Neuroprotective effect of flurbiprofen in focal cerebral ischemia: the possible role of ASIC1a.
The intracellular calcium overload resulting from glutamate excitotoxicity is considered major determinant for neuronal loss during cerebral ischemia. Moreover, acidosis mediated ASIC1a activation has also shown to promote intracellular calcium overload following ischemic insult. Interestingly, ASIC1a was found to be inhibited by NSAIDs particularly flurbiprofen and ibuprofen, which could be exploited in hypoxic conditions like cerebral ischemia. This prompted us to investigate neuroprotective effect of flurbiprofen, besides its possible downstream signaling mechanism in rodent model of focal cerebral ischemia. The flurbiprofen treatment, 30 min prior to ischemia and 4 h post-reperfusion, afforded significant neuroprotection from ischemic injury as evidenced by reduction in cerebral infarct volume and neurobehavioral deficit. Further, an early calcium dependent rise in levels of nitrite and MDA was also found to be significantly (P < 0.01) reduced in ischemic brain regions following flurbiprofen pretreatment. It also reduced the proteolytic products (SBDPs) caused by ischemic activation of calcium dependent protease calpain. In addition, the ex-vivo studies with flurbiprofen in rat brain synaptoneurosomes inhibited the acid mediated rise in intracellular calcium levels. These studies thus provide neuroprotective profile of flurbiprofen in focal cerebral ischemia with its selective effect on ASIC1a.
Mishra
Vikas
V
Division of Pharmacology, Central Drug Research Institute (CSIR), P.O. Box 173, Lucknow 226001, U.P., India.
Verma
Rajkumar
R
Raghubir
Ram
R
D062565:Acid Sensing Ion Channels; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020520:Brain Infarction / Q000473:pathology / Q000517:prevention & control; D002118:Calcium / Q000378:metabolism; D005480:Flurbiprofen / Q000494:pharmacology* / Q000627:therapeutic use; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015222:Sodium Channels / Q000502:physiology*; D013049:Spectrin / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism
D062565:Acid Sensing Ion Channels; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009573:Nitrites; D015222:Sodium Channels; D013049:Spectrin; D008315:Malondialdehyde; D005480:Flurbiprofen; D002118:Calcium