Cerebrospinal fluid from human immunodeficiency virus--infected individuals facilitates neurotoxicity by suppressing intracellular calcium recovery.
Neurologic decline associated with penetration of human immunodeficiency virus type 1(HIV-1) into the central nervous system is thought to be due, in large part, to inflammation and local secretion of neurotoxic substances. To examine the cellular processes that mediate neurotoxicity in vivo, the authors valuated the ability of neurons to maintain intracellular calcium homeostasis in the presence of toxic cerebrospinal fluid (CSF) (CSF(tox)) collected from a subset of HIV-infected individuals. Exposure of rat neural cultures to CSF(tox) resulted in a gradual increase in intracellular calcium in neurons (+63%), microglia (+251%), and astrocytes (+52%). Pretreatment of neural cultures with CSF(tox) resulted in an exaggerated calcium response to a brief pulse of glutamate and a > 90% suppression of the rate of recovery of intracellular calcium. Attempts to model the deficit using inhibitors of calcium transport across endoplasmic reticulum, mitochondrial, or plasma membrane indicated that blockade of the plasma membrane sodium/calcium exchanger was best able to reproduce the deficits seen during exposure to CSF(tox). Because the inability of cells to maintain calcium homeostasis would lead to exaggerated responses from a wide variety of stimuli, therapeutics designed to facilitate calcium transport from the cell may provide more comprehensive and effective intervention than strategies targeted to specific receptor pathways.
Meeker
Rick B
RB
Department of Neurology, University of North Carolina, Chapel Hill, North Carolina 27599, USA. meekerr@neurology.unc.edu
Boles
Jeramiah C
JC
Robertson
Kevin R
KR
Hall
Colin D
CD
D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D018698:Glutamic Acid / Q000494:pharmacology; D015658:HIV Infections / Q000134:cerebrospinal fluid*; D006801:Humans; D017628:Microglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009498:Neurotoxins / Q000134:cerebrospinal fluid*; D051381:Rats; D020318:Rats, Long-Evans
D009498:Neurotoxins; D018698:Glutamic Acid; D002118:Calcium