Just when you thought it was safe to read the thread again, he's back with more boring abstracts.
Actually this is an excellent in vitro study of the process by which AIDS producers dementia and how memantine can block the process. Happy reading!
John de C
Role of Na+/H+ exchangers, excitatory amino acid receptors and
voltage-operated Ca2+ channels in human immunodeficiency virus type
1 gp120-mediated increases in intracellular Ca2+ in human neurons and
astrocytes.
Holden CP, Haughey NJ, Nath A, Geiger JD, Neuroscience 1999;91(4):1369-78
Department of Pharmacology and Therapeutics, University of Manitoba Faculty of Medicine, Winnipeg, Canada.
Human immunodeficiency virus type 1 (HIV-1) dementia is the commonest form of dementia in North American people less than 60 years of age. HIV-1 envelope glycoprotein gp120 has been implicated in the neurotoxicity observed in, and the pathogenesis of, HIV-1 dementia. Recombinant gp120 (gp120) was pressure-applied on to cultured human fetal neurons and astrocytes and, by using single-cell calcium imaging, we determined the mechanisms responsible for gp120-induced increases in the levels of intracellular calcium ([Ca2+]i). Significant dose-related increases in [Ca2+]i were observed in neurons and astrocytes. In neurons, 5 pM gp120 increased [Ca2+]i by 290+/-13 nM and increases of 2210+/-211 nM were found at 209 nM, the highest concentration of gp120 tested. The apparent EC50 value for gp120 of 223+/-40 pM in neurons was not significantly different from that in astrocytes. Immunoelution of gp120 with polyclonal anti-gp120 and Ca2+-free conditions blocked increases in [Ca2+]i by gp120. Increases in [Ca2+]i were significantly (P < 0.005) attenuated by the Na+/H+ exchange blocker 5-(N-methyl-N-isobutyl)-amiloride in neurons and astrocytes. The L-type calcium channel blockers nimodipine, diltiazem and CdCl2 + NiCl2 significantly (P < 0.005) reduced increases in [Ca2+]i in neurons, but not astrocytes. Increases in [Ca2+]i by gp120 were not significantly affected by blockers of N-, P- and Q-type calcium channels. The N-methyl-D-aspartate receptor antagonists +/-)-2-amino-5-phosphonopentanoic acid (AP5), memantine and dizocilpine significantly (P < 0.01) lowered gp120-induced increases in [Ca2+]i in neurons. AP5 and memantine, but not dizocilpine, significantly (P < 0.01) reduced increases in [Ca2+]i by gp120 in astrocytes. Gp120 appears to activate astrocyte Na+/H+ exchangers to release glutamate and potassium and, subsequent to this, increases in
[Ca2+]i in neurons and astrocytes result from activation of excitatory amino acid receptors on astrocytes and neurons, and voltage-operated calcium channels on neurons. Drugs that block gp120-induced changes in [Ca2+]i in neurons and astrocytes may help in the treatment of HIV-1 dementia. |
