No abstract

We 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 (Po0.05) 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.

1 We evaluated changes in contractility of the guinea-pig isolated ileum, using intact segments and myenteric plexus-longitudinal muscle (MPLM) preparations, after several times (5-160 min) of ischemia in situ. 2 Intestinal ischemia was produced by clamping the superior mesenteric artery. Ischemic and nonischemic segments, obtained from the same guinea-pig, were mounted in organ baths containing Krebs-bicarbonate (K-B) solution, maintained at 371C and gassed with 95% O 2 /5% CO 2 . The preparations were allowed to equilibrate for 60 min under continuous superfusion of warm K-B solution and then electrically stimulated at 40 V (0.3 Hz, 3.0 ms). Thereafter, complete noncumulative concentration-response curves were constructed for acetylcholine (ACh), histamine (HIS), potassium chloride (KCl), and barium chloride (BaCl 2 ). Mean E max (maximal response) values were calculated for each drug. 3 Our study shows that alterations of chemically and electrically evoked contractions are dependent on ischemic periods. It also demonstrates that contractile responses of ischemic tissues to neurogenic stimulation decreases earlier and to a significantly greater extent than the non-nerve mediated responses of the intestinal smooth muscle. Contractile responses to smooth muscle stimulants were all similarly affected by ischemia. Electron microscopy images indicated necrotic neuronal death. The decrease in reactivity of ischemic tissues to electrical stimulation was ameliorated by dexrazoxane, an antioxidant agent. 4 We consider the guinea-pig isolated ileum as a useful model system to study the processes involved in neuronal ischemia, and we propose that the reduction in maximal responses to electrical stimulation is a useful parameter to study neuroprotection.

We have previously shown that sequential common carotid artery sectioning (SCAS) in mice produces a persistent forelimb flexion. Here, we have extended that study to show that upper limb motor dysfunction after SCAS can be easily quantified with the sunflower seed test. We found that the second artery occlusion significantly increases the time to reach food and that most animals failed or took a longer time to successfully consume the seed with no evidence of recovery (96 h). These alterations were apparently due to paw and fingers impairments during holding and manipulation of the seed. We view the sunflower seed test as a sensitive, simple, and economic procedure to assess forelimb motor function after brain ischemia. Drug Dev. Res. 67:752-756, 2006.

In this study we determined whether dexrazoxane reduces mortality in mice subjected to bilateral sequential common carotid artery sectioning. Under pentobarbital anesthesia, the left common carotid artery was ligated and sectioned. In one group of experiments, 32 days later mice were injected i.p. with dexrazoxane (16, 64, 256 mg/kg) 30 min before being reanesthetized to ligate and section the right common carotid artery. In the second group of animals dexrazoxane was given, at the same doses, 15 min after ligating and sectioning the right common carotid artery. Dexrazoxane significantly decreased the cumulated mortality rate compared with controls. When given 30 min before the second surgery dexrazoxane was active only at doses of 256 mg/kg. In contrast, when given 15 min after the second ischemic insult the protective effect of dexrazoxane was already evident at 16 mg/kg, increasing dose‐dependently with an almost complete protection at 256 mg/kg during the first 24 h of observation; some degree of protection persisted up to day 4. One possible explanation for this striking difference in efficacy is that dexrazoxane passes through a compromised but not through an intact blood–brain barrier. We conclude that dexrazoxane has important neuroprotective properties against brain ischemia and that its clinical trial in stroke should be considered. Drug Dev. Res. 51:149–152, 2000. © 2001 Wiley‐Liss, Inc.