NMDA receptor antagonists engender neuroprotection against gp120-induced cognitive dysfunction in rats through modulation of PKR activation, oxidative stress, ER stress and IRE1α signal pathway.
Eur J Neurosci
; 56(2): 3806-3824, 2022 07.
Article
em En
| MEDLINE
| ID: mdl-35543645
ABSTRACT
It is widely accepted that the surface glycoprotein (gp120) of human immunodeficiency virus-1 (HIV-1) plays an important role in HIV-1-induced nerve damage and pathogenesis of HIV-associated neurocognitive disorders (HAND). Our previous work has demonstrated that gp120 enhanced excitatory postsynaptic currents (EPSCs) mediated by N-methyl-d-aspartate receptors (NMDARs) and caused neural injury. However, the relationship between gp120, NMDARs and HAND is still unclear. Several lines of evidence indicate that double-stranded RNA-activated protein kinase (PKR) is involved in NMDA-induced cerebral ischaemia and retinal damage, but because its role in neuropathology is still debated, we examined whether PKR links oxidative stress and endoplasmic reticulum (ER) stress to exert a deleterious role in the rat model with gp120-induced dementia. In this study, we found that NMDAR antagonist memantine or PKR inhibitor C16 improved gp120-induced learning and memory impairment and inhibited gp120-induced PKR activity. Furthermore, memantine or C16 was found to attenuate gp120-induced neuroinflammation, oxidative stress, ER stress and its downstream IRE1α/JNK pathway. Additionally, memantine or C16 evidently inhibited apoptotic pathways by reducing the Bax and caspase-3, -8, -9 expressions and increasing Bcl-2 expression. So the NMDA receptor antagonists could alleviate HIV/gp120-induced dementia in the rat model by altering PKR level. In conclusion, this study demonstrates that NMDARs play a key role in HIV/gp120-induced hippocampal damage and cognitive dysfunction through PKR-mediated oxidative stress, ER stress, and IRE1α/JNK signalling pathway in rats, and implicating PKR inhibitors could provide a novel neuroprotective strategy for HAND via inhibiting ER stress and its downstream IRE1α signalling pathway.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteína gp120 do Envelope de HIV
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Receptores de N-Metil-D-Aspartato
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Demência
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Disfunção Cognitiva
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Neuroproteção
Tipo de estudo:
Etiology_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Eur J Neurosci
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
China