Enhanced anandamide degradation is associated with neuronal apoptosis induced by the HIV-1 coat glycoprotein gp120 in the rat neocortex.
Human immunodeficiency virus type-1 coat glycoprotein gp120 causes delayed apoptosis in rat brain neocortex. Here, we investigated the possible role of the endocannabinoid system in this process. It is shown that gp120 causes a time-dependent increase in the activity and immunoreactivity of the anandamide (AEA)-hydrolyzing enzyme fatty acid amide hydrolase (FAAH), paralleled by increased activity of the AEA membrane transporter and decreased endogenous levels of AEA. The AEA-synthesizing phospholipase D and the AEA-binding receptors were not affected by gp120. None of the changes induced by gp120 in the cortex were induced by bovine serum albumin, nor were they observed in the hippocampus of the same animals. Also, the activity of 5-lipoxygenase, which generates AEA derivatives able to inhibit FAAH, decreased down to approximately 25% of the control activity upon gp120 treatment, due to reduced protein level ( approximately 45%). In addition, the FAAH inhibitor methyl-arachidonoyl fluorophosphonate significantly reduced gp120-induced apoptosis in rat brain neocortex, whereas selective blockers of AEA membrane transporter or of AEA-binding receptors were ineffective. Taken together, these results suggest that gp120, by activating FAAH, decreases endogenous levels of AEA, and the latter effect seems instrumental in the execution of delayed neuronal apoptosis in the brain neocortex of rats.
Maccarrone
Mauro
M
Department of Biomedical Sciences, University of Teramo, Piazza A. Moro 45, I-64100 Teramo, Italy. Maccarrone@unite.it
Piccirilli
Silvia
S
Battista
Natalia
N
Del Duca
Claudio
C
Nappi
Giuseppe
G
Corasaniti
M Tiziana
MT
Finazzi-Agrò
Alessandro
A
Bagetta
Giacinto
G
D000581:Amidohydrolases / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001094:Arachidonate 5-Lipoxygenase / Q000187:drug effects / Q000378:metabolism; D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000008:administration & dosage / Q000633:toxicity*; D007276:Injections, Intraventricular; D008297:Male; D019579:Neocortex / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D063065:Organophosphonates / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D051381:Rats; D017208:Rats, Wistar; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001094:Arachidonate 5-Lipoxygenase; D001095:Arachidonic Acids; D002352:Carrier Proteins; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D015699:HIV Envelope Protein gp120; D063065:Organophosphonates; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C104810:methyl arachidonylfluorophosphonate; C078814:anandamide