Neurotoxicity in rat cortical cells caused by N-methyl-D-aspartate (NMDA) and gp120 of HIV-1: induction and pharmacological intervention.
Incubation of highly enriched neurons from rat cerebral cortex with the human immunodeficiency virus type 1 (HIV-1) coat protein gp120 for 18 h results in fragmentation of DNA at internucleosomal linkers, a feature of apoptosis. We report that neurons respond to exposure to gp120 with an increased release of arachidonic acid via activation of phospholipase A2. This process is not inhibited by antagonists of the N-methyl-D-aspartate (NMDA) receptor channels. To investigate the influence of arachidonic acid on the sensitivity of NMDA receptor towards its against, low concentrations of NMDA were coadministered with arachidonic acid. Under these conditions the NMDA-mediated cytotoxicity was enhanced. We conclude that gp120 causes an activation of phospholipase A2, resulting in an increased release of arachidonic acid which in turn sensitizes the NMDA receptor. Two compounds were found to act cytoprotectively against the deleterious effect caused by gp120 on neurons: Memantine [1-amino-3,5-dimethyladamantane] and Flupirtine [2-amino-3-ethoxycarbonylamino-6-(4-fluoro-benzyl-amino)-pyridine maleate]. Both compounds have been found to display a potent cytoprotective effect on neurons treated with the excitatory amino acid NMDA or with the human immunodeficiency virus type 1 (HIV-1) coat protein gp120. The NMDA antagonist Memantine, a drug currently used in the therapy of spasticity and Parkinson's disease, prevented the effects of gp120 at micromolar concentrations. Flupirtine was previously found to be a centrally acting, nonopiate analgesic agent which additionally possesses anticonvulsant and muscle-relaxant activity at doses similar to those producing analgesia. The cytoprotective effect of Flupirtine in vitro was significant (above 10 microM). Considering the fact that both Memantine and Flupirtine display almost no clinical side effects, these drugs may prove useful both in preventing primary infection of brain cells with the HIV virus, as well as in treating the neurological disorders often associated with the immunodeficiency syndrome such as AIDS-related dementia.
Müller
W E
WE
Institut für Physiologische Chemie, Abteilung Angewandte Molekularbiologie, Universität, Duesbergweg, Mainz, Germany.
Pergande
G
G
Ushijima
H
H
Schleger
C
C
Kelve
M
M
Perovic
S
S
D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016718:Arachidonic Acid / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D015497:HIV-1 / Q000737:chemistry; D008559:Memantine / Q000494:pharmacology*; D008954:Models, Biological; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D051381:Rats
D000631:Aminopyridines; D004791:Enzyme Inhibitors; D015699:HIV Envelope Protein gp120; D018696:Neuroprotective Agents; D016718:Arachidonic Acid; D016202:N-Methylaspartate; D010741:Phospholipases A; D054467:Phospholipases A2; C034161:flupirtine; D008559:Memantine