Alpha-tocotrienol enhances arborization of primary hippocampal neurons via upregulation of Bcl-xL

Alpha-tocotrienol ( a-TCT) is a member of the vitamin E family. It has been reported to protect the brain against various pathologies including cerebral ischemia and neurodegeneration. However, it is still unclear if a-TCT exhibits beneficial effects during brain development. We hypothesized that treatment with a-TCT improves intracellular redox homeostasis supporting normal development of neurons. We found that primary hippocampal neurons isolated from rat feti grown in a-TCT-containing media achieved greater levels of neurite complexity compared to ethanol-treated control neurons. Neurons were treated with 1 mu M aTCT for 3 weeks, and media were replaced with fresh a-TCT every week. Treatment with a-TCT increased a-TCT levels (26 pmol/mg protein) in the cells, whereas the control neurons did not contain a-TCT. a-TCT-treated neurons produced adenosine triphosphate (ATP) at a higher rate and increased ATP retention at neurites, supporting formation of neurite branches. Although treatment with a-TCT alone did not change neuronal viability, neurons grown in a-TCT were more resistant to death at maturity. We further found that messenger RNA and protein levels of B-cell lymphoma-extra large (Bcl-xL) are increased by a-TCT treatment without inducing posttranslational cleavage of Bcl-xL. Bcl-xL is known to enhance mitochondrial energy production, which improves neuronal function including neurite out-growth and neurotransmission. Therefore alpha-TCT-mediated Bcl-xL upregulation may be the central mechanism of neuroprotection seen in the alpha-TCT-treated group. In summary, treat-ment with alpha-TCT upregulates Bcl-xL and increases ATP levels at neurites. This correlates with increased neurite branching during development and with protection of mature neu-rons against oxidative stress. (C) 2022 Elsevier Inc. All rights reserved.