The estrogen receptor β-PI3K/Akt pathway mediates the cytoprotective effects of tocotrienol in a cellular Parkinson's disease model

Tocotrienols (T3s) are members of the vitamin E family, have antioxidant properties, and are promising candidates for neuroprotection in the pathogenesis of neurodegenerative disorders such as Parkinson's disease (PD). However, whether their antioxidant capacities are required for their cytoprotective activity remains unclear. In this regard, the antioxidant-independent cytoprotective activity of T3s has received considerable attention. Here, we investigated the signaling pathways that are induced during T3-dependent cytoprotection of human neuroblastoma SH-SY5Y cells, as these cells are used to model certain elements of PD. T3s were cytoprotective against 1-methyl-4-phenylpyridinium ion (MPP+) and other PD-related toxicities. gamma T3 and delta T3 treatments led to marked activation of the PI3K/Akt signaling pathway. Furthermore, we identified estrogen receptor (ER) beta as an upstream mediator of PI3K/Akt signaling following gamma T3/delta T3 stimulation. Highly purified gamma T3/delta T3 bound to ER beta directly in vitro, and knockdown of ERV. in SH-SY5Y cells abrogated both gamma T3/delta T3-dependent cytoprotection and Akt phosphorylation. Since membrane-bound ERL3 was important for the signal-related cytoprotective effects of gamma T3/delta T3, we investigated receptor-mediated caveola formation as a candidate for the early events of signal transduction. Knockdown of caveolin-1 and/or caveolin-2 prevented the cytoprotective effects of gamma T3/delta T3, but did not affect Alct phosphorylation. This finding suggests that T3s and, in particular, gamma T3/delta T3, exhibit not only antioxidant effects but also a receptor signal-mediated protective action following ER beta/PI3K/Akt signaling. Furthermore, receptor-mediated caveola formation is an important event during the early steps following T3 treatment. (C) 2014 Elsevier B.V. All rights reserved.