Cerebroprotective effects of aminoguanidine in a rodent model of stroke.
OBJECTIVE
During a cerebral infarction, a complex cascade of cytotoxic events ultimately determines the volume of brain cell loss. The studies presented here demonstrate that aminoguanidine, an experimental therapeutic currently in clinical trials to prevent diabetic complications, is cerebroprotective in focal cerebral infarction.


METHODS
Adult Lewis rats (n = 6 to 12 per group) were anesthetized with ketamine and subjected to focal cerebral infarction by tandem permanent occlusion of the right middle cerebral artery and ipsilateral common carotid artery (CCA), followed by temporary occlusion of the contralateral CCA. Infarct volume (cortical) was assessed 24 hours after the onset of ischemia by planimetric analysis of coronal brain slices stained with tetrazolium.


RESULTS
Aminoguanidine (320 mg/kg IP) administered 15 minutes after the onset of ischemia resulted in a significant reduction of infarct volume (7.6 +/- 2.6% of hemisphere in controls versus 1.3 +/- 0.2% of hemisphere in aminoguanidine-treated rats; P < .05). Administration of aminoguanidine conferred significant cerebroprotection even when administered 1 or 2 hours after the onset of ischemia (88% and 85% reduction from control, respectively; P < .05). Cerebroprotection by aminoguanidine was independent of systemic physiological variables known to influence stroke size (eg, temperature, mean arterial blood pressure, blood glucose, and arterial pH, PCO2, and PO2).


CONCLUSIONS
These results indicate that the stroke-reducing properties of aminoguanidine are dose and time dependent, with substantial cerebroprotection persisting even with drug delivery up to 2 hours after the onset of ischemia. It is now plausible to pursue development of aminoguanidine as an experimental therapeutic in stroke, and possible mechanisms of these cerebroprotective effects are under consideration.
Cockroft
K M
KM
Laboratory of Biomedical Science, Picower Institute for Medical Research, Manhasset, NY, USA.
Meistrell
M
M
Zimmerman
G A
GA
Risucci
D
D
Bloom
O
O
Cerami
A
A
Tracey
K J
KJ
D000818:Animals; D002544:Cerebral Infarction / Q000188:drug therapy / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D002561:Cerebrovascular Disorders / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D008297:Male; D008991:Monitoring, Physiologic; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000188:drug therapy / Q000473:pathology; D013997:Time Factors; D000097667:Polyamine Oxidase
D004791:Enzyme Inhibitors; D006146:Guanidines; D018696:Neuroprotective Agents; D000587:Oxidoreductases Acting on CH-NH Group Donors; D000097667:Polyamine Oxidase; C004479:pimagedine