Is Testosterone a Risk Factor for Ischemic Stroke and Neurodegeneration in Men?

In the aging population, cardiovascular disease (i.e. stroke) is a common cause of mortality that affects 1 in 3 men. An ischemic event is characterized by oxidative stress (OS) and neuroinflammation. Testosterone is an oxidative stressor, which can be protective or detrimental depending on the environment. In aging males that have high levels of OS, testosterone can increase the risk for ischemic stroke. However, it is unknown if testosterone-induced OS can increase inflammation, such as COX2, a prominent mediator of neuroinflammation and oxidative stress, leading to neuronal death. Therefore, we hypothesize that testosterone, under OS conditions, will further increase OS, induce COX2 inflammation, and increase apoptosis. To test this hypothesis, we exposed a neuronal cell line (N27 cells) to a sublethal concentration of the pro-oxidant, tert-butyl hydrogen peroxide (H2O2) for 24 hours followed by the exposure to physiological levels of testosterone to assess oxidative stress and inflammatory signaling. In addition, N27 cells were exposed to ibuprofen prior to OS (H2O2) and hormone (testosterone) treatment. Under OS conditions, testosterone increased COX2 signaling and apoptosis in neurons. Further, ibuprofen attenuated the effects of testosterone in an OS environment. Our data shows testosterone promotes COX2 inflammation, which contributes to neurodegeneration in an OS environment. Notably, ibuprofen is a common and inexpensive over the counter anti-inflammatory therapeutic. Thus, ibuprofen may be a preventative intervention against ischemic events and neurodegeneration.