Master of Science
Cregan, Sean P
Apoptosis is a highly regulated mode of cell death in the development and progression of neurodegenerative diseases and neuronal injuries. The Bcl-2 protein family are key regulators of the intrinsic mitochondrial apoptotic pathway. Our lab and others have demonstrated that the pro-apoptotic Bcl-2 family member Bax plays a prominent role in regulating neuronal apoptosis. Eltrombopag has been identified as an inhibitor of Bax in in vitro non-neuronal cells. We hypothesized that Eltrombopag would provide neuroprotection against Bax-mediated apoptosis in neurons. Specifically, we investigated whether Eltrombopag could inhibit apoptosis induced by ER-stress using Thapsigargin and oxidative stress using 6OHDA, both of which we have previously shown to be Bax-mediated. In both models of neuronal apoptosis, Eltrombopag administration prevented cytochrome-3 release, inhibited caspase-3 activation, and attenuated neuronal death. Our findings suggest that utilizing Eltrombopag as an inhibitor of the Bcl-2 family protein Bax may be therapeutic in attenuating disease and injury-associated neuronal apoptosis.
Summary for Lay Audience
Death of neurons, the primary cell type within the brain, plays a key role in many different neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease, as well as different types of brain injuries like stroke and concussions. There are many different ways that neurons may die, and targeting the mechanisms that are responsible for neuronal death is a possible form of therapeutics to treat these diseases and injuries. One way that neurons can die is by apoptosis. Apoptosis is a very regulated form of cell death, which means that there is the opportunity to target and prevent this type of cell death when it is implicated in diseases and injuries. When a cell experiences a stressor, such as damage to DNA, stress to the endoplasmic reticulum, or oxidative stress a specific apoptotic pathway called the intrinsic mitochondrial pathway can become activated. A key protein that is required for activation and recruitment of this pathway is Bax. When Bax becomes activated, as a result of cellular stress, it translocates to the mitochondria and triggers the rest of the intrinsic pathway, ultimately resulting in the cell dying. Therefore, if we can stop Bax from becoming activated and initiating this pathway, we can prevent apoptotic death from occurring. One way to prevent Bax from becoming activated in response to stress is to use a pharmacological small molecule that can bind to Bax and inhibit it. Eltrombopag is a drug that has been shown to be able to bind to Bax and keep it in its inactive form. We wanted to see if Eltrombopag could prevent neuron death caused by toxins that are known to induce neuronal apoptosis. To do this we treated neurons with a compound that causes apoptosis in the presence or absence of Eltrombopag and assessed neuronal survival. We found that neurons that received Eltrombopag were partially protected against the effects of the apoptotic toxins, as seen by increased survival and decreased proxy measurements of apoptosis. These results suggest that Eltrombopag may be of therapeutic benefit when trying to attenuate neuronal death that is implicated in neurodegenerative disease and injuries.
Beda, Jordyn, "Investigating the neuroprotective effects of pharmacological Bax inhibition" (2024). Electronic Thesis and Dissertation Repository. 9922.
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