Abstract
The neurological manifestations of AIDS include dementia, encountered even in the absence of opportunistic superinfection or malignancy. The AIDS Dementia Complex appears to be associated with several neuropathological abnormalities, including astrogliosis and neuronal injury or loss. How can HIV-1 result in neuronal damage if neurons themselves are only rarely, if ever, infected by the virus? In vitro experiments from several different laboratories have lent support to the existence of HIV- and immune-related toxins. In one recently defined pathway to neuronal injury, HIV-infected macrophages/microglia as well as macrophages activated by HIV-1 envelope protein gp120 appear to secrete excitants/neurotoxins. These substances may include arachidonic acid, platelet-activating factor, free radicals (NO· and O2·−), glutamate, quinolinate, cysteine, cytokines (TNF-α, IL1-β, IL-6), and as yet unidentified factors emanating from stimulated macrophages and possibly reactive astrocytes. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, and several neurodegenerative diseases, including Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. This mechanism involves excessive activation of N-methyl-d-aspartate (NMDA) receptor-operated channels, with resultant excessive influx of Ca2+ leading to neuronal damage, and thus offers hope for future pharmacological intervention.
This chapter reviews two clinically-tolerated NMDA antagonists, memantine and nitroglycerin: (i) Memantine is an open-channel blocker of the NMDA-associated ion channel and a close congener of the anti-viral and anti-parkinsonian drug amantadine. Memantine blocks the effects of escalating levels of excitotoxins to a greater degree than lower (physiological) levels of these excitatory amino acids, thus sparing to some extent normal neuronal function, (ii) Nitroglycerin acts at a redox modulatory site of the NMDA receptor/channel complex to downregulate its activity. The neuroprotective action of nitroglycerin at this site is mediated by a chemical species related to nitric oxide, but in a higher oxidation state, resulting in transfer of an NO group to a critical cysteine on the NMDA receptor. Because of the clinical safety of these drugs, they have the potential for trials in humans. As the structural basis for redox modulation is further elucidated, it may become possible to design even better redox reactive reagents of clinical value.
To this end, redox modulatory sites of NMDA receptors have begun to be characterized at a molecular level using site-directed mutagenesis of recombinant subunits (NMDAR1, NMDAR2A-D). Two types of redox modulation can be distinguished. The first type gives rise to a persistent change in the functional activity of the receptor, and we have identified two cy steine residues on the NMDAR1 subunit (#744 and #798) that are responsible for this action. A second site, presumably also a cysteine(s) because ≤ mM N-ethylmaleimide can block its effect in native neurons, underlies the other, more transient redox action. It appears to be at this, as yet unidentified, site on the NMDA receptor that the NO group acts, at least in recombinant receptors.
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Lipton, S.A. (1996). AIDS Dementia as a Form of Excitotoxicity: Potential Therapy with NMDA Open-Channel Blockers and Redox Congeners of Nitric Oxide. In: Fiskum, G. (eds) Neurodegenerative Diseases. GWUMC Department of Biochemistry and Molecular Biology Annual Spring Symposia. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-0209-2_41
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