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.