References for this Review were identified through searches of PubMed with the search terms “Parkinson's disease”, “inflammation”, “cytokine”, glial cell”, “microglia”, “astrocyte”, “lymphocyte”, “MPTP”, and “6-hydroxydopamine” between January, 1988, and January, 2009. Further papers were identified from the references cited in those articles. Only papers published in English were reviewed. The final reference list was generated from papers that were relevant to the topics covered in this
ReviewNeuroinflammation in Parkinson's disease: a target for neuroprotection?
Introduction
Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. It is characterised by a slow and progressive degeneration of dopaminergic neurons in the substantia nigra. Yet, other dopaminergic neurons are also affected, although to a lesser extent.1 This loss of dopaminergic neurons causes most of the motor symptoms of Parkinson's disease, which can be alleviated by restoring neurotransmission with the dopamine precursor levodopa or with dopaminergic agonists. Nevertheless, patients with Parkinson's disease also have levodopa-resistant symptoms, suggesting that non-dopaminergic systems are affected as well.2 For example, non-dopaminergic neurons, including norepinephrinergic neurons in the locus coeruleus, cholinergic neurons in the basal forebrain and the brainstem, and serotoninergic neurons in the raphe nuclei, are also affected by the pathological process. Even neurons outside the CNS, such as those in the olfactory bulb or mesenteric system, degenerate in Parkinson's disease. In addition to the neuronal loss, this disorder is pathologically characterised by the presence of proteinaceous inclusions, such as Lewy bodies or Lewy neurites. These inclusions seem to emerge following an ascending gradient that originates within the lower brainstem, expands to the basal ganglia, and ends in the cerebral cortex.3
Despite intensive research, the cause of neuronal loss in Parkinson's disease and the role of these protein inclusions are not fully understood. However, several molecular and cellular changes that might be involved in neuronal degeneration have been identified, including abnormal protein handling, oxidative stress, mitochondrial dysfunction, excitotoxicity, and apoptotic processes. Neuroinflammatory mechanisms probably also contribute to the cascade of events leading to neuronal degeneration. These mechanisms comprise microglial activation, astrogliosis, and lymphocytic infiltration (figure 1). However, it must be emphasised that these changes are unlikely to be specific for Parkinson's disease, because neuroinflammatory processes contribute to several neurodegenerative disorders, such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and progressive supranuclear palsy.4 This does not imply that neuroinflammation is merely a consequence of neuronal degeneration, as several lines of evidence suggest that it might be involved in the progression of neuronal degeneration by producing deleterious proinflammatory molecules. In this Review, we describe the evidence for neuroinflammatory processes in Parkinson's disease, and the cellular and molecular events associated with neuroinflammation involved in the degeneration of dopaminergic neurons in animal models. Finally, we highlight possible therapeutic targets associated with inflammation that might help to slow down the progression of this neurodegenerative disease.
Section snippets
Post-mortem studies
Data from post-mortem studies provided the first evidence for neuroinflammatory processes in Parkinson's disease. In 1988, McGeer and co-workers5 reported the presence of activated microglial cells within the substantia nigra of patients with Parkinson's disease at post-mortem. These cells were identified by their immunoreactivity to human leucocyte antigen DR (HLA-DR), a cell-surface receptor belonging to the MHC class II. This seminal finding was confirmed by other investigators using
Animal models
Both the cellular and molecular changes seen in the brains of patients with Parkinson's disease have been reproduced in several animal models. The blockade of these changes in animals has provided strong evidence to suggest that neuroinflammatory processes are involved in the death of dopaminergic neurons. In this section we discuss the cellular changes and describe the molecular pathways involved in the neuroinflammatory processes in various animal models of Parkinson's disease.
Therapeutic developments and future directions
The extensive, and still growing, body of evidence discussed above indicates that neuroinflammatory processes are probably involved in the pathophysiology of Parkinson's disease. However, the origin and role of these neuroinflammatory changes need to be established. Neuroinflammation might be a simple consequence of neuronal changes or degeneration. Alternatively, neuroinflammatory processes might be a main cause of the disease. The role of an autoimmune reaction in Parkinson's disease is
Conclusions
Since microglial cell activation was first characterised in the brains of patients with parkinsonian symptoms 20 years ago,5 there has been great interest and developments in the study of neuroinflammation in Parkinson's disease. As can be seen from the data reviewed here, neuroinflammation is now recognised as an important pathophysiological feature of this neurodegenerative disorder. However, despite the progress made so far, one question remains: are immune-associated mechanisms the main
Search strategy and selection criteria
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