Inflammation as a causative factor in the aetiology of Parkinson's disease

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting mainly the elderly, although a small proportion of PD patients develop the illness at a much younger age. In the former group, idiopathic PD patients, the causes of the illness have been the subject of longstanding debate with environmental toxins, mitochondrial dysfunction, abnormal protein handling and oxidative stress being suggested. One problem has been that the epidemiology of PD has offered few clues to provide evidence for a single major causative factor. Comparatively recently it has been found that in both patients and experimental models of PD in animals neuroinflammation appears to be a ubiquitous finding. These cases present with all of the classical features of inflammation including phagocyte activation, increased synthesis and release of proinflammatory cytokines and complement activation. Although this process is vital for normal function and protection in both the CNS, as in the periphery, it is postulated that in the aetiology of PD this process may spiral out of control with over activation of microglia, over production of cytokines and other proinflammatory mediators as well as the release of destructive molecules such as reactive oxygen species. Given that dopaminergic neurons in the substantia nigra are relatively vulnerable to 'stress' and the region has a large population of microglia in comparison to other CNS structures, these events may easily trigger neurodegeneration. These factors are examined in this review along with a consideration of the possible use of anti-inflammatory drugs in PD.

Figure 1

A simplified schematic of the interaction between microglia and dopaminergic neurons leading to nigral cell damage and death. Activated microglia (subsequent to immune activation or neuronal lesion caused by exposure to toxins such as MPTP or 6-OHDA) can contribute to the degeneration of DA neurons by releasing neurotoxic factors such as PHOX-induced superoxide (H₂O₂) and cytokines (e.g. TNF-α, IL-1β). Cytokines can then activate receptor-mediated proapoptotic pathways within the DA neuron as well as further stimulation of the microglia in the form of iNOS and COX2 induction. The former will lead to greatly increased NO generation and resulting elevation of ROS, which damage the cell as a result of DNA damage, protein disruption and lipid peroxidation. The latter causes increased PGE₂ production leading to direct toxicity to the DA neuron. Superoxide further stimulates microglial cytokine production as well as increases the quantities of ROS in the dopaminergic neuron. As signals from damaged DA cells further recruit and also stimulate microglia, the process can readily spiral out of control into full-blown neurodegeneration.