Hormesis refers to a dose-response relationship that is generally characterized as a biphasic dose response, induces an adaptive beneficial effect on a cell or organism at low doses but inhibits at high doses. Recently, the hormesis concept has been receiving increasing attention in the field of neural research, indicating that improving cellular adaptive ability provides a new idea and method for the prevention and treatment of neurological diseases. A class of useful stressors could markedly increase the neuronal resistance to more drastic stress, which is defined as neurohormesis. Here we reported that natural compound Berberine, PTS and anticancer drugs can induced an obvious hormetic response in rat pheochromocytoma PC12 cells. Moreover we studied their neuroprotective effects in vitro and in vivo. MTT assay showed that the compounds stimulated the cell growth of PC12 cell and exhibited potent neuroprotective effects against injury induced by 6-OHDA and H2O2. TUNEL staining further confirmed that pretreatment of BBR and PTS significantly reduced the cell apoptosis in 6-OHDA-induced injury. Western blot analysis demonstrated that antioxidant and anti-apoptosis proteins were up regulated by low doses of BBR, PTS and CPT, as evidenced by increased levels of p-PI3K, p-AKT, p-mTOR, AMPK, Sir1, Sir3, Nrf2, and HO-1. And inhibition of PI3K by LY294002 abolished the growth promoting effect of CPT and BBR. These results suggest that the hormetic and neuroprotective effects of CPT and BBR at low doses on PC12 cells were attributable, at least partially, to up-regulated PI3K/Akt and Nrf2/HO-1 pathways. Our results provide new ideas for the investigation of neuroprotective mechanisms and drug screening.

毒物興奮效應（Hormesis）是有毒物質在低劑量時對生物體表現爲有利作用， 但是在高劑量時表現出不良效應的雙相劑量效應，也可看作是細胞或機體在不利 環境中的一種自適應機制。最近，研究人員將 Hormesis 理論應用到神經保護中， 指出增強神經細胞自適應能力將成爲神經疾病預防治療的新思路和新方法。一些 低劑量的有利刺激能夠明顯增強神經細胞對于更劇烈刺激的抵抗能力，這種現象 被稱爲“neurohormesis”。本論文提出了天然化合物小檗堿、三七皂苷和抗腫瘤 藥物喜樹堿等可引起 hormesis 現象，产生保护蛋白，帮助细胞抵御进一步的损 伤。並對它們的神經保護作用進行了研究。MTT 結果顯示低劑量的小檗堿、三 七皂苷對 PC12 細胞有明顯的促增長作用，並可抵禦 6-OHDA 對 PC12 造成的損 傷。Tunnel/Hochest 染色結果顯示小檗堿與三七三醇型皂苷預處理可降低 6-OHDA 對 PC12 細胞誘導的凋亡。Western blot 結果顯示小檗堿與三七三醇型皂 苷預處理還可以上調 PC12 細胞中抗氧化蛋白 Nrf2，HO-1 的表達。通過 western blot 結果我們還發現小檗堿預處理可激活 PI3K/Akt 促進神經生長通路，三七三 醇型皂苷預處理可激活 AMPK/Sirt1/ FOXO3 通路。MTT 實驗中使用抑制劑證實 PI3K/Akt 通路參與到小檗堿對 PC12 的促生長作用਀神经保护作用中。我們還發 現拓撲異構酶 I 抑制劑喜樹堿在 PC12 細胞中顯示出了很明顯的 Hormesis 效應和 神經保護作用。拓撲異構酶 II 抑制劑鹽酸阿黴素和依托泊苷在低濃度下同樣可 以在 PC12 細胞中誘導 Hormesis 效應。這些結果說明細胞毒類抗腫瘤藥拓撲異構 酶抑制劑能夠誘導典型的毒物興奮反應。Western blot 結果顯示拓撲異構酶 I 抑 制劑喜樹堿可上調抗氧化蛋白 Nrf2，HO-1，並激活 PI3K/Akt/mTOR 通路。我們 的實驗結果爲神經保護藥物的篩選和作用機制的研究提供了新的思路。 關鍵詞：毒物興奮效應；神經保護; 适应性反应