Catecholamine monoamine oxidase a metabolite in adrenergic neurons is cytotoxic in vivo.

Abstract

3,4-Dihydroxyphenylglycolaldehyde is the monoamine oxidase-A metabolite of two catecholamine neurotransmitters, epinephrine and norepinephrine. This aldehyde metabolite and its synthesizing enzymes increase in cell bodies of catecholamine neurons in Alzheimer's disease. To test the hypothesis that 3,4-dihydroxyphenylglycolaldehyde, but not epinephrine or its major metabolite 4-hydroxy-3-methoxyphenylglycol, is a neurotoxin, we injected 3,4-dihydroxyphenylglycolaldehyde onto adrenergic neurons in the rostral ventrolateral medulla. Injections of epinephrine or 4-hydroxy-3-methoxyphenylglycol were made into the same area of controls. A dose response and time study were performed. Adrenergic neurons were identified by their content of the epinephrine synthesizing enzyme, phenylethanolamine N-methyltransferase, immunohistochemically. Apoptosis was evaluated by in situ terminal deoxynucleotidyl-transferase mediated dUTP nick end label staining. Injection of 3,4-dihydroxyphenylglycolaldehyde in amounts as low as 50 ng results in loss of adrenergic neurons and apoptosis after 18 h. The degree of neurotoxicity is dose and time dependent. Doses of 3,4-dihydroxyphenylglycolaldehyde 10-fold higher produce necrosis. Neither epinephrine nor 4-hydroxy-3-methoxyphenylglycol are toxic. A 2.5 microg injection of 3,4-dihydroxyphenylglycolaldehyde is toxic to cortical neurons but not glia. Active uptake of the catecholamine-derived aldehyde into differentiated PC-12 cells is demonstrated. Implications of these findings for catecholamine neuron death in neurodegenerative diseases are discussed.

• Authors: W J Burke, S W Li, D S Zahm, H Macarthur, L L Kolo, T C Westfall, M Anwar, S B Glickstein, D A Ruggiero
• Journal: Brain research (Brain Res) Vol. 891 Issue 1-2 Pg. 218-27 (Feb 09 2001) ISSN: 0006-8993 [Print] Netherlands
• PMID: 11164826 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Aldehydes
• Catechols
• Neurotoxins
• 3,4-dihydroxyphenylglycolaldehyde
• Epinephrine

Topics

• Aldehydes (metabolism, pharmacology)
• Animals
• Apoptosis (drug effects, physiology)
• Catechols
• Cerebral Cortex (cytology, drug effects, metabolism)
• Dose-Response Relationship, Drug
• Epinephrine (metabolism)
• Immunohistochemistry
• Male
• Medulla Oblongata (cytology, drug effects, enzymology)
• Nerve Degeneration (chemically induced, enzymology, physiopathology)
• Neurons (cytology, drug effects, enzymology)
• Neurotoxins (pharmacology)
• PC12 Cells (drug effects, metabolism)
• Rats
• Rats, Sprague-Dawley
• Reticular Formation (cytology, drug effects, enzymology)