期刊
NEUROPHARMACOLOGY
卷 79, 期 -, 页码 249-261出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2013.11.022
关键词
Angiotensin II AT(1) Receptor Blockers; Telmisartan; PPAR gamma; Neuroprotection; Glutamate neurotoxicity; Apoptosis
资金
- Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department Of Health and Human Services, USA [MH 002762-16]
- Natural Science Foundation of Jiangsu Province, P.R.China [BK 20130653]
- Fundamental Research Funds for the Central Universities, P.R.China [JKZD 2013006]
- China Pharmaceutical University
Sartans (Angiotensin II AT(1) Receptor Blockers, ARBs) are powerful neuroprotective agents in vivo and protect against IL-1 beta neurotoxicity in vitro. The purpose of this research was to determine the extent of sartan neuroprotection against glutamate excitotoxicity, a common cause of neuronal injury and apoptosis. The results show that sartans are neuroprotective, significantly reducing glutamate-induced neuronal injury and apoptosis in cultured rat primary cerebellar granule cells (CGCs). Telmisartan was the most potent sartan studied, with an order of potency telmisartan > candesartan > losartan > valsartan. Mechanisms involved reduction of pro-apoptotic caspase-3 activation, protection of the survival PI3K/Akt/GSK-3 beta pathway and prevention of glutamate-induced ERK1/2 activation. NMDA receptor stimulation was essential for glutamate-induced cell injury and apoptosis. Participation of AT(1A) receptor was supported by glutamate-induced upregulation of AT(1A) gene expression and AT(1) receptor binding. Conversely, AT(1B) or AT(2) receptors played no role. Glutamate-induced neuronal injury and the neuroprotective effect of telmisartan were decreased, but not abolished, in CGCs obtained from AT(1A), knock-out mice. This indicates that although AT(1) receptors are necessary for glutamate to exert its full neurotoxic potential, part of the neuroprotective effect of telmisartan is independent of AT(1) receptor blockade. PPAR gamma activation was also involved in the neuroprotective effects of telmisartan, as telmisartan enhanced PPAR gamma nuclear translocation and the PPAR gamma antagonist GW9662 partially reversed the neuroprotective effects of telmisartan. The present results substantiate the therapeutic use of sartans, in particular telmisartan, in neurodegenerative diseases and traumatic brain disorders where glutamate neurotoxicity plays a significant role. Published by Elsevier Ltd.
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