Progesterone Attenuates Aβ(25-35)-induced Neuronal Toxicity Via JNK Inactivation and Progesterone Receptor Membrane Component 1-dependent Inhibition of Mitochondrial Apoptotic Pathway

Progesterone, which acts as a neurosteroid in nervous system, has been shown to have neuroprotective effects in different experiments in vitro and in vivo. Our previous study demonstrates that progesterone exerts neuroprotections in Alzheimer's disease-like rats. Present study attempted to evaluate the protective effects of progesterone on Aβ-treated neurons and potential mechanisms involved in neuroprotection. Results showed that treatment with progesterone protected primary cultured rat cortical neurons against Aβ(25-35)-induced apoptosis. Furthermore, we observed that progesterone alleviated mitochondrial dysfunction by rescuing mitochondrial membrane potential under Aβ challenge. Moreover, progesterone could also attenuate Bax/Bcl-2 proteins ratio upregulation and inhibit the activation of caspase-3 in Aβ-treated neurons. These indicate that progesterone attenuates Aβ(25-35)-induced neuronal toxicity by inhibiting mitochondria-associated apoptotic pathway. Both classic progesterone receptors (classic PR) and progesterone receptor membrane component 1 (PGRMC1), a special progesterone membrane receptor, are broadly expressed throughout the brain. The protective effect of progesterone was partially abolished by PGRMC1 inhibitor AG205 rather than classic PR antagonist RU486 in this study. Additionally, progesterone protected neurons by inhibiting Aβ-induced activation of JNK, which was an upstream signaling component in Aβ-induced mitochondria-associated apoptotic pathway. But this process was independent of PGRMC1. Taken together, these results suggest that progesterone exerts a protective effect against Aβ(25-35)-induced insults at least in part by two complementary pathways: (1) progesterone receptor membrane component 1-dependent inhibition of mitochondrial apoptotic pathway, and (2) blocking Aβ-induced JNK activation. The present study provides new insights into the mechanism by which progesterone brings neuroprotection. This article is part of a Special Issue entitled 'Steroids & Nervous System'.