No abstract

In mammalians, toll-like receptors (TLR) signal-transduction pathways induce the expression of a variety of immune-response genes, including inflammatory cytokines. It is therefore plausible to assume that TLRs are mediators in glial cells triggering the release of cytokines that ultimately kill DA neurons in the substantia nigra in Parkinson disease (PD). Accordingly, recent data indicate that TLR4 is up-regulated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in a mouse model of PD. Here, we wished to evaluate the role of TLR4 in the acute mouse MPTP model of PD: TLR4-deficient mice and wild-type littermates control mice were used for the acute administration way of MPTP or a corresponding volume of saline. We demonstrate that TLR4-deficient mice are less vulnerable to MPTP intoxication than wild-type mice and display a decreased number of Iba1+ and MHC II+ activated microglial cells after MPTP application, suggesting that the TLR4 pathway is involved in experimental PD.

There is evidence that an inflammatory microglial reaction participates in the pathophysiology of dopaminergic neuronal death in Parkinson's disease and in animal models of the disease. However, this phenomenon remains incompletely characterized. Using an in vitro model of neuronal/ glial mesencephalic cultures, we show that the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD) and is associated with a progressive loss of dopaminergic neurones in the substantia nigra pars compacta (SNpc). The ensuing diminution of the dopamine (DA) concentration in the main projection area of these neurones, the caudate nucleus and the putamen, induces the characteristic motor symptoms of the disease, which include bradykinesia/ akinesia, rest tremor and rigidity (Agid 1991).Whereas the cause of PD remains unknown, the mechanisms of neuronal death are beginning to be understood. Thus, it is becoming increasingly probable that inflammation plays an important role in the pathogenesis of this neurodegenerative disorder (Hirsch et al. 2003). This hypothesis is supported by several lines of evidence. First, an increased number of major histocompatibility complex class II-positive microglial cells has been found in the SNpc of patients who developed PD (McGeer et al. 1988) or suffered from parkinsonism due to accidental administration of the DA toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Langston et al. 1999). The same observation was also made in the SNpc of MPTPtreated mice (Liberatore et al. 1999)