EFFECTS OF POLYAMINE SYNTHESIS BLOCKADE ON NEURONAL LOSS AND ASTROGLIAL REACTION AFTER TRANSIENT FOREBRAIN ISCHEMIA

Polyamines and ornithine decarboxylase, the polyamine biosynthetic enz yme, have been demonstrated to increase in the early phase of several types of brain lesion. However, their role in the pathogenesis of tiss ue damage is still debated. In the present paper the effects of treatm ents with alpha-difluoromethylomithine, a suicide inhibitor of omithin e decarboxylase, have been investigated in a model of transient forebr ain ischemia. Three treatment schedules were used: alpha-difluoromethy lomithine treatment was either started 3 hr before and repeated 1 hr a fter the insult, or started at the time of the insult and continued fo r 3 or 7 days after post-ischemic reperfusion. The rats were sacrifice d 4 hT, 7 or 40 days after reperfusion, respectively. The acute experi ment demonstrated that alpha-difluoromethylomithine can reduce the inc rease of glial fibrillary acidic protein immunoreactivity, an early ma rker of astroglial reaction, in ischemic striatum. Subchronic and chro nic alpha-difluoromethylomithine treatments induced a worsening of the morphological outcome of the ischemic lesion. In caudate-putamen a tr end for an increase of the area of neuronal loss was present after bot h treatments. In the hippocampal formation, a significant increase in the severity of neuronal lesion was observed in the mildly lesioned CA 3 field. In addition, other alterations of lesioned tissue were observ ed in alpha-difluoromethylomithine-treated animals, including increase s of non-neuronal cells at 7 and especially 40 days post-lesion in str iatum and CA3 hippocampal field. In conclusion, present data indicate that omithine decarboxylase activation after ischemic lesion is a cruc ial factor for survival of mildly lesioned neurons and proper tissue r eaction to the ischemic lesion. The experiment on acute alpha-difluoro methylomithine treatment suggests that these effects may be, at least in part, related to putrescine-induced activation of astroglial cells in the early post-lesion period.