α7-Nicotinic acetylcholine receptor inhibition by indinavir: implications for cognitive dysfunction in treated HIV disease.
AIDS
; 31(8): 1083-1089, 2017 05 15.
Article
em En
| MEDLINE
| ID: mdl-28358738
ABSTRACT
OBJECTIVE:
The study set out to determine if the HIV protease inhibitor, indinavir, alters responsiveness of α7-nicotinic acetylcholine receptors to acetylcholine.DESIGN:
Treatment with HAART has dramatically reduced development of HIV-associated dementia and more severe forms of cognitive impairment. However, many individuals continue to experience cognitive decline of uncertain cause. Previous studies have failed to demonstrate significant alterations of functional brain connectivity, structural brain changes, or changes in cerebral blood flow sufficient to explain cognitive decline in virally suppressed individuals. This suggests that the mechanisms underlying development and progression of cognitive problems likely occurs at a micro rather than macro level, such as disruptions in neurotransmitter system signaling. MATERIALS ANDMETHODS:
Indinavir's effects on α7-nicotinic acetylcholine receptor activity was tested using a ScreenPatch IonWorks Barracuda-based assay in a mammalian cell model.RESULTS:
At low concentrations (0.0003-10âµmol/l) indinavir acts as a positive allosteric modulator (EC50â=â0.021âµmol/l), whereas at concentrations greater than 10âµmol/l (30-100âµmol/l) indinavir acts as an inhibitor of the α7-nicotinic acetylcholine receptor.CONCLUSION:
At concentrations greater than 10âµmol/l indinavir reduces synaptic transmission in the acetylcholine neurotransmitter system, which could possibly contribute to cognitive dysfunction. These results suggest that further experiments should be considered to assess whether patients might benefit from treatment with cholinesterase inhibitors that counteract the effects of indinavir.
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Base de dados:
MEDLINE
Assunto principal:
Infecções por HIV
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Inibidores da Protease de HIV
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Antagonistas Nicotínicos
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Indinavir
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Disfunção Cognitiva
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Receptor Nicotínico de Acetilcolina alfa7
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article