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Andrographolide suppresses NLRP3 inflammasome activation in microglia through induction of parkin-mediated mitophagy in in-vitro and in-vivo models of Parkinson disease
Institution:1. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;2. College of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;3. Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai 264005, China;1. Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, Jinan University College of Pharmacy, Guangzhou 510632, China;2. State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Avenue Padre Tomás Pereira S.J., Macao SAR, China;3. Guangdong–Hong Kong–Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China;2. Department of Neurology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 440104, No.151, Yanjiang west Road, China
Abstract:Cellular communication linking microglia activation and dopaminergic neuronal loss play an imperative role in the progression of Parkinson’s disease (PD); however, underlying molecular mechanisms are not precise and require further elucidation. NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation is extensively studied in context to microglial activation and progressive dopaminergic neuronal loss in PD. Several pathophysiological factors such as oxidative stress, mitochondrial dysfunction impaired mitophagy plays a crucial role in activating NLRP3 inflammasome complex. Hence, regulation of microglial activation through mitophagy could be a valuable strategy in controlling microglia mediated neurodegeneration. In this study we have developed a model of inflammasome activation by combining LPS with a mitochondrial complex-I inhibitor MPP+. The idea of using MPP+ after priming mouse microglia with LPS was to disrupt mitochondria and release reactive oxygen species, which act as Signal 2 in augmenting NLRP3 assembly, thereby releasing potent inflammatory mediators such as active interleukin-1 beta (IL-1β) and IL-18. LPS-MPP+ combination was seen to impaired the mitophagy by inhibiting the initial step of autophagosome formation as evidenced by protein expression and confocal imaging data. Treatment with Andrographolide promoted the parkin-dependent autophagic flux formation in microglia; resulting in the removal of defective mitochondria which in turn inhibit NLRP3 inflammasome activation. Additionally, the neuroprotective role of Andrographolide in inhibiting NLRP3 activation together with salvage ATP level via promoting parkin-dependent mitophagy was seen in the substantial nigra par compacta (SNpc) region of mice brain. Furthermore, Andrographolide rescued the dopaminergic neuron loss and improved the behavioural parameters in animal model. Collectively, our results reveal the role of mitophagy in the regulation of NLRP3 inflammasome by removing defective mitochondria. In addition, andrographolide was seen to abate NLRP3 inflammasome activation in microglia and rescue dopaminergic neuron loss.
Keywords:Andrographolide  Mitochondrial dysfunction  Mitophagy  NLRP3 inflammasome  Andro"}  {"#name":"keyword"  "$":{"id":"k0030"}  "$$":[{"#name":"text"  "_":"Andrographolide  ATP"}  {"#name":"keyword"  "$":{"id":"k0040"}  "$$":[{"#name":"text"  "_":"Adenosine triphosphate  CNS"}  {"#name":"keyword"  "$":{"id":"k0050"}  "$$":[{"#name":"text"  "_":"Central nervous system  CQ"}  {"#name":"keyword"  "$":{"id":"k0060"}  "$$":[{"#name":"text"  "_":"Chloroquine  DAMPS"}  {"#name":"keyword"  "$":{"id":"k0070"}  "$$":[{"#name":"text"  "_":"Damage-associated molecular pattern  DCFDA"}  {"#name":"keyword"  "$":{"id":"k0080"}  "$$":[{"#name":"text"  "_":"7′-dichlorodihydrofluorescein diacetate  Drp-1"}  {"#name":"keyword"  "$":{"id":"k0090"}  "$$":[{"#name":"text"  "_":"Dynamin-Related Protein  ELISA"}  {"#name":"keyword"  "$":{"id":"k0100"}  "$$":[{"#name":"text"  "_":"Enzyme-linked immunosorbent assay  HPLC-ECD"}  {"#name":"keyword"  "$":{"id":"k0110"}  "$$":[{"#name":"text"  "_":"High Performance Liquid Chromatography- Electrochemical detection  Iba-1"}  {"#name":"keyword"  "$":{"id":"k0120"}  "$$":[{"#name":"text"  "_":"Ionized calcium binding adaptor molecule 1  IL-1β"}  {"#name":"keyword"  "$":{"id":"k0130"}  "$$":[{"#name":"text"  "_":"Interleukin 1 beta  IL-18"}  {"#name":"keyword"  "$":{"id":"k0140"}  "$$":[{"#name":"text"  "_":"Interleukin-18  JC-1"}  {"#name":"keyword"  "$":{"id":"k0150"}  "$$":[{"#name":"text"  "_":"(5  5′  6  6′-tetrachloro-1  1′  3  3′-tetraethylbenzimi- dazolylcarbocyanine iodide  LC3"}  {"#name":"keyword"  "$":{"id":"k0160"}  "$$":[{"#name":"text"  "_":"Microtubule-associated protein 1A/1B-light chain 3  LPS"}  {"#name":"keyword"  "$":{"id":"k0170"}  "$$":[{"#name":"text"  "_":"Lipopolysaccharides  1-methyl-4-phenylpyridinium  MPTP"}  {"#name":"keyword"  "$":{"id":"k0190"}  "$$":[{"#name":"text"  "_":"1-methyl-4-phenyl-1  2  3  6-tetrahydropyridine  MTT"}  {"#name":"keyword"  "$":{"id":"k0200"}  "$$":[{"#name":"text"  "_":"3-(4  5-dimethylthiazol-2-yl)-2  5-diphenyltetrazolium bromide  NE"}  {"#name":"keyword"  "$":{"id":"k0210"}  "$$":[{"#name":"text"  "_":"Nor-adrenaline  NLRP3"}  {"#name":"keyword"  "$":{"id":"k0220"}  "$$":[{"#name":"text"  "_":"NLR family  pyrin domain containing 3  PAMPS"}  {"#name":"keyword"  "$":{"id":"k0230"}  "$$":[{"#name":"text"  "_":"Pathogen-associated molecular pattern  Parkin"}  {"#name":"keyword"  "$":{"id":"k0240"}  "$$":[{"#name":"text"  "_":"465-residue E3 ubiquitin ligase  PCA"}  {"#name":"keyword"  "$":{"id":"k0250"}  "$$":[{"#name":"text"  "_":"Perchloric acid  PD"}  {"#name":"keyword"  "$":{"id":"k0260"}  "$$":[{"#name":"text"  "_":"Parkinson’s disease  PFA"}  {"#name":"keyword"  "$":{"id":"k0270"}  "$$":[{"#name":"text"  "_":"Paraformaldehyde  q-RT-PCR"}  {"#name":"keyword"  "$":{"id":"k0280"}  "$$":[{"#name":"text"  "_":"Real-time polymerase chain reaction  RIPA"}  {"#name":"keyword"  "$":{"id":"k0290"}  "$$":[{"#name":"text"  "_":"Radio immunoprecipitation assay  ROS"}  {"#name":"keyword"  "$":{"id":"k0300"}  "$$":[{"#name":"text"  "_":"Reactive oxygen species  RPMI"}  {"#name":"keyword"  "$":{"id":"k0310"}  "$$":[{"#name":"text"  "_":"Roswell Park Memorial Institute  SDS-PAGE"}  {"#name":"keyword"  "$":{"id":"k0320"}  "$$":[{"#name":"text"  "_":"Sodium dodecyl sulfate and polyacrylamide gel electrophoresis  SNpc"}  {"#name":"keyword"  "$":{"id":"k0330"}  "$$":[{"#name":"text"  "_":"Substantia nigra par compacta  SQSTM"}  {"#name":"keyword"  "$":{"id":"k0340"}  "$$":[{"#name":"text"  "_":"Sequestosome  TEM"}  {"#name":"keyword"  "$":{"id":"k0350"}  "$$":[{"#name":"text"  "_":"Transmission Electron microscopy  TNF-α"}  {"#name":"keyword"  "$":{"id":"k0360"}  "$$":[{"#name":"text"  "_":"Tumour necrosis factor alpha  VDAC"}  {"#name":"keyword"  "$":{"id":"k0370"}  "$$":[{"#name":"text"  "_":"Voltage-dependent anion channels  6-OHDA"}  {"#name":"keyword"  "$":{"id":"k0380"}  "$$":[{"#name":"text"  "_":"6-hydroxydopamine  5-HT"}  {"#name":"keyword"  "$":{"id":"k0390"}  "$$":[{"#name":"text"  "_":"Serotonin  5-HIAA"}  {"#name":"keyword"  "$":{"id":"k0400"}  "$$":[{"#name":"text"  "_":"5-Hydroxyindoleacetic acid  Δψm"}  {"#name":"keyword"  "$":{"id":"k0410"}  "$$":[{"#name":"text"  "_":"mitochondrial membrane potential
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