Aminoguanidine inhibits caspase‐3 and calpain activation without affecting microglial activation following neonatal transient cerebral ischemia

• Published in: Journal of neurochemistry Vol. 96; no. 5; pp. 1467 - 1479
• Main Authors: Dingman, Andra, Lee, Sarah Y., Derugin, Nikita, Wendland, Michael F., Vexler, Zinaida S.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-03-2006; Blackwell
• Subjects: Ageing, cell death; aminoguanidine; Animals; Animals, Newborn; Biological and medical sciences; Blotting, Western - methods; Brain; Calpain - metabolism; Caspase 3; Caspases - metabolism; Cell Count - methods; Cell Death - drug effects; Cell physiology; Cells; Disease Models, Animal; DNA-Binding Proteins - metabolism; Drosophila Proteins - metabolism; Ectodysplasins; Enzyme Activation - drug effects; Enzyme Inhibitors - administration & dosage; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Guanidines - administration & dosage; Immunohistochemistry - methods; Inhibitor drugs; Injuries; Ischemic Attack, Transient - drug therapy; Male; Medical sciences; Membrane Proteins - metabolism; microglia; Microglia - drug effects; Molecular and cellular biology; neonatal; Neurology; Nitric oxide; Nitric Oxide Synthase Type II - metabolism; Pregnancy; Rats; Rats, Sprague-Dawley; Reperfusion - methods; stroke; Time Factors; Tumor Necrosis Factors - metabolism; Vascular diseases and vascular malformations of the nervous system; Neonatal; Rat; Cysteine endopeptidases; Neuroglia; Central nervous system; Cardiovascular disease; Activation; aminoguanidine; Cerebral artery; Encephalon; Ischemia; Diffusion; microglia; Enzyme; Rodentia; Caspase; Calpain; stroke; Nitric-oxide synthase; Peptidases; Vertebrata; Mammalia; Hydrolases; Models; Oxidoreductases; Artery occlusion; Macrophage
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2006.03672.x

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.