Neuronal injury associated with HIV-1 and potential treatment with calcium-channel and NMDA antagonists.
A substantial number of adults and half of the children with acquired immunodeficiency syndrome (AIDS) suffer from neurological manifestations. Among the various pathologies reported in brains of patients with AIDS is neuronal injury and loss, although neurons themselves do not appear to be infected by HIV-1. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions between macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells, especially after interacting with astrocytes, secrete neurotoxic substances. Not all of these substances are yet known, but they may include eicosanoids, platelet-activating factor, quinolinate, cysteine, cytokines, and free radicals. Macrophages activated by HIV-1 envelope protein gp120 also appear to release similar toxins. Some of these factors can lead to increased glutamate release or decreased glutamate reuptake. A final common pathway for neuronal suceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-asparate (NMDA) receptor-operated channels, and therefore offers hope for future pharmacological intervention. This review focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.
Lipton
S A
SA
Department of Neurology, Children's Hospital, Boston, Mass.
D015526:AIDS Dementia Complex / Q000188:drug therapy* / Q000473:pathology*; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D015658:HIV Infections / Q000150:complications / Q000473:pathology*; D015497:HIV-1; D006801:Humans; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000502:physiology*
D002121:Calcium Channel Blockers; D016202:N-Methylaspartate