Parkinson's disease (PD) has been associated with exposure to a variety of environmental agents, including pesticides, heavy metals, and organic pollutants; and inflammatory processes appear to constitute a common mechanistic link among these insults. Indeed, toxin exposure has been repeatedly demonstrated to induce the release of oxidative and inflammatory factors from immunocompetent microglia, leading to damage and death of midbrain dopamine (DA) neurons. In particular, proinflammatory cytokines such as tumor necrosis factor- and interferon- , which are produced locally within the brain by microglia, have been implicated in the loss of DA neurons in toxin-based models of PD; and mounting evidence suggests a contributory role of the inflammatory enzyme, cyclooxygenase-2. Likewise, immune-activating bacterial and viral agents were reported to have neurodegenerative effects themselves and to augment the deleterious impact of chemical toxins upon DA neurons. The present paper will focus upon the evidence linking microglia and their inflammatory processes to the death of DA neurons following toxin exposure. Particular attention will be devoted to the possibility that environmental toxins can activate microglia, resulting in these cells adopting a “sensitized” state that favors the production of proinflammatory cytokines and damaging oxidative radicals. 1. Introduction Parkinson’s disease (PD) is the most common neurodegenerative disorder of motor functioning, affecting nearly six million people worldwide. The disorder is particularly prevalent in the elderly population, with a typical clinical onset after 60？65 years of age. Notwithstanding the rare familial forms of PD that appear to have a strong genetic component, the vast majority of PD cases (upwards of 90%) are idiopathic in nature. Regardless of etiology, PD is characterized primarily by the progressive degeneration of dopamine (DA) neurons within the substantia nigra pars compacta (SNc) region of the midbrain, resulting in the diminished monoamine release at downstream striatal nerve terminals. Clinically, the Parkinsonian syndrome, which typically becomes manifest following 50？60% SNc DA neuron loss, comprises a constellation of well-defined motor symptoms, including bradykinesia, hypokinesia (or akinesia), cogwheel rigidity, resting tremor, and postural instability [1]. In addition to the motor impairment evident in all PD cases, a substantial number of PD patients also display prominent “nonmotor” symptoms (many of which manifest before the onset of motor decline and PD diagnosis), including
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