Aging Intensifies Myeloperoxidase Activity after Ischemic Stroke.

Abstract

Abnormally elevated oxidative stress underlies many diseases and contributes to aging. The myeloid enzyme myeloperoxidase (MPO) generates oxidative stress and contributes to damage after stroke. How aging changes MPO in stroke has not been studied. We aimed to determine the effects aging has on MPO and how these changes contribute to age-related differences in outcomes after ischemic stroke. To investigate tissue MPO activity we developed MPO Activatable Fluorescent Agent (MAFA). We found that aged mice exhibited worse neurological outcomes and higher mortality within the first few days after stroke. Accordingly, neuronal loss was higher in aged mice on day 3. MAFA imaging revealed that aged brains have markedly higher MPO activity that increased after stroke on day 3 compared to young adult brains. Correspondingly, we found more Iba1⁺ cells in aged brains compared to young adult brains before and after stroke. Interestingly, we found decreased percentage of MPO⁺ cells and lower MPO protein levels in aged on day 3, suggesting that most Iba1⁺ cells in aged mice have degranulated and secreted MPO in response to stroke. By day 10 MPO activity and Iba1⁺ cells decreased in both age groups, although MPO activity remained higher in aged mice. MPO inhibition in aged mice decreased MAFA signal and Iba1⁺ cells and improved neurobehavioral outcomes to near young adult stroke mice levels and improved mortality rate. While aging is an unmodifiable risk, by uncovering the connection between aging and MPO-related changes after stroke, new therapies can be developed to mitigate these adverse changes brought upon by aging.