| Abstract | The integration of recent, multifactor theories of Parkinson's disease (PD) etiology into animal models of the disease comprise a relatively small portion of the research. In most environmental models of PD, a single neurodegenerative agent is introduced to cause nigrostriatal dopamine depletion. It has been argued, however, that cell loss in human PD often might derive, at least in part, from multiple toxins or vulnerabilities, any one of which alone does not lead to chronic dopamine depletion. Based on previous in vitro research, two agents were delivered to mice peripherally to promote chronic dopamine depletion and neurological impairment: the inflammatory bacterial endotoxin, lipopolysaccharide (LPS) and the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Male C57BL/6J mice received treatment with LPS+MPTP, MPTP-only, LPS-only, or saline and then were evaluated for four months on stride length and motor function in an open field. Mice in the two-factor (LPS+MPTP) group, but not in the single-factor groups, showed dopamine depletion and impaired motor function, including reduced stride length at four months post-injection. The LPS- and MPTP-only groups showed no dopamine depletion or parkinsonian, behavioral deficits. These data are consistent with the view that nigrostriatal dopamine neurons conceivably might succumb chronically to multiple toxic agents that independently may have only a transient adverse effect. In addition to providing preliminary behavioral and neurochemical data consistent with PD, the present LPS+MPTP C57BL/6J mouse model holds advantages for evaluation of early PD that include use of (theoretically) causally-oriented toxic agents, relative cost effectiveness, and simple, systemic administration methods. |
