Neuroprotective actions of aminoguanidine involve reduced the activation of calpain and caspase-3 in a rat model of stroke.
Two intracellular cysteine proteases (calpains and caspases) and inducible nitric oxide synthase (iNOS) participate in the ischemic brain injury. In vitro nitric oxide (NO) regulates calpain and caspase-3 activation. The present study investigated whether aminoguanidine (AG), an iNOS inhibitor, protected brain against experimental stroke through inhibiting calpain and caspase-3 activation. Rats received 1h ischemia by intraluminal filament, then, reperfused for 23 h (R 23 h). AG (100 mg/kg) was administered intraperitoneally 5 min before ischemia. Our data showed that treatment with AG markedly improved neurological deficit, reduced brain swelling, decreased infarct volume, and attenuated the necrotic cell death in ischemic penumbra and core, and apoptotic cell death in penumbra at R 23 h. Enzymatic studies demonstrated the significant inhibition of the activities of mu- and m-calpain and caspase-3, and Western blot analysis revealed marked increases in the levels of MAP-2 and spectrin in penumbra and core in AG-treated rats versus vehicle-treated rats. AG also significantly enhanced the calpastatin levels in core, although it had no significant effects on that in penumbra. These data demonstrate that inhibiting calpain and caspase-3 activation is one mechanism of AG against experimental stroke, suggesting that NO produced by iNOS may be involved in calpain- and caspase-3-mediated ischemic cell death, at least in part.
Sun
Ming
M
Department of Neurochemistry, Beijing Neurosurgical Institute, Chongwen District, Beijing 100050, China.
Zhao
Yumei
Y
Gu
Yi
Y
Xu
Chao
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001711:Biotransformation / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology / Q000473:pathology; D001929:Brain Edema / Q000473:pathology / Q000517:prevention & control; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002154:Calpain / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism*; D002544:Cerebral Infarction / Q000473:pathology / Q000517:prevention & control; D003600:Cytosol / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D018696:Neuroprotective Agents; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D013049:Spectrin / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*
D002135:Calcium-Binding Proteins; D006146:Guanidines; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D013049:Spectrin; C033668:calpastatin; D002154:Calpain; D053148:Caspase 3; C004479:pimagedine