Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2020.181
Matrix Metalloproteinase-8 Inhibitor Ameliorates Inflammatory Responses and Behavioral Deficits in LRRK2 G2019S Parkinson’s Disease Model Mice
Taewoo Kim1,†, Jeha Jeon1,†, Jin-Sun Park2, Yeongwon Park1, Jooeui Kim1, Haneul Noh1, Hee-Sun Kim2,* and Hyemyung Seo1,*
1Department of Molecular & Life Sciences, Center for Bionano Intelligence Education and Research, Hanyang University, Ansan 15588,
2Department of Molecular Medicine and Medical Research Institute, School of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea
*E-mail: hseo@hanyang.ac.kr (Seo H), hskimp@ewha.ac.kr (Kim HS)
Tel: +82-31-400-5511 (Seo H), +82-2-6986-6270 (Kim HS)
Fax: +82-31-419-1760 (Seo H), +82-2-6986-7014 (Kim HS)
The first two authors contributed equally to this work.
Received: October 15, 2020; Revised: March 15, 2021; Accepted: April 28, 2021; Published online: May 28, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder that involves the loss of dopaminergic neurons in the substantia nigra (SN). Matrix metalloproteinases-8 (MMP-8), neutrophil collagenase, is a functional player in the progressive pathology of various inflammatory disorders. In this study, we administered an MMP-8 inhibitor (MMP-8i) in Leucine-rich repeat kinase 2 (LRRK2) G2019S transgenic mice, to determine the effects of MMP-8i on PD pathology. We observed a significant increase of ionized calcium- binding adapter molecule 1 (Iba1)-positive activated microglia in the striatum of LRRK2 G2019S mice compared to normal control mice, indicating enhanced neuro-inflammatory responses. The increased number of Iba1-positive activated microglia in LRRK2 G2019S PD mice was down-regulated by systemic administration of MMP-8i. Interestingly, this LRRK2 G2019S PD mice showed significantly reduced size of cell body area of tyrosine hydroxylase (TH) positive neurons in SN region and MMP-8i significantly recovered cellular atrophy shown in PD model indicating distinct neuro-protective effects of MMP-8i. Furthermore, MMP-8i administration markedly improved behavioral abnormalities of motor balancing coordination in rota-rod test in LRRK2 G2019S mice. These data suggest that MMP-8i attenuates the pathological symptoms of PD through anti-inflammatory processes.
Keywords: Parkinson’s disease (PD), Matrix metalloproteinase-8 (MMP-8), Neuro-inflammation, Neuroprotection


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