LAUSR

Objectives B-cell lymphoma-extra large (Bcl-xL) is a pro-survival protein localized to mitochondria. Bcl-xL is reported to support brain function by enhancing neuronal energy metabolism, synapse formation, and neurite outgrowth. However, under exposure to excitotoxic stimulation and subsequent oxidative stress, Bcl-xL undergoes caspase dependent cleavage to ∆N-Bcl-xL. Accumulation of ∆N-Bcl-xL is associated with neuronal death; thus, approaches that prevent ∆N-Bcl-xL accumulation protect neurons from excitotoxic insult. In this study, we hypothesize that ∆N-Bcl-xL formation is regulated by redox status in mitochondria. We thus tested if production of ∆N-Bcl-xL can be inhibited by the fat-soluble antioxidant α-tocotrienol (TCT) given its ability to scavenge free radicals produced in the mitochondrial membrane. Methods Primary hippocampal neurons were treated with α-TCT, glutamate, or a combination of both, and mitochondrial oxidative stress, mitochondrial potential, caspase activity, and ∆N-Bcl-xL protein levels were quantified. Results Glutamate caused abnormalities in mitochondrial function leading to neuronal death. The antioxidant α-TCT protected neurons from glutamate-induced mitochondrial dysfunction and cytotoxicity. α-TCT treatment protected against cleavage of full length anti-apoptotic Bcl-xL to form pro-death ∆N-Bcl-xL. α-TCT significantly attenuated glutamate-induced reactive oxygen species (ROS) formation, caspase 3 activation and ∆N-Bcl-xL formation at mitochondria. Conclusions Our data suggests that oxidative stress production during excitotoxicity is responsible for the formation of ∆N-Bcl-xL. Thus, application of a lipophilic antioxidant such as vitamin E is neuroprotective by improving mitochondrial redox status and preventing production of neurotoxic ∆N-Bcl-xL. Funding Sources -NINDS, RO1-University of Alabama, RGC internal grant.