Estrogen protection against mitochondrial toxin-induced cell death in hippocampal neurons: Antagonism by progesterone

Previously we demonstrated that mitochondrial dysfunction plays a critical role in the pathogenesis of Alzheimer's disease. Further, we have shown that the neuroprotective effects of 17β-estradiol (E2) are dependent upon mitochondrial function. In the current study, we sought to identify mitochondrial sites of E2 action that mediate neuroprotection by assessing the efficacy of E2 to protect neurons against inhibitors of mitochondrial respiration which target specific complexes within the respiratory chain. Subsequently, the impact of progesterone (P4) on E2-induced prevention against mitochondrial toxins was investigated. Mitochondrial inhibitors, rotenone, 3-NPA, antimycin, KCN, and oligomycin, exhibited concentration dependent toxicity in primary hippocampal neurons. The concentration inducing 30% cell death (LD30) was selected for analyses assessing the neuroprotective efficacy of ovarian hormones (E2 and P4). Pretreatment of hippocampal neurons with E2 significantly protected against 3-NPA (7.5 mM) and antimycin (125 μM) induced cell death and was moderately neuroprotective against rotenone (3 μM). E2 was ineffective against KCN and oligomycin-induced cell death. Pretreatment with P4 was without effect against these mitochondrial inhibitors. Co-administration of P4 with E2 abolished E2 induced neuroprotection against 3-NPA and antimycin. Additional metabolic analyses indicated that E2 and P4 separately increased mitochondrial respiratory capacity whereas the co-administration of E2 and P4 resulted in diminished mitochondrial respiration. These findings indicate that E2 protects against mitochondrial toxins that target complexes I, II and III whereas P4 was without effect. The data also predict that continuous combined co-administration of estrogen and progesterone common to many hormone therapy regimens is unlikely to prevent the deficits in mitochondrial function.