Microglial activation‐mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson's disease

• Published in: Journal of neurochemistry Vol. 81; no. 6; pp. 1285 - 1297
• Main Authors: Gao, Hui‐Ming, Jiang, Janwei, Wilson, Belinda, Zhang, Wanqin, Hong, Jau‐Shyong, Liu, Bin
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01-06-2002; Blackwell
• Subjects: Animals; Biological and medical sciences; Cell Survival - drug effects; Cells, Cultured; Coculture Techniques; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; dopamine; Dopamine - physiology; inflammation; Lipopolysaccharides - pharmacology; Male; Medical sciences; Mesencephalon - cytology; microglia; Microglia - physiology; Multienzyme Complexes - physiology; NADH, NADPH Oxidoreductases - physiology; Nerve Degeneration - physiopathology; Neuroglia - drug effects; Neuroglia - physiology; Neurology; Neurons - drug effects; Neurons - physiology; Neurotoxins - metabolism; Parkinson Disease - physiopathology; Parkinson's disease; Rats; Rats, Inbred F344; Substantia Nigra - physiopathology; superoxide; Superoxides - metabolism; Time Factors; Rat; Pathogenesis; Neuroglia; Parkinson disease; Activation; Endotoxin; Free radical; NADPH oxidase; Lipopolysaccharide; Degenerative disease; Nervous system diseases; Dopamine; Rodentia; Inflammation; Catecholamine; Cerebral disorder; Microglia; Toxin; Vertebrata; Mammalia; Locus niger; Animal; Central nervous system disease; Neurotransmitter; Dopaminergic neuron; Extrapyramidal syndrome
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2002.00928.x

The etiology of sporadic Parkinson's disease (PD) remains unknown. Increasing evidence has suggested a role for inflammation in the brain in the pathogenesis of PD. However, it has not been clearly demonstrated whether microglial activation, the most integral part of the brain inflammatory process, will result in a delayed and progressive degeneration of dopaminergic neurons in substantia nigra, a hallmark of PD. We report here that chronic infusion of an inflammagen lipopolysaccharide at 5 ng/h for 2 weeks into rat brain triggered a rapid activation of microglia that reached a plateau in 2 weeks, followed by a delayed and gradual loss of nigral dopaminergic neurons that began at between 4 and 6 weeks and reached 70% by 10 weeks. Further investigation of the underlying mechanism of action of microglia‐mediated neurotoxicity using rat mesencephalic neuron‐glia cultures demonstrated that low concentrations of lipopolysaccharide (0.1–10 ng/mL)‐induced microglial activation and production of neurotoxic factors preceded the progressive and selective degeneration of dopaminergic neurons. Among the factors produced by activated microglia, the NADPH oxidase‐mediated release of superoxide appeared to be a predominant effector of neurodegeneration, consistent with the notion that dopaminergic neurons are particularly vulnerable to oxidative insults. This is the first report that microglial activation induced by chronic exposure to inflammagen was capable of inducing a delayed and selective degeneration of nigral dopaminergic neurons and that microglia‐originated free radicals play a pivotal role in dopaminergic neurotoxicity in this inflammation‐mediated model of PD.