在我們過去的研究發現，格蘭氏陰性菌細胞壁上的脂多醣能夠減緩甲基安非他命在黑核紋狀核胺徑路中所造成多巴胺神經末梢的毒性，本研究試圖探討：1）脂多醣可以減緩甲基安非他命毒性作用的關鍵時間點；2）說明脂多醣減緩甲基安非他命所產生毒性的機制。我們的研究顯示，在甲基安非他命注射前一個星期施打單一劑量的脂多醣(1 mg/kg)沒有保護效果，在三天之前或是兩小時後施打脂多醣都可以見到保護效果。脂多醣注射後，在紋狀體的組織中的細胞激素（包括TNF-α, IL-1β, IL-6, IL-2, IL-5和 IFN-）都有顯著的上升，NFB也有活化的現象，因此我們針對NFB上游的TNF-α施打抑制劑(thalidomide)，發現脂多醣減緩毒性的作用消失。因此我們認為脂多醣能夠減緩甲基安非他命所造成的毒性，是透過在紋狀體中TNF-α表現或是NFB的活化。最後我們注射抑制蛋白質合成的茴香黴素來證實，脂多醣保護機制的確是經由蛋白質的合成來進行。

We previously reported that lipopolysaccharide (LPS) treatment attenuated methamphetamine (MA)-induced nigrostriatal dopaminergic toxicity. This study was undertaken 1) to delineate the critical time window for the protective effects of LPS treatment against the MA-induced dopamine neurotoxicity and 2) to elucidate the underlying mechanism for such protective effects of LPS. We hereby reported that pretreatment with single LPS injection (1 mg/kg) one week before did not affect MA-induced nigrostriatal dopaminergic toxicity. An LPS injection (1 mg/kg) 72 hours before and 2 hours after the MA dosing protocol were effective to diminish the MA-induced nigrostriatal dopamine toxicity. Cytokine assay revealed that TNF-α, IL-1β, IL-6, IL-2, IL-5 and IFN- expressions were all elevated in striatal tissues following peripheral LPS treatment. We further demonstrated that nuclear NFB activation in striatum was enhanced following single LPS injection. Finally, thalidomide, a TNF-α antagonist, pretreatment was found to abolish the LPS pretreatment-associated protective effects in this model. Taken together, these results suggest a critical time window for peripheral LPS treatment in exerting effective protection against MA-induced central dopamine toxicity. Moreover, such protective effects are mediated by enhanced TNF-α expression and/or NFB activation in striatum. Such neuroprotective effects of LPS pretreatment was mitigated by anisomycin treatment, suggesting the roles of genetic expression and protein synthesis in mediating such neuroprotective effects.

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