N-cystaminylbiguanide MC001 prevents neuron cell death and alleviates motor deficits in the MPTP-model of Parkinson's disease

Binglin Xu; Xiaoquan Wang; Zhengshuang Xu; Qinkai Li; Junmin Quan

doi:10.1016/j.neulet.2022.136751

N-cystaminylbiguanide MC001 prevents neuron cell death and alleviates motor deficits in the MPTP-model of Parkinson's disease

Neurosci Lett. 2022 Jul 27:784:136751. doi: 10.1016/j.neulet.2022.136751. Epub 2022 Jun 20.

Authors

Binglin Xu¹, Xiaoquan Wang¹, Zhengshuang Xu², Qinkai Li³, Junmin Quan⁴

Affiliations

¹ State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
² Shenzhen Bay Laboratory, Shenzhen 518055, China.
³ State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China. Electronic address: liqk@pku.edu.cn.
⁴ State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China. Electronic address: quanjm@pku.edu.cn.

PMID: 35738458
DOI: 10.1016/j.neulet.2022.136751

Abstract

Parkinson's disease (PD) is a common neurodegenerative disease characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN), which is highly associated with oxidative stress. Antioxidants are therefore considered as potential therapies in PD treatment. In this study, we examined the neuroprotective effect of a cysteamine-based biguanide N-cystaminylbiguanide (MC001) in the MPTP mouse model of PD. The results showed that MC001 prevented neuron cell death and alleviated motor deficits in the MPTP mouse model of PD. Both in vitro and in vivo data indicated that MC001 may exert its neuroprotective effect by alleviating ROS production, suppressing neuroinflammation, and upregulating BDNF expression. Further mechanistic studies revealed that MC001 promoted GSH synthesis by inducing the expression of Glutamate-cysteine ligase catalytic subunit (Gclc) and enhancing the activity of Glutamate-cysteine ligase (Gcl). Our results suggest that MC001 warrants further investigation as a potential candidate for the treatment of PD.

Keywords: GSH synthesis; Inflammation; N-cystaminylbiguanide; Oxidative stress; Parkinson’s disease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
Animals
Cell Death
Cysteamine / pharmacology*
Disease Models, Animal
Dopaminergic Neurons / metabolism
Glutamate-Cysteine Ligase / metabolism
Glutamate-Cysteine Ligase / pharmacology
Mice
Mice, Inbred C57BL
Neurodegenerative Diseases* / metabolism
Neuroprotective Agents* / metabolism
Neuroprotective Agents* / pharmacology
Parkinson Disease* / drug therapy
Parkinson Disease* / metabolism
Substantia Nigra / metabolism

Substances

Neuroprotective Agents
Cysteamine
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Glutamate-Cysteine Ligase