Chronic microglial activation and progressive dopaminergic neurotoxicity

Abstract

PD (Parkinson's disease) is characterized by the selective and progressive loss of DA neurons (dopaminergic neurons) in the substantia nigra. Inflammation and activation of microglia, the resident innate immune cell in the brain, have been strongly linked to neurodegenerative diseases, such as PD. Microglia can respond to immunological stimuli and neuronal death to produce a host of toxic factors, including cytokines and ROS (reactive oxygen species). Microglia can also become persistently activated after a single stimulus and maintain the elevated production of both cytokines and ROS, long after the instigating stimulus is gone. Current reports suggest that this chronic microglial activation may be fuelled by either dying/damaged neurons or autocrine and paracrine signals from local glial cells, such as cytokines. Here, we review proposed mechanisms responsible for chronic neuroinflammation and explain the interconnected relationship between deleterious microglial activation, DA neuron damage and neurodegenerative disease.

Cannabinoid Receptor Type 1 Protects Nigrostriatal Dopaminergic Neurons against MPTP Neurotoxicity by Inhibiting Microglial Activation

“…Numerous studies have shown evidence of oxidative stress in PD patients and MPTP-treated mice, including high levels of oxidative nucleic acid damage (64,65) and protein oxidation (5,46). The ROS inducing these molecular modifications are generated by microglial NADPH oxidase and play an important role in the development of oxidative stress in the MPTP model of PD (66). Several studies (7,67), including our recent investigations (4,5), have implicated the activation of microglial NADPH oxidase in DA neuron degeneration in SN of MPTP-treated mice.…”

Glial cells and energy balance

“…If the release of these inflammatory and oxidative stress factors becomes chronic, microglia reactivity worsens, causing toxicity in the surrounding area and possibly affecting neighboring neurons. Hypothalamic POMC neurons have been shown to be particularly vulnerable to this reaction (Block & Hong 2007). Microglia are responsive to metabolic neuropeptides, with NPY and αMSH modulating their secretion of cytokines and NO (Delgado et al 1998, Ferreira et al 2011.…”

The role of neuroinflammation on the pathogenesis of Parkinson's disease

“…Recent reviews have suggested that excessive inflammation may result in DA neuronal loss during the progression of PD (37). Proinflammatory substances such as cyclooxygenase 2 (COX2) and proinflammatory cytokines, including interleukine-1 beta (IL-1β), interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), have been elevated in the postmortem PD brain (38)(39)(40)(41)(42).…”