Effects of dimethylthiourea on ischemic brain damage in hyperglycemic rats

Abstract

Hyperglycemia is known to worsen the outcome of transient global or forebrain ischemia. The aggravating effect is believed to be mediated by the additional formation of lactate- and of H+. Recent evidence suggests that reactive oxygen species contribute to the damage after brain ischemia. Since acidosis accelerates free radical damage in vitro, we decided to explore if ischemic damage in hyperglycemic subjects is ameliorated by dimethylthiourea (DMTU), an established free radical scavenger. In one series of hyperglycemic rats, we studied whether preischemic administration of DMTU alters the clinical outcome, notably the incidence and frequency of seizures. In two different series, the effect of DMTU on tissue damage was assessed by light microscopy after 15 h of recovery. Longer periods could not be studied since seizures developed. In the first of these series the animals were anesthetized with isoflurane, and in the second with halothane. The latter anesthesia largely suppressed the "early" postischemic seizures, i.e. those occurring after 1-4 h. Dimethylthiourea treatment altered the clinical outcome after ischemia. Thus, the "late" postischemic seizures appeared milder and occurred significantly later than in untreated animals. The fatal outcome was also delayed since treated animals died after 35.5 +/- 8.2 h (mean +/- SD) of recirculation, as compared to 19.8 +/- 3.6 h of recirculation in control animals. However, all DMTU-treated (and control) animals died. In the first morphological series (isoflurane anesthesia) the histopathological analysis was complicated by the occurrence of prefixation seizures; such seizures were recognized in 4/16 animals. When these 4 animals were excluded from the analysis (2 treated and 2 control animals), DMTU pretreatment did not ameliorate the damage, except in the substantia nigra pars reticulata (P < 0.05). In the second series, comprising animals anesthetized with halothane, only one animal out of 16 had "early" seizures, and none showed "late" seizures before death. Among these animals DMTU treatment significantly ameliorated damage to caudoputamen and cingulate cortex (P < 0.01). We conclude that treatment with the free radical scavenger DMTU partly ameliorates ischemic brain damage associated with excessive acidosis, and marginally delays the development of post-ischemic seizures. However, the effects were moderate and could, at least in part, have been caused by nonspecific effects of DMTU. Furthermore, all DMTU-treated animals died. The results thus give little support to the notion that the aggravating effects of acidosis is due to enhancement of free radical production.