Inhibition
of GluN2D-Containing NMDA Receptors
Protects Dopaminergic
Neurons against 6‑OHDA-Induced Neurotoxicity via Activating
ERK/NRF2/HO‑1 Signaling
posted on 2024-01-26, 17:04authored byJin-Bao Zhang, Fen Wang, Yu-Ting Tang, Meng-Zhu Pang, Dan Li, Chun-Feng Liu
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.