SELEGILINE ENHANCES NGF SYNTHESIS AND PROTECTS CENTRAL-NERVOUS-SYSTEMNEURONS FROM EXCITOTOXIC AND ISCHEMIC DAMAGE

It has been previously demonstrated that selegiline, an irreversible m onoamine oxidase B (MAO-B) inhibitor, potentiates glial reaction to in jury and possesses some 'trophic-like' activities which do not depend on the inhibition of MAO-B and which are probably associated with the induction of astrocyte-derived neurotrophic substances. Based on these findings, we tried to find out whether selegiline is able to modify t he expression of nerve growth factor (NGF) and to protect central nerv ous system (CNS) neurons from excitotoxic and ischemic damage. Selegil ine (10 pM-1 nM) induced NGF messenger RNA (mRNA) expression in cultur ed rat cortical astrocytes as determined by reverse transcription-poly merase chain reaction (RT-PCR) followed by a corresponding increase in NGF protein content measured by two-site NGF-enzyme-linked immunosorb ent assay (ELISA) in astrocyte-conditioned medium. Additionally, expos ure of hippocampal cultures containing neuronal and glial cells to thi s drug at the same concentrations enhanced significantly the content o f NGF measured in the culture medium after 6 h of incubation. We hypot hesize that selegiline could rescue hippocampal neurons from injury by induction of astrocyte-derived NGF in this cell culture system. To te st this hypothesis, an excitotoxic damage was induced in the same type of cells by exposure to 0.5 mM L-glutamate for 1 h. Selegiline(10 pM- 1 nM) present in the growth medium 6 h before until 18 h after inducti on of injury (the point of glutamate-toxicity measurement) protected h ippocampal neurons from excitotoxic death. Furthermore, administered i ntraperitoneally (i.p.) (8 X 15 mg/kg per day) this drug enhanced the expression of NGF message in intact rat cerebral cortex and protected rat cortical tissue from ischemic insult due to permanent occlusion of the middle cerebral artery (MCA). The neuroprotective activity of sel egiline (5 X 10 mg/kg per day i.p.) was also demonstrated in a mouse m odel of focal cerebral ischemia. The present data show that selegiline induced NGF expression in cultured rat cortical astrocytes. In mixed primary cultures of hippocampal neuronal and glial cells, selegiline i ncreased NGF protein content and protected hippocampal neurons from ex citotoxic degeneration. In vivo, this drug induced NGF gene expression in cerebral cortex from intact rats and protected rat and mouse corti cal tissue from ischemic insult after occlusion of the MCA. Our result s indicate that the induction of astrocyte-derived NGF could contribut e to the neuroprotective activity of selegiline demonstrated both in v ivo and in vitro and can explain, in part, the 'trophic-like' properti es of this compound which has been observed by others.