Medroxyprogesterone promotes neuronal survival after cerebral ischemic stroke by inhibiting PARthanatos

Chang-ling Yue ¹ Yan-xia Ding ² Meng Chen ² Yu-xin Shen ³ Ao-meng Hu ² Hai Huang ¹ Zhaohuan Zhang ⁴ Ying-xin Zhou ² Xiao-Hui Xu ^2,5*

• ¹ Shanghai University, Shanghai, Shanghai Municipality, China
• ² School of Preclinical Medicine, Wannan Medical College, Wuhu 241002, China, Wuhu, China
• ³ School of Nursing, Henan University of Chinese Medicine, Zhengzhou, Henan Province, China
• ⁴ Department of Laboratory Medicine, Changzheng Hospital, Naval Medical University, Shanghai 200003, China, Shanghai, China
• ⁵ Wannan Medical College, Wuhu, China

Cerebral Ischemic Stroke (CIS) is caused by the interruption of cerebral blood circulation due to thrombosis or embolism and is the second leading cause of mortality worldwide. The neuronal death and motor dysfunction that result from CIS are primarily attributed to the induction of PARthanatos in neurons at the site of ischemia. Through a comprehensive screening of a pharmacological library using a PARthanatos cell model, we identified medroxyprogesterone as an effective suppressor of MNNG-induced PARthanatos. Further analysis revealed that medroxyprogesterone does not inhibit PARP-1 activity; instead, it directly binds to ERK and stabilizes the active phosphorylated ERK, thereby inhibiting AIF translocation. Preclinical research using animal models has demonstrated that medroxyprogesterone significantly reduces neuronal death in mouse models of CIS by inhibiting PARthanatos. As an approved pharmaceutical agent, medroxyprogesterone exhibits minimal toxicity and side effects, making it suitable for clinical application. These findings suggest that medroxyprogesterone has potential as a neuroprotective agent for patients with CIS, potentially enhancing post-stroke recovery and reducing societal burdens.