Outstanding neuroprotective efficacy of dexrazoxane in mice subjected to sequential common carotid artery sectioning

Abstract

AbstractWe evaluated the efficacy of the iron chelator, dexrazoxane, to reduce the neurological alterations and mortality produced by sequential common carotid artery sectioning (SCAS) in mice. Deferoxamine (32 and 128 mg/kg), dexrazoxane (32 and 128 mg/kg), dizolcipine (0.8 and 3.2 mg/kg), or nimodipine (0.4 and 1.6 mg/kg) were injected ip 15 min after the second artery sectioning. Animals were evaluated at 24, 48, and 72 h after compound or vehicle injection using three procedures: neurological examination, spontaneous locomotor activity, and motor coordination. Based on neurological evaluation, we designed and used a disability status scale (NDSS) to determine the degree of functional incapacity after brain ischemia for each animal. The scale comprises 10 progressive grades or steps beyond 0 (normal), extending to status 10 (death due to SCAS). In this scale, the higher the number, the greater is the neurological dysfunction. For the vehicle‐treated animals, the survival rate ranged from 41 to 30% and the neurological scores ranged from 6.6 to 7.8 between 24 and 72 h after the second surgery. The survival rate was significantly increased with low and high doses of dexrazoxane (ranges, 57–52% and 66–60%, respectively). Total neurological scores with 32 and 128 mg/kg of dexrazoxane (ranges, 4.5–5.4 and 3.3–4.0, respectively) were significantly lower (P<0.05) than its corresponding solvent. Dexrazoxane administration also avoided hypolocomotion and motor incoordination produced by SCAS. None of three known putative neuroprotective agents tested in this study reduced the mortality and/or consistently diminished neurological deficits. We conclude that dexrazoxane has very important neuroprotective properties and that our scale is useful to quantify the degree of neurological impairment after brain ischemia. Drug Dev. Res. 60:294–302, 2003. © 2003 Wiley‐Liss, Inc.