of memantine and other NMDA receptor antagonists. Moreover, the restoration of lysosomes function and the modulation of sigma receptors are potential targets in the treatment of AD.

Introduction: We previously reported that datumetine possesses binding affinity with N-methyl-D-aspartate receptor (NMDAR) and that 14-day exposure to datumetine altered NMDAR signaling by mimicking glutamate toxicity. Here, we investigated the potential neuroprotective effect of a single shot of a low dose of datumetine administration in BALB/c mice. Methods: 30 male adult BALB/c mice were used for the study. The mice were randomly divided into three groups of ten mice each with an intraperitoneal injection of 0. 1 mL of 10% DMSO for the Vehicle group, Datumetine group were administered 0. 1 mg/kg body weight (bw) of datumetine and MK-801+Datumetine group were administered 0. 5 mg/kg bw of MK-801 (to block NMDAR) followed by 0. 1 mg/kg bw of datumetine after 30 minutes. 24 hours after administration, mice were euthanized in an isoflurane chamber followed by perfusion with 1X PBS. Brains were excised and stored at-200C till further processing. Mice designated for IHC were further perfused with 4% PFA and brain excised and stored in 4% PFA till further processing. NMDAR signalling molecules expression was evaluated in frozen brain samples and the fixed brain samples were stained for neuron, vGlut and NMDAR subtypes. Results: Relative to vehicle (Veh), datumetine downregulate calcium calmodulin kinase II alpha (CamKIIα, ) expression in the hippocampus and prefrontal cortex (PFC) but not in the cerebellum, cyclic AMP response element binding protein (CREB) was also upregulated only in the PFC but phosphorylated CREB (pCREB) was also upregulated in three brain regions observed, while brain-derived neurotrophic factor (BDNF) was only upregulated in hippocampus and PFC of Datumetine relative to vehicle (Veh). On the other hand, dizocilpine (MK-801) reversed some of the effects of datumetine in the observed brain regions. No major histological alterations were observed in the different brain regions immunohistochemically. Conclusion: We conclude that a low dose of datumetine moderately enhances NMDAR activity. This showed the neuroprotective potentials of low datumetine exposure.

Food intake is the primary factor for body weight regulation in animals. Eating behavior is known to be modulated by various neurotransmitters and receptors. The central nucleus of the amygdala (CeA) is the forebrain structures which are important in regulation of ingestive behavior. There is direct and circumstantial evidence to indicate that some circuits involved with feeding behavior include glutamatergic elements. The present study examined whether administration of NMA or MK801 in the CeA alters food intake under deprivation. Animals were deprived for 24 h before tested for food intake. NMDA glutamatergic receptor agonist, NMA (N-Methyl-DL-aspartic acid) and its antagonist, MK801 (Dizocilpine hydrogen maleate) were infused bilaterally, and food intakes were measured for 12 h post-injection.The intra-CeA injection of NMDA glutamatergic agonist NMA (0.25, 0.5 and 0.75 mg/rat) showed no effect on cumulative food intake. However, administration of NMDA glutamatergic antagonist, MK801 (0.25, 0.5 and 1 mg/rat) increased food intake in the deprived rats. The finding suggest that NMDA receptors in the CeA are responsible for the glutamatergic modulation of feeding in this nucleus.

Ketamine and its combinations with valproate and carbamazepine are ineffective against convulsions induced by atropine treatment and food intake in fasted miceObjective(s): Fasted rodents treated with antimuscarinics develop convulsions after refeeding. Food deprivation for 48 hr produces changes in [3H]glutamate binding suggesting glutamatergic contribution to the underlying mechanism of the seizures that are somewhat unresponsive to antiepileptics. Studies in animals and epileptic patients yielded considerable information regarding the anticonvulsant effect of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. Thus, this study evaluated the efficacy of ketamine and its combinations with valproate and carbamazepine on convulsions in fasted animals. Materials and Methods: Following 24 hr of fasting, mice were given saline, 5 or 10 mg/kg ketamine, 250 mg/kg sodium valproate, 24 mg/kg carbamazepine, 5 mg/kg ketamine+sodium valproate, or 5 mg/kg ketamine+carbamazepine and then were treated with saline or 2. 4 mg/kg atropine (5-9 mice per group). The animals were observed for the occurrence of convulsions after being allowed to eat ad libitum. Results: Ketamine, valproate and carbamazepine pretreatments were ineffective in preventing the convulsions developed after atropine treatment and food intake in fasted animals. The incidence of convulsions was significantly higher in 5 and 10 mg/kg ketamine, carbamazepine, and carbamazepine+ketamine groups, but not in the valproate and valproate+ketamine treated animals. Conclusion: In contrast to previous findings obtained with the NMDA antagonist dizocilpine (MK-801), ketamine lacks activity against convulsions developed after fasting. The drug does not enhance the efficacy of valproate and carbamazepine either. Using different doses of ketamine or other NMDA antagonists, further studies may better clarify the anticonvulsant effect of ketamine and/or role of glutamate in these seizures.