Trends in Pharmacological Sciences
Novel anti-inflammatory therapy for Parkinson's disease
Section snippets
The deleterious role of neuroinflammation in PD
Inflammation is the first line of defence against injury and infection; however, an excessive inflammatory response can also be a source of additional injury to host cells [16]. The brain has a relatively low adaptive immune response but is vulnerable to innate immune reactions. Neurons, as a result of a lack of ability to divide and little ability to recover from injury, are extremely vulnerable to autodestructive immune and inflammatory processes 17, 18, 19. This might hinder the recovery of
The protective effect of glial cells in PD
As described above, an inflammatory response might contribute to neuronal degeneration in PD. However, some aspects of inflammation might actually be beneficial in combating the disease [16]. Different populations of glia can influence the fate of the injured neurons by complicated and perhaps conflicting actions. For example, it is believed that microglia secrete primarily neurotoxic factors whereas astroglia are a primary source of neurotrophic factors, although activated microglia and
Glial reaction in PD patients and experimental models
A glial response has been observed in the vicinity of dying dopamine-containing neurons in human postmortem SN from PD patients [2] and MPTP-intoxicated patients [1]. Markers of elevated accumulation of NO, ROS and pro-inflammatory cytokines such as TNF-α, IL-1β and interferon γ (IFN-γ) in the SN of PD patients have been demonstrated [21], indicating a state of chronic inflammation in the PD brain. Inflammation has also been implicated in the neurodegenerative process in animal models of PD
Protective effect of inhibition of microglial activation
Given that neuroinflammation is an important contributor to the chronic neurodegenerative process in PD models, and perhaps in PD itself, we propose that inhibition of inflammation could be a promising neuroprotective strategy (Table 1, Fig. 2). Indeed, emerging experimental evidence demonstrates that inhibition of the inflammatory response can attenuate the degeneration of dopamine-containing neurons in several models of PD, which lends strong support to our hypothesis. For example,
Inhibition of inflammation is a promising disease-modifying therapy for PD
The progressive nature of PD presents opportunities for therapeutic intervention aimed at halting the degenerative process. In idiopathic PD, symptoms become apparent when up to 70–80% of striatal dopamine and ∼50% of nigral dopamine-containing neurons are lost. Before reaching the clinically symptomatic stage, there is a preclinical period of 5–7 years. Both positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging seem to be able to detect a decline in
Concluding remarks
The activation of microglia and astroglia observed in the nigrostriatal system of PD patients and animal models of PD suggests the involvement of neuroinflammation in the progression of PD. The observations that the inflammatory process, induced by pro-inflammatory agents, can result in the degeneration of dopamine-containing neurons further indicates that neuroinflammation is an important contributor to the neuronal loss in PD. Moreover, the experimental evidence that inhibition of the
Acknowledgements
We thank Michelle Block for reading this manuscript.
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