Biomol Ther  
Neuroprotective Effect of β-Lapachone in MPTP-Induced Parkinson’s Disease Mouse Model: Involvement of Astroglial p-AMPK/Nrf2/HO-1 Signaling Pathways
Jin-Sun Park, Yea-Hyun Leem, Jung-Eun Park, Do-Yeon Kim and Hee-Sun Kim*
Department of Molecular Medicine, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 07985, Republic of Korea
E-mail: hskimp@ewha.ac.kr
Tel: +82-2-2650-5823, Fax: +82-2-2653-8891
The first two authors contributed equally to this work.
Received: December 13, 2018; Revised: January 2, 2019; Accepted: January 4, 2019; Published online: February 8, 2019.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
Parkinson’s disease is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons within the substantia nigra pars compacta. In the present study, we investigated whether β-Lapachone (β-LAP), a natural naphthoquinone compound isolated from the lapacho tree (Tabebuia avellanedae), elicits neuroprotective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease mouse model. β-LAP reduced the tyrosine hydroxylase (TH)-immunoreactive fiber loss induced by MPTP in the dorsolateral striatum, and alleviated motor dysfunction as determined by the rotarod test. In addition, β-LAP protected against MPTP-induced loss of TH positive neurons, and upregulated B-cell lymphoma 2 protein (Bcl-2) expression in the substantia nigra. Based on previous reports on the neuroprotective role of nuclear factor-E2-related factor-2 (Nrf2) in neurodegenerative diseases, we investigated whether β-LAP induces upregulation of the Nrf2-hemeoxygenae-1 (HO-1) signaling pathway molecules in MPTP-injected mouse brains. Western blot and immunohistochemical analyses indicated that β-LAP increased HO-1 expression in glial fibrillary acidic protein-positive astrocytes. Moreover, β-LAP increased the nuclear translocation and DNA binding activity of Nrf2, and the phosphorylation of upstream adenosine monophosphate-activated protein kinase (AMPK). β-LAP also increased the localization of p-AMPK and Nrf2 in astrocytes. Collectively, our data suggest that β-LAP exerts neuroprotective effect in MPTP-injected mice by upregulating the p-AMPK/Nrf2/HO-1 signaling pathways in astrocytes.
Keywords: β-Lapachone, Parkinson’s disease, Neuroprotection, Astrocyte, Nrf2/HO-1 signaling


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