Cytoprotection of sumatriptan in glutamate induced neurotoxicity by targeting NO/cGMP and p-ERK signaling through inhibiting NMDA receptors in cerebellar granular neurons of rat

سال انتشار: 1398
نوع سند: مقاله کنفرانسی
زبان: انگلیسی
مشاهده: 319

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شناسه ملی سند علمی:

NSCMED08_378

تاریخ نمایه سازی: 15 دی 1398

چکیده مقاله:

Background and Aim : The glutamate induced neurotoxicity in cerebellar granular neurons (CGNs) is mediated through N-methyl-D-aspartate (NMDA) receptors hyperactivation. The activated glutamate receptors affect the functional activity and expression of nitric oxide (NO), cyclic guanylyl monophosphate (cGMP) and extracellular signal-regulated kinase (ERK) in CGNs. Cellular mechanisms underlying sumatriptan neuroprotection remained unexplored. Thus, we aimed to investigate the unique ability of sumatriptan to protect CGNs in primary cultures against glutamate toxicity and its underlying mechanisms.Methods : The neuroprotective effect of sumatriptan at different concentrations (0.01-20 μM) was assessed in CGNs treated with/without glutamate (100 μM), MK-801 (1 μM), 7-NI (50 μM) and MB (1 μM) using MTT and lactate dehydrogenase (LDH) assays. The quantitative measurement of nitrite levels, involved genes and proteins in different treatment doses and times was performed using NO assay, qRT-PCR studies and western blot analysis respectively to investigate the molecular mechanisms leading to sumatriptan neuroprotection in primary CGN cultures.Results : The results of cellular viability assays showed a significant glutamate induced reduction cellular viability (P<0.001). The acute treatment of CGN cultures with sumatriptan (5μM) for 30 mint with/without glutamate or inhibitors of NMDA/NO and cGMP pathway revealed a significant cytoprotective effect (P<0.001). The pretreatment of cells with sumatriptan significantly reversed (P<0.01) the glutamate induced higher NO levels in CGNs. Furthermore, pretreatment of CGNs with sumatriptan significantly down regulated the glutamate induced mRNA expression (P<0.001) of NR2B, nNOS, α2 and β1 genes and protein expression (P<0.001) of phosphorylated ERK in CGN cultures.Conclusion : In conclusion, the acute sumatriptan treatment significantly protects the primary CGN cultures from glutamate induced neurotoxicity through inhibiting NMDA mediated NO/cGMP activation and p-ERK pathway.

نویسندگان

Faiza Mumtaz

Experimental Medicine Research Center, Department of Pharmacology, School of Medicine,Tehran University of Medical Sciences, Tehran, Iran

Jamileh Esmaeli

Department of Biology,Science and research branch,Islamic Azad University Central Tehran Branch, Tehran, Iran

Muhammad Zubari

Key Laboratory of Integrated Management of Crop Diseases and Pests, College of Plant Protection, Nanjing Agriculture University, Nanjing, ۲۱۰۰۹۵, PR China