Oxytocin Alleviates MPTP-Induced Neurotoxicity in Mice by Targeting MicroRNA-26a/Death-Associated Protein Kinase 1 Pathway

Article type: Research Article

Authors: Almansoub, Hasan A.M.M.^{a; b; c} | Tang, Hui^{a; b} | Wu, Ying^{a; b} | Wang, Ding-Qi^{a; b} | Mahaman, Yacoubou Abdoul Razak^{a; b; d} | Salissou, Maibouge Tanko Mahamane^{a; b} | Lu, Youming^b | Hu, Fan^{a; b} | Zhou, Lan-Ting^{a; b} | Almansob, Yusra A.M.^e | Liu, Dan^{a; f; *}

Affiliations: [a] Department of Pathophysiology, Key lab of a neurological disorder of Education Ministry, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China | [b] The Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, P.R. China | [c] Department of Biology, Faculty of Science – Marib, Sana’a University, Marib, Yemen | [d] Department of Cognitive Impairment Ward of Neurology, The Third Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong Province, China | [e] Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China | [f] Department of Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China

Correspondence: [*] Correspondence to: Dan Liu, Department of Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, No. 13, Hangkong Road, Wuhan, 430030, P.R. China. Tel.: +86 2783692625; Fax: +86 2783692608; E-mail: [email protected].

Abstract: Neurotoxicity is one of the major pathological changes in multiple neurological disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), the second popular neurodegenerative disease in aged people. It is known that the AD and PD share the similar neuropathological hallmarks, such as the oxidative stress, loss of specific neurons, and aggregation of specific proteins. However, there are no effective therapeutic drugs for both AD and PD yet. Oxytocin (OXT) is a small peptide with 9 amino acids that is neuroprotective to many neurological disorders. Whether OXT administration confers neuroprotection to 1-methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine (MPTP)-induced neurotoxicity in mice are still not known. In this study, we first found that the OXT levels are decreased in MPTP mice. Supplementation with OXT effectively rescues the locomotor disabilities and anxiety-like behaviors in MPTP mice. OXT also alleviates the hyperphosphorylation of α-synuclein at S129 site and the loss of dopaminergic neurons in the substantia nigra pars compacta, as well as the oxidative stress in the MPTP mice, and alleviates both oxidative stress and cell cytotoxicity in vitro. Furthermore, we found that OXT could inhibit the miR-26a/DAPK1 signal pathway in MPTP mice. In summary, our study demonstrates protective effects of OXT in MPTP mice and that miR-26a/DAPK1 signaling pathway may play an important role in mediating the protection of OXT.

Keywords: Alpha-synuclein, behavior deficit, MPTP, neurotoxicity, oxidative stress, oxytocin, Parkinson’s disease

DOI: 10.3233/JAD-191091

Journal: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 883-901, 2020