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Inhibition of GluN2D-Containing NMDA Receptors Protects Dopaminergic Neurons against 6-OHDA-Induced Neurotoxicity via Activating ERK/NRF2/HO-1 Signaling.
Zhang, Jin-Bao; Wang, Fen; Tang, Yu-Ting; Pang, Meng-Zhu; Li, Dan; Liu, Chun-Feng.
Afiliação
  • Zhang JB; Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
  • Wang F; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215004, China.
  • Tang YT; Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
  • Pang MZ; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215004, China.
  • Li D; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215004, China.
  • Liu CF; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215004, China.
ACS Chem Neurosci ; 15(3): 572-581, 2024 02 07.
Article em En | MEDLINE | ID: mdl-38277219
ABSTRACT
Abnormal glutamate signaling is implicated in the heightened vulnerability of dopaminergic neurons in Parkinson's disease (PD). NMDA receptors are ion-gated glutamate receptors with high calcium permeability, and their GluN2D subunits are prominently distributed in the basal ganglia and brainstem nuclei. Previous studies have reported that dopamine depletion led to the dysfunctions of GluN2D-containing NMDA receptors in PD animal models. However, it remains unknown whether selective modulation of GluN2D could protect dopaminergic neurons against neurotoxicity in PD. In this study, we found that allosteric activation of GluN2D-containing NMDA receptors decreased the cell viability of MES23.5 dopaminergic cells and the GluN2D inhibitor, QNZ46, showed antioxidant effects and significantly relieved apoptosis in 6-OHDA-treated cells. Meanwhile, we demonstrated that QNZ46 might act via activation of the ERK/NRF2/HO-1 pathway. We also verified that QNZ46 could rescue abnormal behaviors and attenuate dopaminergic cell loss in a 6-OHDA-lesioned rat model of PD. Although the precise mechanisms underlying the efficacy of QNZ46 in vivo remain elusive, the inhibition of the GluN2D subunit should be a considerable way to treat PD. More GluN2D-selective drugs, which present minimal side effects and broad therapeutic windows, need to be developed for PD treatment in future studies.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Síndromes Neurotóxicas Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: ACS Chem Neurosci Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Síndromes Neurotóxicas Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: ACS Chem Neurosci Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China