zed: 1) Development of an inflammation-associated two-hit PD model After a single intra-peritoneal injection (i.p.) of LPS (1 mg/kg) in 7 month-old male a-synuclein over-expressing mice (Tg mice) and wild type controls (WT mice), delayed, progressive degeneration of nigral DA neurons, as measured by decreases in the number of tyrosine hydroxylase immuno-reactive (TH-IR) neurons, was observed in Tg mice but not in WT mice. At 5 months after LPS injection, Tg mice lost 58% of nigral DA neurons, and their striatal TH levels (at the terminals of DA neuron projection) were reduced by 46%. In contrast, neither nigral DA neurons nor striatal TH levels were altered significantly in LPS-injected WT mice and phosphate buffered saline (PBS)-injected Tg mice compared with PBS-injected WT mice. These results demonstrate synergistic neurotoxicity of LPS treatment and a-synuclein overexpression and strongly indicate gene-environment interactions. The relative selectivity of nigral neuro-degeneration was assessed by double-label immunofluorescence. The number of nigral DA neurons was decreased by 52% in LPS-injected Tg mice, whereas non-DA neurons were relatively spared with only a 9.2% reductiona pattern that is consistent with the neuronal loss observed in PD patients. Collectively, this two-hit PD model reproduced the signature lesion of PD by its chronic, progressive and relatively selective degeneration of DA neurons in the SN. In addition to developing delayed, progressive neuro-degeneration, LPS-injected Tg mice also displayed a-synuclein-related pathology 5 months after treatment as shown by a 25% increase in whole brain levels of a-synuclein compared to PBS-injected Tg mice. We therefore proceeded to characterize these changes in a-synuclein. Sequential extraction using buffers with increasing solubilization strengths identified highly insoluble a-synuclein in the midbrain fractions of Tg mice 5 months after LPS injection. By contrast, a-synuclein from the midbrain fractions of PBS-injected Tg mice and age-matched WT mice injected with either PBS or LPS remained soluble. Double-label immunofluorescence revealed accumulation of a-synucleinpositive aggregates in perinuclear compartments of TH-IR neurons in the SN of LPS-injected Tg mice. LPS-injected Tg mice also had enhanced nitrated human a-synuclein accumulated in neurons to form cytoplasmic inclusions compared with PBS-injected Tg mice. Together, these findings indicate that LPS-induced neuro-inflammation in this two-hit model accelerates a-synuclein accumulation, aggregation and nitration. 2) Development of novel therapeutic drug for treatementof Parkinson's disease Mechanistic studies from our laboratory demonstrated the critical role of microglial activation in inflammation-mediated neuro-degeneration in PD and may also potentially contribute to the pathogenesis of other neuro-degenerative diseases. In support of this finding, epidemiological reports indicate that frequent use of the non-steroidal anti-inflammatory drug (NSAIDs) Ibuprofen is associated with a lower risk for PD. Nonetheless, given the failure of recent clinical trials, the potential of NSAIDs for the treatment of PD remains unclear. Most NSAIDs are designed to target a limited number of pro-inflammatory factors released from immune cells under inflammatory conditions. For example, COX-2 inhibitors mainly reduce the production of prostaglandins, without affecting other factors. This narrow spectrum of action limits the efficacy of the agent as a general anti-inflammatory drug. With this in mind, our laboratory has focused on discovering a novel class of anti-inflammatory drugs for the treatment of PD. Unlike most NSAIDs, our strategy targets upstream neuro-inflammatory signaling by inhibiting microglial NOX2,which in turn reduces superoxide production and over-activation of microglia and thereby reducing the release of most pro-inflammatory factors. This novel class of anti-inflammatory drugs is more efficacious than most of the conventional regimens and thus has received wide attention. Recent studies in this line of approach are highlighted below. Post-treatment with sub-picomolar-acting compounds exhibits neuro-protection While evaluating the dose-related neuro-protective efficacies of some anti-inflammatory compounds we made a fortuitous discovery that some compounds have activities at sub-picomolar concentrations. Specifically, we found that both naloxone and dextromethorphan display anti-inflammatory and neuro-protective effects in neuron-glia cultures at the concentration of 10-13 or 10-14 M. The sub-picomolar acting research is novel and important as a new avenue for therapy, because the safety profile is greatly improved and there is a distinct advantage using minute amounts of drugs. Over the last year we have made significant progress in discovering that the commonly used NOX2 inhibitor diphenylene-iodonium (DPI) also exhibits activity at sub-picomolar concentrations and shows great promise as a potential therapy for PD. In addition, we have gone to great efforts to further understand the mechanism of these sub-picomolar-acting compounds.

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