Aminoguanidine inhibits caspase-3 and calpain activation without affecting microglial activation following neonatal transient cerebral ischemia.
Microglial cells, the resident macrophages of the CNS, can be both beneficial and detrimental to the brain. These cells play a central role as mediators of neuroinflammation associated with many neurodegenerative states, including cerebral ischemia. Because microglial cells are both a major source of inducible nitric oxide synthase (iNOS)/nitric oxide (NO) production locally in the injured brain and are activated by NO-mediated injury, we tested whether iNOS inhibition reduces microglial activation and ischemic injury in a neonatal focal ischemia-reperfusion model. Post-natal day 7 rats were subjected to a 2 h transient middle cerebral artery (MCA) occlusion. Pups with confirmed injury on diffusion-weighted magnetic resonance imaging (MRI) during occlusion were administered 300 mg/kg/dose aminoguanidine (AG) or vehicle at 0, 4 and 18 h after reperfusion, and animals were killed at 24 or 72 h post-reperfusion. The effect of AG on microglial activation as judged by the acquisition of ED1 immunoreactivity and proliferation of ED1-positive cells, on activation of cell death pathways and on injury volume, was determined. The study shows that while AG attenuates caspase 3 and calpain activation in the injured tissue, treatment does not affect the rapidly occurring activation and proliferation of microglia following transient MCA occlusion in the immature rat, or reduce injury size.
Dingman
Andra
A
Department of Neurology, University of California San Francisco, California 94143-0663, USA.
Lee
Sarah Y
SY
Derugin
Nikita
N
Wendland
Michael F
MF
Vexler
Zinaida S
ZS
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D002154:Calpain / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000378:metabolism; D053331:Ectodysplasins; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006146:Guanidines / Q000008:administration & dosage*; D007150:Immunohistochemistry / Q000379:methods; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion / Q000379:methods; D013997:Time Factors; D048069:Tumor Necrosis Factors / Q000378:metabolism
C109219:Brd protein, Drosophila; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D053331:Ectodysplasins; D004791:Enzyme Inhibitors; D006146:Guanidines; D008565:Membrane Proteins; D048069:Tumor Necrosis Factors; D052247:Nitric Oxide Synthase Type II; D002154:Calpain; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C004479:pimagedine