Cerebroprotective effects of aminoguanidine in a rodent model of stroke

Kevin Cockroft, Malcolm Meistrell, Gary A. Zimmerman, Donald Risucci, Ona Bloom, Anthony Cerami, Kevin J. Tracey

Research output: Contribution to journalArticle

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Abstract

Background and Purpose: 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.

Original languageEnglish (US)
Pages (from-to)1393-1398
Number of pages6
JournalStroke
Volume27
Issue number8
DOIs
StatePublished - Jan 1 1996

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Rodentia
Stroke
Cerebral Infarction
Ischemia
Common Carotid Artery
Arterial Pressure
Middle Cerebral Artery Infarction
Brain
Ketamine
Diabetes Complications
pimagedine
Cell Size
Blood Glucose
Clinical Trials
Temperature
Therapeutics
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

Cite this

Cockroft, K., Meistrell, M., Zimmerman, G. A., Risucci, D., Bloom, O., Cerami, A., & Tracey, K. J. (1996). Cerebroprotective effects of aminoguanidine in a rodent model of stroke. Stroke, 27(8), 1393-1398. https://doi.org/10.1161/01.STR.27.8.1393
Cockroft, Kevin ; Meistrell, Malcolm ; Zimmerman, Gary A. ; Risucci, Donald ; Bloom, Ona ; Cerami, Anthony ; Tracey, Kevin J. / Cerebroprotective effects of aminoguanidine in a rodent model of stroke. In: Stroke. 1996 ; Vol. 27, No. 8. pp. 1393-1398.
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Cockroft, K, Meistrell, M, Zimmerman, GA, Risucci, D, Bloom, O, Cerami, A & Tracey, KJ 1996, 'Cerebroprotective effects of aminoguanidine in a rodent model of stroke', Stroke, vol. 27, no. 8, pp. 1393-1398. https://doi.org/10.1161/01.STR.27.8.1393

Cerebroprotective effects of aminoguanidine in a rodent model of stroke. / Cockroft, Kevin; Meistrell, Malcolm; Zimmerman, Gary A.; Risucci, Donald; Bloom, Ona; Cerami, Anthony; Tracey, Kevin J.

In: Stroke, Vol. 27, No. 8, 01.01.1996, p. 1393-1398.

Research output: Contribution to journalArticle

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T1 - Cerebroprotective effects of aminoguanidine in a rodent model of stroke

AU - Cockroft, Kevin

AU - Meistrell, Malcolm

AU - Zimmerman, Gary A.

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AU - Cerami, Anthony

AU - Tracey, Kevin J.

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N2 - Background and Purpose: 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.

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Cockroft K, Meistrell M, Zimmerman GA, Risucci D, Bloom O, Cerami A et al. Cerebroprotective effects of aminoguanidine in a rodent model of stroke. Stroke. 1996 Jan 1;27(8):1393-1398. https://doi.org/10.1161/01.STR.27.8.1393