Neuroprotection mediated via neurotrophic factors and induction of neurotrophic factors

Abstract

Neurotrophins and other neurotrophic factors have been shown to support the survival and differentiation of many neuronal populations of the central and peripheral nervous system. Therefore, administering neurotrophic factors could represent an alternative strategy for the treatment of acute and chronic brain disorders. However, the delivery of neurotrophic factors to the brain is one of the largest obstacles in the development of effective therapy 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 β-adrenoceptor agonists, shown to increase endogenous nerve growth factor (NGF) synthesis in the brain, would be an elegant way to overcome these problems of application. Stimulation of β-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 β-adrenoceptor antagonist propranolol. Furthermore, clenbuterol protected rat hippocampal neurons subjected to excitotoxic damage. The neuroprotective effect of clenbuterol in vitro depended 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 transient forebrain ischemia and reduced the infarct volume in a rat model of permanent middle cerebral artery occlusion (MCAo). The neuroprotective effect of clenbuterol in vivo was accompanied by enhanced NGF synthesis in brain tissue. These findings support our hypothesis that orally active NGF inducers may have a potential as therapeutic agents for the treatment of neurodegenerative disorders and stroke.