A new pathway for tocotrienol-mediated neuroprotection in primary hippocampal neurons has been discovered in a recent study conducted by a group of researchers from Yale University and the University of Alabama.
The new study has been published in International Journal of Molecular Sciences, adding to the foundation of non-antioxidant pathway found by Prof Dr Chandan Sen (Indiana University) in the previous two decades, namely - 5 molecular checkpoints.
This new research paper explains that tocotrienol, a compound in the vitamin E family, exerts its neuroprotective effect via a pathway that involves both antioxidant and non-antioxidant functions.
Mitochondrial reactive oxygen species (ROS) are produced in hippocampal neurons during excitotoxic conditions such as after glutamate toxicity. Glutamate toxicity typically occurs during injuries such as stroke or trauma to the head. The resulting ROS production subsequently activates caspase 3, a protein responsible for induction of apoptosis.
In a normal condition, a protein called B-cell lymphoma extra-large (Bcl-xL) supports neurite outgrowth and neurotransmission. However, in excitotoxic situations, caspase 3 would convert Bcl-xL to a fragmented form known as ΔN-Bcl-xL. As opposed to the anti-apoptotic function of Bcl-xL, accumulation of mitochondrial ΔN-Bcl-xL would cause mitochondrial dysfunction and neuronal death. Hence, it is of importance to have a therapeutic agent that could inhibit or slows down the production of pro-apoptotic ΔN-Bcl-xL.
In this study, the role of alpha-tocotrienol (the most neuroprotective isoform of tocotrienol) in protecting primary hippocampal neurons against excitotoxicity was investigated. The study shows that glutamate-induced excitotoxicity increases hippocampal neuronal death, whereas application of alpha-tocotrienol before the induction of excitotoxicity protects hippocampal neurons against excitotoxic stimulation. In addition to that, alpha-tocotrienol is able to significantly attenuate generation of oxidative stress and therefore prevent ROS-induced neuronal death signalling.
Alpha-tocotrienol is able to scavenge ROS, thus indirectly reduces the formation of ΔN-Bcl-xL in neurons via its strong antioxidant activity.
More interestingly, this study also reported another novel pathway in that alpha-tocotrienol plays an important role in blocking the binding of ΔN-Bcl-xL and Bax through competitive inhibition. Naturally, the binding of ΔN-Bcl-xL with Bax will eventually lead to neuronal mitochondrial apoptosis. However, in the presence of alpha-tocotrienol, it competitively binds with ΔN-Bcl-xL and consequentially preventing mitochondrial death.
The researchers concluded that tocotrienol may be a novel nutritional strategy to prevent ROS-mediated ΔN-Bcl-xL formation in neuronal mitochondria and therefore, may be able to protect neuronal cell death.
“This new study shows that tocotrienol could act via the antioxidant pathway and competitive inhibition as well in protecting neurons especially hippocampal neurons against excitotoxicity,” said Bryan See, Business Development Manager of ExcelVite.