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Pentamidine is an N-methyl-D-aspartate receptor antagonist and is neuroprotective in vitro
1Department of Pharmacology, University of Pittsburgh School of Medicine, Pennsylvania 15261.
Abstract:
Acquired immunodeficiency syndrome (AIDS) is frequently associated with dementia. The wide spectrum of neurological abnormalities associated with this dementia may involve a neurotoxin that activates the NMDA subtype of glutamate receptor in neurons. We have found that the antimicrobial agent pentamidine, which is prescribed for AIDS patients for the prophylaxis and treatment of Pneumocystis carinii pneumonia, is an effective NMDA receptor antagonist. Pentamidine inhibited 3H-dizocilpine binding to the NMDA receptor in rat brain membranes at a site separate from glutamate, glycine, and spermidine, with an affinity near 2 microM. Similar concentrations of pentamidine block NMDA-induced increases in intracellular Ca2+ and NMDA-induced currents in cultured forebrain and cortical neurons, apparently without use dependence or voltage dependence, suggesting that pentamidine may represent a novel chemical class of NMDA receptor antagonist. Finally, pentamidine protects neurons from the lethal effects of acute NMDA exposure in vitro. AS pentamidine may accumulate in the brain at relevant concentrations following repeated high-dose parenteral administration, these findings suggest that the drug may be neuroprotective in vivo.
Insights
Pentamidine, an antimicrobial drug for AIDS patients, acts as an NMDA receptor antagonist. This property suggests pentamidine may offer neuroprotection against NMDA-induced neuronal damage in acquired immunodeficiency syndrome (AIDS) dementia.
Area of Science:
- Neuroscience
- Pharmacology
- Infectious Diseases
Background:
- Acquired immunodeficiency syndrome (AIDS) is often linked to dementia.
- Neurological abnormalities in AIDS dementia may stem from neurotoxins activating NMDA receptors.
Purpose of the Study:
- To investigate the potential of pentamidine, an antimicrobial agent used in AIDS treatment, as an NMDA receptor antagonist.
- To explore pentamidine's neuroprotective capabilities.
Main Methods:
- Assessed pentamidine's inhibition of 3H-dizocilpine binding to NMDA receptors in rat brain membranes.
- Examined pentamidine's effect on NMDA-induced intracellular Ca2+ increases and currents in cultured neurons.
- Evaluated pentamidine's neuroprotective effects against NMDA toxicity in vitro.
Main Results:
- Pentamidine demonstrated NMDA receptor antagonist activity with an affinity around 2 microM.
- It blocked NMDA-induced neuronal responses without apparent use or voltage dependence.
- Pentamidine protected neurons from NMDA-induced cell death in vitro.
Conclusions:
- Pentamidine functions as a novel NMDA receptor antagonist.
- Given its potential brain accumulation, pentamidine may offer in vivo neuroprotection for AIDS patients with dementia.