Neuroprotection mediated via neurotrophic factors and induction of neurotrophic factors

Neurotrophins and other neurotrophic factors have been shown to support the survival and differentiation of many neuronal populations of the central a nd peripheral nervous system. Therefore, administering neurotrophic factors could represent an alternative strategy for the treatment of acute and chr onic brain disorders, However, the delivery of neurotrophic factors to the brain is one of the largest obstacles in the development of effective thera py for neurodegenerative disorders, because these proteins are not able to cross the blood-brain barrier. The induction of growth factor synthesis in the brain tissue by systemically administered lipophilic drugs, such as bet a-adrenoceptor agonists, shown to increase endogenous nerve growth factor ( NGF) synthesis in the brain, would be an elegant way to overcome these prob lems of application. Stimulation of beta-adrenoceptors with clenbuterol led to increased NGF synthesis in cultured central nervous system (CNS) cells and rat brain tissue, Clenbuterol-induced NGF expression was reduced to the control levels by coadministration of beta-adrenoceptor antagonist propran olol, Furthermore, clenbuterol protected rat hippocampal neurons subjected to excitotoxic damage. The neuroprotective effect of clenbuterol in vitro d epended on increased NGF synthesis, since the neuroprotection was abolished by NGF antisense oligonucleotide as well as by antibodies directed against NGF itself. In vivo, clenbuterol protected rat hippocampus in a model of t ransient forebrain ischemia and reduced the infarct volume in a rat model o f permanent middle cerebral artery occlusion (MCAo). The neuroprotective ef fect of clenbuterol in vivo was accompanied by enhanced NGF synthesis in br ain tissue. These findings support our hypothesis that orally active NGF in ducers may have a potential as therapeutic agents far the treatment of neur odegenerative disorders and stroke. (C) 1999 Elsevier Science B.V. All righ ts reserved.