Matrix Metalloproteinase-8 Inhibitor Ameliorates Inflammatory Responses and Behavioral Deficits in LRRK2 G2019S Parkinson's Disease Model Mice
Open Access
- 1 September 2021
- journal article
- research article
- Published by The Korean Society of Applied Pharmacology in Biomolecules & Therapeutics
- Vol. 29 (5), 483-491
- https://doi.org/10.4062/biomolther.2020.181
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
Funding Information
- National Research Foundation of Korea (R1A2B4008456, 2020R1H1A2013386)
- Ministry of Science and ICT, South Korea (2020-0-01343, #2021R1A2C1006369)
This publication has 47 references indexed in Scilit:
- A novel role for matrix metalloproteinase-8 in sepsis*Critical Care Medicine, 2012
- Microglial glucocorticoid receptors play a pivotal role in regulating dopaminergic neurodegeneration in parkinsonismProceedings of the National Academy of Sciences of the United States of America, 2011
- Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic miceNeurobiology of Disease, 2010
- Matrix metalloproteinase-2 in the development of diabetic retinopathy and mitochondrial dysfunctionLaboratory Investigation, 2010
- Chloramphenicol Causes Mitochondrial Stress, Decreases ATP Biosynthesis, Induces Matrix Metalloproteinase-13 Expression, and Solid-Tumor Cell InvasionToxicological Sciences, 2010
- Leucine-Rich Repeat Kinase 2 Regulates the Progression of Neuropathology Induced by Parkinson's-Disease-Related Mutant α-synucleinNeuron, 2009
- Compensatory changes in the ubiquitin-proteasome system, brain-derived neurotrophic factor and mitochondrial complex II/III in YAC72 and R6/2 transgenic mice partially model Huntington's disease patientsHuman Molecular Genetics, 2008
- Selective inhibition of NF-κB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson's diseaseProceedings of the National Academy of Sciences of the United States of America, 2007
- Increased inflammation delays wound healing in mice deficient in collagenase‐2 (MMP‐8)The FASEB Journal, 2007
- Modulation of microglial pro-inflammatory and neurotoxic activity for the treatment of Parkinson’s diseaseThe AAPS Journal, 2006