Systemic lipopolysaccharide plus MPTP as a model of dopamine loss and gait instability in C57Bl/6J mice

In most environmental models of Parkinson's disease (PD), a single neurodegenerative agent is introduced to cause nigrostriatal dopamine depletion. However, cell loss in human PD often might derive, at least in part, from multiple toxins or vulnerabilities, any one of which alone does not inevitably lead to chronic dopamine depletion. In the present research, male C57BL/6J mice were systemically administered the inflammatory bacterial endotoxin, lipopolysaccharide (LPS) and the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) alone or in combination and the behavior as well as striatal dopamine levels were compared to saline-treated mice. Mice in the combination (LPS + MPTP) group, but not in the single-factor groups, showed both dopamine depletion and parkinsonian symptoms, i.e., reduced stride length, at 4 months post-injection. MPTP alone acutely reduced striatal dopamine levels but this effect was transient as striatal dopamine recovered to normal levels after time (4 months). The LPS-only group showed no dopamine depletion or reduced stride length. These data are consistent with the view that nigrostriatal dopamine neurons might succumb after time to multiple toxic agents that independently may have only a transient, adverse effect.