PACAP/PAC1-R activation contributes to hyperalgesia in 6-OHDA-induced Parkinson’s disease model rats via promoting excitatory synaptic transmission of spinal dorsal horn neurons

Dong, Li-Guo; An, Meng-Qi; Gu, Han‐Ying; Zhang, Li-Ge; Zhang, Jinbao; Li, Chengjie; Mao, Cheng‐Jie; Wang, Fen; Liu, Chunfeng

doi:10.1038/s41401-023-01141-3

Cited by 2 publications

(1 citation statement)

References 67 publications

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“…The rotarod test was conducted to evaluate motor coordination of the rats using a Rotarod apparatus (ZH-300, Zhenghua, China) as previously reported with minor modification. , The rats underwent training for three consecutive days at a constant speed of 10 rpm over three trials, each lasting 5 min with 30 min interval. On the test day, the rats were subjected to an accelerating protocol that increased from 4 to 40 rpm over 5 min.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of GluN2D-Containing NMDA Receptors Protects Dopaminergic Neurons against 6-OHDA-Induced Neurotoxicity via Activating ERK/NRF2/HO-1 Signaling

Zhang,

Wang,

Tang

et al. 2024

ACS Chem. Neurosci.

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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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Section: Methodsmentioning

confidence: 99%

Inhibition of GluN2D-Containing NMDA Receptors Protects Dopaminergic Neurons against 6-OHDA-Induced Neurotoxicity via Activating ERK/NRF2/HO-1 Signaling

Zhang,

Wang,

Tang

et al. 2024

ACS Chem. Neurosci.

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Serum neurotransmitter analysis of motor and non-motor symptoms in Parkinson’s patients

Fan,

Yang,

et al. 2024

Front. Aging Neurosci.

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Clinical symptoms of Parkinson’s disease (PD) are classified into motor and non-motor symptoms. Mental disorders, especially depression, are one of the major non-motor manifestations of PD. However, the underlying mechanisms remain poorly understood. In the present study, 21 neurotransmitters associated with mental disorders were measured in serum samples from patients and controls using the ultra-high performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) assay. Additionally, five clinical scales—the MDS Unified Parkinson’s Disease Rating Scale (UPDRS), the Non-Motor Symptoms Scale (NMSS), the Mini-Mental State Examination (MMSE), the Hamilton Anxiety Scale (HAMA), and the Hamilton Depression Scale (HAMD)—were used to evaluate the severity of both motor and non-motor symptoms in PD patients. Analysis of neurotransmitter metabolism revealed significant changes in the tryptophan (Trp) metabolic pathway in PD patients. Specifically, levels of Trp, kynurenine (KYN), kynurenic acid (KA), nicotinamide (NAM), and 5-methoxyltryptamine (MeOTA) were substantially decreased. Additionally, three other excitation/inhibiting amino acids—glutamic acid (Glu), 4-aminobutyric acid (GABA), and aspartic acid (Asp)—also declined. Moreover, neurotransmitter conversion ratios, such as KA/KYN, nicotinamide/niacin (NAM/NA), 5-hydroxytryptophan/tryptophan (5-HTP/Trp), and quinolinic acid/kynurenic acid (QA/KA), provided more dynamic insights into disrupted neurotransmitter metabolism. Correlation analyses between scale scores and neurotransmitter levels showed that concentrations of xanthurenic acid (XA) and the turnover rate of 3-hydroxykynurenine (3-HK) were negatively correlated with UPDRS scores, while 5-hydroxytryptamine (5-HT) and GABA levels were negatively correlated with non-motor symptoms in PD patients. In summary, this study elucidates, for the first time, the potential association and dynamics between altered neurotransmitter metabolism and the etiology of PD in terms of motor and non-motor functions. These findings offer novel biomarkers and therapeutic targets for the treatment of PD.

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PACAP/PAC1-R activation contributes to hyperalgesia in 6-OHDA-induced Parkinson’s disease model rats via promoting excitatory synaptic transmission of spinal dorsal horn neurons

Cited by 2 publications

References 67 publications

Inhibition of GluN2D-Containing NMDA Receptors Protects Dopaminergic Neurons against 6-OHDA-Induced Neurotoxicity via Activating ERK/NRF2/HO-1 Signaling

Inhibition of GluN2D-Containing NMDA Receptors Protects Dopaminergic Neurons against 6-OHDA-Induced Neurotoxicity via Activating ERK/NRF2/HO-1 Signaling

Serum neurotransmitter analysis of motor and non-motor symptoms in Parkinson’s patients

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