Showing papers by "Nima Naderi published in 2015"

Anticonvulsant activity of 1,2,4-triazine derivatives with pyridyl side chain: synthesis, biological, and computational study

Abstract: A series of 5,6-bisaryl-1,2,4-triazine-3-thiol-substituted derivatives were synthesized by condensation of 1,2-diketones and thiosemicarbazide under microwave irradiations and subsequent alkylation of thiol group by chloromethylpyridinium chloride. Evaluation of anticonvulsant activity of compounds was performed by maximal electroshock and pentylenetetrazole-induced seizures tests. In order to evaluate their neuroprotective potential, the ability of compounds to inhibit soybean 15-lipoxygenase was also assessed. Further molecular modeling and docking study on Na+ channel and GABAA receptor was performed to elucidate their mechanisms of action and necessary interactions in the active site. Compounds 2c and 2d with bis(4-bromophenyl) and pyridyl substituents showed highest protection up to 70 and 80 % in PTZ and MES-induced seizures, respectively, compared to the control group. Molecular docking study revealed their possible antiseizure mechanism of action through GABAA receptor, and in silico assessment of their BBB permeability indicated them as CNS active agents.

Preventing effect of L-type calcium channel blockade on electrophysiological alterations in dentate gyrus granule cells induced by entorhinal amyloid pathology.

Abstract: The entorhinal cortex (EC) is one of the earliest affected brain regions in Alzheimer’s disease (AD). EC-amyloid pathology induces synaptic failure in the dentate gyrus (DG) with resultant behavioral impairment, but there is little known about its impact on neuronal properties in the DG. It is believed that calcium dyshomeostasis plays a pivotal role in the etiology of AD. Here, the effect of the EC amyloid pathogenesis on cellular properties of DG granule cells and also possible neuroprotective role of L-type calcium channel blockers (CCBs), nimodipine and isradipine, were investigated. The amyloid beta (Aβ) 1–42 was injected bilaterally into the EC of male rats and one week later, electrophysiological properties of DG granule cells were assessed. Voltage clamp recording revealed appearance of giant sIPSC in combination with a decrease in sEPSC frequency which was partially reversed by CCBs in granule cells from Aβ treated rats. EC amyloid pathogenesis induced a significant reduction of input resistance (Rin) accompanied by a profound decreased excitability in the DG granule cells. However, daily administration of CCBs, isradipine or nimodipine (i.c.v. for 6 days), almost preserved the normal excitability against Aβ. In conclusion, lower tendency to fire AP along with reduced Rin suggest that DG granule cells might undergo an alteration in the membrane ion channel activities which finally lead to the behavioral deficits observed in animal models and patients with early-stage Alzheimer’s disease.

Interaction between Cannabinoid Compounds and Capsazepine in Protection against Acute Pentylenetetrazole-induced Seizure in Mice.

Abstract: The pharmacological interaction between cannabinoidergic system and vanilloid type 1 (TRPV1) channels has been investigated in various conditions such as pain and anxiety. In some brain structure including hippocampus, CB1 and TRPV1 receptors coexist and their activation produces opposite effect on excitability of neurons. In this study, we tested the hypothesis that TRPV1 channel is involved in the modulation of cannabinoid effects on pentylenetetrazole (PTZ)-induced seizure threshold. In single therapy, male mice (n = 10 per group) received either TRPV1 receptor antagonist capsazepine, CB1 receptor agonist ACEA or anandamide reuptake inhibitor VDM11. In combination therapy, mice were treated with either capsazepine-ACEA or capsazepine-VDM11 combination prior to seizure test. Thirty min later, mice were submitted to infusion of PTZ (1%, 0.25 mL/min) into tail vein and the dose of PTZ to induce clonic convulsion was considered as seizure threshold. Administration of capsazepine and ACEA per se produced protective effects against PTZ-induced seizure, while administration of VDM11 per se did not produce such a protection effect. The anticonvulsant actions of both capsazepine and ACEA were attenuated after co-administration of these compounds. Moreover, the anticonvulsant action of capsazepine was attenuated after co-administration with VDM11. The results suggest an interaction between cannabinoidergic system and TRPV1 receptors in protection against acute PTZ-induced seizure in mice.

Repeated administration of cannabinoid receptor agonist and antagonist impairs short and long term plasticity of rat’s dentate gyrus in vivo

Abstract: Introduction: The effects of cannabinoids (CBs) on synaptic plasticity of hippocampal dentate gyrus neurons have been shown in numerous studies. However, the effect of repeated exposure to cannabinoids on hippocampal function is not fully understood. In this study, using field potential recording, we investigated the effect of repeated administration of the nonselective CB receptor agonist WIN55212-2, and the CB1 receptor antagonist AM251, on both short- and long-term synaptic plasticity in dentate gyrus (DG) of hippocampus. Materials and Methods: Drugs were administered three times daily for seven consecutive days into lateral ventricle of rats. Short term synaptic plasticity was assessed by measuring paired - pulse index (PPI) in DG neurons after stimulation of perforant pathway. Long-term plasticity was assessed through measurement of both population spike (PS) amplitude and field excitatory postsynaptic potential (fEPSP) slope after high frequency stimulation (HFS) of DG neurons. Results: Repeated administration of WIN55212-2 not only significantly decreased PPI in 20, 30 and 50 ms intervals but also blocked LTP. This effect was reversed by pretreatment of rats with CB1 receptor antagonist AM251. Moreover, AM251 by itself increased PPI in 10 and 20 ms interval stimulations, but had no effect on HFS-induced PS amplitude and fEPSP slope. Conclusion: These results suggest that repeated administration of cannabinoids could impair short term and long term synaptic plasticity that may be due to desensitization of cannabinoid receptors and/or changes in synaptic spine density of hippocampus which leads to alteration in short and long term memories that remains to be elucidated.