Objective/Rationale:
Researchers have reported that early-life inflammation in the brain may increase a risk for development of Parkinson’s disease (PD), but the mechanisms involved remain unclear. This study will use a pre-clinical model to test a potential mechanism by which neonatal brain inflammation may result in a chronic inflammatory environment and prolonged exposure to such an environment may enhance susceptibility of the adult brain to develop Parkinson’s symptoms upon exposures to a toxin at an ordinarily non- or sub-toxic dose.
Project Description:
Five-day old pre-clinical models will be exposed to lipopolysaccharide (LPS), a bacteria endotoxin, through an injection to body cavity (or brain). Inflammatory responses in the brain and alterations in motor function will be monitored. From postnatal day 70, pre-clinical models will be challenged with an ordinarily non- or sub-toxic dose of rotenone, a pesticide used in pre-clinical models of PD, for 14 days. Two weeks later, losses of dopamine neurons, contents of dopamine and its metabolites in the brain and PD-like motor dysfunction will be examined in the LPS-exposed and the control groups. In an additional experiment, anti-inflammatory drugs will be used to prevent the chronic brain inflammation induced by neonatal LPS exposure, and brain injury and motor function will be determined upon the adult rotenone challenge in LPS-exposed pre-clinical models with or without the anti-inflammatory drug treatment.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If this pre-clinical model demonstrates that neonatal central inflammation, an event commonly occurring in human infants, enhances susceptibility of the adult brain to an ordinarily non- or sub-toxic dose of environmental toxins to develop PD-like symptoms, the resulting data will be a strong indication of the importance of anti-inflammation strategies in prevention, or even treatment of PD. This pre-clinical model will be useful for investigating the pathogenesis of non-familial PD.
Anticipated Outcome:
Upon challenges with a low dose of rotenone, significant dopaminergic neuron loss and PD-like motor dysfunction are expected in adult pre-clinical models with the neonatal LPS exposure, but not in those without this exposure. With the treatment of anti-inflammatory drugs, dopaminergic neuron loss and PD-like motor dysfunction following the rotenone challenge will be prevented or attenuated in neonatal LPS-exposed pre-clinical models as compared to those without the drug treatment.