Selegiline enhances NGF synthesis and protects central nervous system neurons from excitotoxic and ischemic damage.
It has been previously demonstrated that selegiline, an irreversible monoamine oxidase B (MAO-B) inhibitor, potentiates glial reaction to injury 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 the expression of nerve growth factor (NGF) and to protect central nervous system (CNS) neurons from excitotoxic and ischemic damage. Selegiline (10 pM-1 nM) induced NGF messenger RNA (mRNA) expression in cultured rat cortical astrocytes as determined by reverse transcription-polymerase chain reaction (RT-PCR) followed by a corresponding increase in NGF protein content measured by two-site NGF-enzyme-linked immunosorbent assay (ELISA) in astrocyte-conditioned medium. Additionally, exposure of hippocampal cultures containing neuronal and glial cells to this drug at the same concentrations enhanced significantly the content of NGF measured in the culture medium after 6 h of incubation. We hypothesize that selegiline could rescue hippocampal neurons from injury by induction of astrocyte-derived NGF in this cell culture system. To test 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 induction of injury (the point of glutamate-toxicity measurement) protected hippocampal neurons from excitotoxic death. Furthermore, administered intraperitoneally (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 selegiline (5 x 10 mg/kg per day i.p.) was also demonstrated in a mouse model 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 increased NGF protein content and protected hippocampal neurons from excitotoxic degeneration. In vivo, this drug induced NGF gene expression in cerebral cortex from intact rats and protected rat and mouse cortical tissue from ischemic insult after occlusion of the MCA. Our results indicate that the induction of astrocyte-derived NGF could contribute to the neuroprotective activity of selegiline demonstrated both in vivo and in vitro and can explain, in part, the 'trophic-like' properties of this compound which has been observed by others.
Semkova
I
I
Institut für Pharmakologie und Toxikologie, Fachbereìch Pharmazie and Lebensminelchemle, Philipps-Universität, Marburg, Germany.
Wolz
P
P
Schilling
M
M
Krieglstein
J
J
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D002545:Brain Ischemia / Q000517:prevention & control; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D018698:Glutamic Acid; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009414:Nerve Growth Factors / Q000096:biosynthesis*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D012642:Selegiline / Q000494:pharmacology*
D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D012642:Selegiline; D018698:Glutamic Acid