The Role of Glial Reaction and Inflammation in Parkinson's Disease

Abstract

The glial reaction is generally considered to be a consequence of neuronal death in neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. In Parkinson's disease, postmortem examination reveals a loss of dopaminergic neurons in the substantia nigra associated with a massive astrogliosis and the presence of activated microglial cells. Recent evidence suggests that the disease may progress even when the initial cause of neuronal degeneration has disappeared, suggesting that toxic substances released by the glial cells may be involved in the propagation and perpetuation of neuronal degeneration. Glial cells can release deleterious compounds such as proinflammatory cytokines (TNF‐α, Il‐1β, IFN‐γ), which may act by stimulating nitric oxide production in glial cells, or which may exert a more direct deleterious effect on dopaminergic neurons by activating receptors that contain intracytoplasmic death domains involved in apoptosis. In line with this possibility, an activation of proteases such as caspase‐3 and caspase‐8, which are known effectors of apoptosis, has been reported in Parkinson's disease. Yet, caspase inhibitors or invalidation of TNF‐α receptors does not protect dopaminergic neurons against degeneration in experimental models of the disease, suggesting that manipulation of a single signaling pathway may not be sufficient to protect dopaminergic neurons. In contrast, the antiinflammatory drugs pioglitazone, a PPAR‐γ agonist, and the tetracycline derivative minocycline have been shown to reduce glial activation and protect the substantia nigra in an animal model of the disease. Inhibition of the glial reaction and the inflammatory processes may thus represent a therapeutic target to reduce neuronal degeneration in Parkinson's disease.

Pharmacological inhibition of neuronal NADPH oxidase protects against 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress and apoptosis in mesencephalic dopaminergic neuronal cells

“…These studies demonstrate that the neuroprotective properties of DPI and apocynin are not due to inhibition of microglial NADPH oxidase, but rather are due to inhibition of endogenously expressed NADPH oxidase. In animal studies, DPI and apocynin protect against global cerebral ischemia (Wang et al, 2006), and rotenone- (Gao et al, 2003a), paraquat- (Purisai et al, 2006), 6-OHDA- (Yasuhara et al, 2004), MPTP- (Gao et al, 2003b) and IFN-gamma/LPS- (Hirsch et al, 2003a) induced dopaminergic degeneration. In these studies, the neuroprotective properties of apocynin and DPI were associated with inhibition of microglial NADPH oxidase activity, but the role of neuronal NADPH oxidase was not investigated.…”

Nuclear factor kappa-B mediates selective induction of neuronal nitric oxide synthase in astrocytes during low-level inflammatory stimulation with MPTP

“…While the causes of PD remain unclear, recent evidence strongly supports a role for perturbations in astrocyte physiology and altered expression of the nitric oxide synthase (NOS; E.C. 1.14.13.39) isoforms in progression of the disease (Hirsch et al, 2003;Pekny and Nilsson, 2005;Teismann and Schulz, 2004). Studies exploring pathophysiologic expression of NOS have typically focused on the inducible isoform (NOS2) but induction of the constitutively expressed neuronal nitric oxide synthase (NOS1) has emerged as an underlying component of a diverse array of neurologic disorders, including ischemic cerebral injury (e.g.…”

Potentiation of in vivo neuroprotection by BclXL and GDNF co-expression depends on post-lesion time in deafferentiated CNS neurons

“…27 (ii) BclX L but not Bcl2 can inhibit tumour necrosis factora-activated TRAILmediated apoptotic and non-apoptotic cell death (necrosis and autophagy), 28,29 which play important roles in several neurodegenerative paradigms. [30][31][32] Accordingly, in both model systems evaluated in this study, BclX L plus GDNF co-expression resulted in the most effective prevention of neurodegeneration reported so far.…”