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Neuroprotection by regulation of neuroinflammation and histone acetylation in the genetic mice models of Parkinson's disease

Title
Neuroprotection by regulation of neuroinflammation and histone acetylation in the genetic mice models of Parkinson's disease
Author
Taewoo Kim
Alternative Author(s)
김태우
Advisor(s)
Hyemyung Seo
Issue Date
2019. 8
Publisher
한양대학교
Degree
Doctor
Abstract
Parkinson’s disease (PD) is one of the most common late-onset neurodegenerative diseases. It is widely known that environmental factors and/or genetic mutations contribute to the pathogenesis of PD. Major characteristics of PD are progressive loss of dopaminergic neurons and the presence of Lewy bodies. In addition, one of the recent outstanding pathological feature of PD is neuroinflammation. Strictly regulated inflammatory responses are of course necessary, but excessive and chronic inflammatory responses lead to neuronal death and continue to induce the progression of PD. Herein, we have attempted to present neuroprotective effect on dopaminergic neurons by controlling neuroinflammtion and histone acetylation in the genetic mice model of PD as a potential therapeutic targets. Matrix metalloproteinases-8 (MMP-8), neutrophil collagenase, is a functional player in the progressive pathology of various inflammatory disorders. In the first series of experiments, we administered an MMP-8 inhibitor (MMP-8i, 5 mg/kg) in LRRK2 G2019S transgenic mice, to determine the effects of MMP-8i on PD pathology. We observed a significant increase in inflammatory markers (CD45 and CD11b) and the number of Iba1-positive activated microglia in the striatum of LRRK2 G2019S mice, indicating increased neuroinflammation. MMP-8i significantly decreased both mRNA and protein level of MMP-8 as well as the number of Iba1-positive activated microglia. MMP-8i increased the levels of cellular ATP and mitochondrial complex IV activity. In addition, MMP-8i significantly increased the cell body area of TH-positive dopaminergic neurons in the SN region of LRRK2 G2019S mice indicating neuroprotective effects on cellular atrophy in PD model mice. Furthermore, MMP-8i markedly improved behavioral abnormalities in LRRK2 G2019S mice in the rota-rod and openfield tests. Previously we demonstrated that VPA, pan histone deacetylase (HDAC) inhibitor, improved an impaired memory and increased nerve growth factor (NGF) protein levels and decreased cytokine levels in Tg6799 Alzheimer’s disease (AD) model mice. We conducted a final series of experiments to determine the effect of HDAC inhibitor on the pathology and symptoms of PD by administering Valproic acid (VPA, 200 mg/kg) in LRRK2 R1441G PD model mice. Administration of VPA improved the motor balance and locomotor activity of PD model mice. Moreover, VPA significantly decreased cytokine mRNA expression levels in midbrain and increased the number of tyrosine hydroxylase (TH)-positive neurons in substantia nigra of LRRK2 R1441G mice, compared to age matched control. Taken together, inhibition of exaggerated inflammatory response could improve and recover the clinical and pathological symptoms of PD. These data suggest that regulation of neuroinflammation by epigenetic control of histone acetylation or inhibition of inflammatory inducer enzyme may be a promising therapeutic targets for PD.
URI
http://dcollection.hanyang.ac.kr/common/orgView/000000110787http://repository.hanyang.ac.kr/handle/20.500.11754/109845
Appears in Collections:
GRADUATE SCHOOL[S](대학원) > MOLECULAR & LIFE SCIENCE(분자생명과학과) > Theses (Ph.D.)
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