Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Matrix Metalloproteinase-8 Inhibitor Ameliorates Inflammatory Responses and Behavioral Deficits in LRRK2 G2019S Parkinson's Disease Model Mice

  • Kim, Taewoo (Department of Molecular & Life Sciences, Center for Bionano Intelligence Education and Research, Hanyang University) ;
  • Jeon, Jeha (Department of Molecular & Life Sciences, Center for Bionano Intelligence Education and Research, Hanyang University) ;
  • Park, Jin-Sun (Department of Molecular Medicine and Medical Research Institute, School of Medicine, Ewha Womans University) ;
  • Park, Yeongwon (Department of Molecular & Life Sciences, Center for Bionano Intelligence Education and Research, Hanyang University) ;
  • Kim, Jooeui (Department of Molecular & Life Sciences, Center for Bionano Intelligence Education and Research, Hanyang University) ;
  • Noh, Haneul (Department of Molecular & Life Sciences, Center for Bionano Intelligence Education and Research, Hanyang University) ;
  • Kim, Hee-Sun (Department of Molecular Medicine and Medical Research Institute, School of Medicine, Ewha Womans University) ;
  • Seo, Hyemyung (Department of Molecular & Life Sciences, Center for Bionano Intelligence Education and Research, Hanyang University)
  • Received : 2020.10.15
  • Accepted : 2021.04.28
  • Published : 2021.09.01
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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

Acknowledgement

This research was supported by NRF Grants #2017 R1A2B4008456, 2020R1H1A2013386, IITP grant from MSIT 2020-0-01343 (to HS), and #2021R1A2C1006369 (to HK).

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