Protective Effect of Tocotrienol on In Vitro and In Vivo Models of Parkinson's Disease.

Parkinson's disease (PD) is a common progressive neurodegenerative disease. It has been reported that oxidative stress contributes, at least in part, to its pathogenesis. Although dietary epidemiological studies suggest that sufficient intake of vitamin E may prevent the onset of PD, antioxidative therapy for PD with exogenous antioxidants involving α-tocopherol has not been successful in the clinical setting thus far. In recent years, the non-antioxidant activities of vitamin E have been given attention to. In the present study, to determine the antioxidant-independent cytoprotective activity of vitamin E, we investigated whether tocotrienols (T3s), another members of vitamin E family, exhibit the neuroprotective effect in cell and mouse models of PD independently of their antioxidant activities. Treatment with T3s, especially γ- and δ-T3s, exhibited cytoprotective effects via activation of PI3K/Akt signaling pathway in a cellular PD model. We also identified estrogen receptor (ER) β as an upstream mediator of PI3K/Akt signaling and demonstrated the direct binding of T3 to ERβ in vitro. Silencing expression of caveolin suppressed the cytoprotective effects of T3, indicating that caveola formation plays an important role in the cytoprotection by T3 via ERβ/PI3K/Akt signaling pathway. Thus it has been shown that T3 exerts cytoprotective function by a novel mechanism, which includes membrane ERβ/PI3K/Akt signaling via caveola formation as well as its antioxidant activity. Furthermore, we revealed that δ-T3 treatment relieved PD-related symptoms in PD model mice. These results suggest that T3 elicits the cytoprotective effects via ERβ/PI3K/Akt signaling pathway in cellular and murine PD models.