title: Neuroprotective effect of aminoguanidine on transient focal ischaemia in the rat brain.
abstract: Using serial magnetic resonance imaging we have evaluated the effectiveness of aminoguanidine (AG) as a neuroprotective agent in a rat model of transient middle cerebral artery occlusion (MCAO). Because aminoguanidine's neuroprotective properties have primarily been ascribed to its action as iNOS inhibitor, we also performed a biochemical analysis of nitric oxide metabolites and NOS isoforms in our model of ischaemia. Daily injections of AG (100 mg/kg) or saline, were started at 6 h after the occlusion and the effects of this treatment on lesion progression monitored by T(2)-weighted MRI at 6 (pre-treatment scan), 24 and 72 h. Measurements of lesion volumes showed that between 6 and 72 h post-MCAO, lesion growth was slower in AG-treated rats than in control rats. This difference was most pronounced between 24 and 72 h post-MCAO when AG halted the lesion volume expansion observed in control rats. Measurements of plasma NOx (nitrite plus nitrate) at 0, 24, 48 and 72 h after MCAO, showed that NO levels did not differ significantly between the AG- and saline-treated groups at any time-point. Moreover, NOS activity assays revealed that no iNOS activity was present in any of the brains tested and that constitutive neuronal NOS activity was similar across the two hemispheres between both groups. The absence of iNOS protein in the ischaemic and contralateral hemispheres at 48 and 72 h after MCAO (control group only) was confirmed by Western blot analysis. These results suggest that AG treatment reduces the rate of growth of ischaemic lesions, perhaps preserving the functioning of perifocal neurons. Our observations contradict suggestions that high levels of NO generated by iNOS are partially responsible for exacerbating the neuronal damage in the postischaemic phase of MCAO. Although this does not rule out a role for AG as a neuroprotective agent via its ability to inhibit iNOS, these findings indicate that neuroprotective actions of AG may also be mediated via other cellular targets.
authors: Institute of Psychiatry, King's College, University of London, London, UK. d.cash@iop.kcl.ac.uk
authors: D
authors: D
authors: Cash
authors: J S
authors: JS
authors: Beech
authors: R C
authors: RC
authors: Rayne
authors: P M
authors: PM
authors: Bath
authors: B S
authors: BS
authors: Meldrum
authors: S C
authors: SC
authors: Williams
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D002384:Catalysis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D015151:Immunoblotting; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D009410:Nerve Degeneration / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D018696:Neuroprotective Agents; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C004479:pimagedine