Inflammatory Process as a Determinant Factor for the Degeneration of Substantia Nigra Dopaminergic Neurons: Possible Relevance to the Etiology of Parkinson's Disease

The pathological hallmark of Parkinson's disease (PD) is a specific degeneration of dopaminergic neurons in the substantia nigra (SN). The cause of chronic nigral cell death in PD and its underlying mechanisms remain elusive. The initial degeneration of dopaminergic neurons that occurs at early stages of the disease may activate secondary phenomena, aggravating the pathological process and accounting for the continuous progression of the disease. Since 1988, when McGeer's group showed the presence of inflammatory marks in CNS tissue of patients with PD, the substantial involvement of inflammatory events in the pathogenesis of PD has been postulated. We have developed an animal model of dopaminergic neurons degeneration by a single intranigral injection of lipopolysaccharide (LPS), an inflammatory compound. This single injection produced the induction of inflammatory process with the activation of microglia along with the specific degeneration of dopaminergic neurons in SN without effect in neither other neurotransmitter systems nor other structures of CNS. Inflammatory features have been described in models of PD, such as 6-hydroxydopamine (6- OHDA), 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and rotenone. Moreover, the synergic effect of inflammation on the dopaminergic degenerative process by these toxins strongly suggests the interaction between both degeneration-inducing toxins and inflammation. These evidence strongly suggest that the degenerative process could be produced by toxins, oxidative stress or bioenergetic failure along with the inflammatory process induced by these or other factors, including specific inflammatory compounds. Different inductors of inflammatory process have also been discussed in relationship to dopaminergic degeneration in the SN.