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

Neurotrophins render neurons highly vulnerable to certain injuries. We exam ined the possibility that NT-4/5 would enhance free radical neurotoxicity i n vivo as well as in vitro. Striatal neurons exposed to 10 mu M Fe2+ or 1 m M 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 follo wing exposure to Fe2+ or BSO was significantly increased and suppressed by addition of 100 mu M trolox, an antioxidant. In the adult brain, the intras triatal injections of 20 nmol Fe2+ revealed features of neuronal necrosis s uch as swelling cell body and mitochondria, fenestration of plasma membrane prior to nuclear membrane, and scattering condensation of nuclear chromati n. Cotreatment with 1.8 mu g NT-4/5 augmented the striatal damage 24 h foll owing the injections of Fe2+. This study implies that free radicals produce necrotic degeneration in vive as well as in vitro that becomes more sensit ive in the presence of neurotrophins. (C) 2000 Academic Press.