NT-4/5 exacerbates free radical-induced neuronal necrosis in vitro and in vivo.

Neurotrophins render neurons highly vulnerable to certain injuries. We examined the possibility that NT-4/5 would enhance free radical neurotoxicity in vivo as well as in vitro. Striatal neurons exposed to 10 microM Fe(2+) or 1 mM l-buthionine-[S, R]-sulfoximine (BSO) underwent mild degeneration within 24 h. With concurrent addition of 10-100 ng/ml NT-4/5, neuronal death following exposure to Fe(2+) or BSO was significantly increased and suppressed by addition of 100 microM trolox, an antioxidant. In the adult brain, the intrastriatal injections of 20 nmol Fe(2+) revealed features of neuronal necrosis such as swelling cell body and mitochondria, fenestration of plasma membrane prior to nuclear membrane, and scattering condensation of nuclear chromatin. Cotreatment with 1.8 microg NT-4/5 augmented the striatal damage 24 h following the injections of Fe(2+). This study implies that free radicals produce necrotic degeneration in vivo as well as in vitro that becomes more sensitive in the presence of neurotrophins.