[논문]Matrix Metalloproteinase-8 Inhibitor Ameliorates Inflammatory Responses and Behavioral Deficits in LRRK2 G2019S Parkinson's Disease Model Mice

Kim, Taewoo; Jeon, Jeha; Park, Jin-Sun; Park, Yeongwon; Kim, Jooeui; Noh, Haneul; Kim, Hee-Sun; Seo, Hyemyung

doi:10.4062/biomolther.2020.181

Matrix Metalloproteinase-8 Inhibitor Ameliorates Inflammatory Responses and Behavioral Deficits in LRRK2 G2019S Parkinson's Disease Model Mice 원문보기

Biomolecules & therapeutics, v.29 no.5, 2021년, pp.483 - 491

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)

Abstract ▼ AI-Helper

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.

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표/그림 (6)

표 Table 1. List of primers used for quantitative RT-PCR
그림 Fig. 1. The effects of MMP-8i on proinflammatory markers and microglial activation. (A) The number of Iba1-positive activated microglial cells in the striatum was visualized and quantified by immunohistochemical analysis (LM *ANOVA F=78.804, p=0.000, ^§ANOVA F=66.663, p=0.000, MT *ANOVA F=7.108, p=0.000). (B) The mRNA levels of proinflammatory markers were detected by RT-PCR in the striatum of LRRK2 G2019S (MT) and littermate (LM) control mice (ANOVA F=3.602, p=0.052). (*p<0.05, between the MMP-8i and vehicle (Veh) injection groups; ^§p<0.05, between MT and LM mice). Data are expressed as the mean ± SEM of four independent experiments. Scale bars indicate 50 μm.
그림 Fig. 2. The effects of MMP-8i on protein expression levels in the striatum of LRRK2 G2019S mice. The protein levels of LRRK2, CD45, and MMP8 were detected from the striatum sample of LRRK2 G2019S mice using Western blot (A) and slot immunoblot (B). The protein expression levels were normalized by cellular β-actin and GAPDH respectively.
$Fig. 3. The effects of MMP-8i on the level of GSH/GSSG, ATP, and mitochondrial complex I, II/III, and IV activities, in the striatum of LRRK2 G2019S mice. (A) Endogenous oxidative stress levels were measured by GSH/GSSG ratio that did not show significant changes by MMP- 8i. (B) Oxidative phosphorylation, which was measured by ATP levels in mitochondrial fraction, showed significant increase after MMP-8i administration (ANOVA F=8.917, p=0.01). (C) Mitochondrial complex I, II/III, and IV activities were detected by substrate-enzyme reactions and complex IV activity showed significant increase by MMP-8i in littermate control mice (ANOVA F=6.120, p=0.028) (*p<0.05, between the MMP-8i and vehicle (Veh) injection groups). Data are expressed as the mean ± SEM of four independent experiments.$ 그림 Fig. 3. The effects of MMP-8i on the level of GSH/GSSG, ATP, and mitochondrial complex I, II/III, and IV activities, in the striatum of LRRK2 G2019S mice. (A) Endogenous oxidative stress levels were measured by GSH/GSSG ratio that did not show significant changes by MMP- 8i. (B) Oxidative phosphorylation, which was measured by ATP levels in mitochondrial fraction, showed significant increase after MMP-8i administration (ANOVA F=8.917, p=0.01). (C) Mitochondrial complex I, II/III, and IV activities were detected by substrate-enzyme reactions and complex IV activity showed significant increase by MMP-8i in littermate control mice (ANOVA F=6.120, p=0.028) (*p<0.05, between the MMP-8i and vehicle (Veh) injection groups). Data are expressed as the mean ± SEM of four independent experiments.
그림 Fig. 4. TH-positive neurons in the substantia nigra (A) and ChAT-positive neurons in the basolateral amygdala (BLA) (B) were stained and analyzed by immunohistochemical techniques to determine the effects of MMP-8i on the population of the designated neurons (A, ^§ANOVA F=44.374, p=0.000, *ANOVA F=8.281, p=0.009; B, *ANOVA F=7.320, p=0.008, ^§ANOVA F=85.116, p=0.000) (*p<0.05, between the MMP-8i and vehicle (Veh) injection groups; ^§p<0.05, between MT and LM mice, n=7 for each experimental group). Data are expressed as the mean ± SEM of four independent experiments. Scale bars indicate 50 μm.
그림 Fig. 5. The effect of MMP-8i on motor behavior in LRRK2 G2019S mice using the rota-rod test and the open field test. (A) Latency to fall was detected to evaluate motor coordination in the rota-rod test. (B) Rearing was counted in the open field test to detect general activity. (C) Time spent in the center was counted in the open field test to detect anxiety-like activity (ANOVA F=10.980, p=0.008) (*p<0.05, between the MMP-8i and vehicle (Veh) injection groups; ^§p<0.05, between MT and LM mice). Data are expressed as the mean ± SEM of four independent experiments.

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