REDUCTION OF CORTICAL INFARCTION AND IMPAIRMENT OF APOPTOSIS IN NGF-TRANSGENIC MICE SUBJECTED TO PERMANENT FOCAL ISCHEMIA

The neuroprotective potential of the nerve growth factor (NGF) against permanent ischemic brain damage has been investigated in vivo using N GF-transgenic (tg) mice. The expression of the transgene is driven by part of the promoter of the proto-oncogene c-fos, which belongs to the first set of genes activated after brain ischemic insult. Wild-type ( wt) mice and tg mice were subjected to permanent focal ischemia induce d by electrocoagulation of the middle cerebral artery. Twenty four hou rs (h) after the ischemic shock, when compared to wt, tg mice displaye d a 40% reduction of the infarcted area, which lasted up to 1 week. Ho wever, infarcted brain areas were similar in wt and tg mice within the first hours post-occlusion, indicating that NGF acted to block the pr ogression of neuronal damage. Kinetics of NGF synthesis assessed by EL ISA was in good agreement with the observed neuroprotective effect, si nce NGF content peaked 6 h post-ischemia. This was further correlated with the time-course of c-Fos immunoreactivity, detectable only from 6 h post-ischemia. The neuroprotective effect of NGF involved the impai rment of apoptotic cell death, as evidenced by a marked decrease of th e number of apoptotic profiles inside the ischemic zone in tg mice. Th ese results underline the potential of c-fos-NGF-tg mice to study in v ivo the molecular and cellular mechanisms of the NGF-induced neuroprot ective effect against ischemic damage. (C) 1998 Elsevier Science B.V.