During the neonatal period of life, hypoxia appears as a major risk factor which may result in complex cerebral dysfunctions like cerebral palsy or seizure disabilities. Natural neuroprotection against hypoxia-induced injury in females is considered to be due to the effects of circulating ovarian hormones, which are lost after ovariectomy or reproductive senescence. Although anti-hypoxic effects of estrogen have been documented, its clinical use has certain limitations. Selective estrogen receptor modulators (SERMs) and selective aryl hydrocarbon receptor modulators (SAhRs) may act as receptor agonists or antagonists in a tissue-specific manner, thus representing a novel approach for the treatment or the prevention of various types of neural degeneration and seizures. In this study we evaluated the mechanism of action of raloxifene and 3,3’-diindolylmethane (DIM) in response to hypoxia in mouse embryonic neuronal cells in primary cultures. Raloxifene is known to bind to estrogen receptors with SERM properties, whereas (DIM) exhibits properties of SAhRs. In our study, hypoxic conditions (5% CO2/95% nitrogen) induced caspase-3 activity and lactate dehydrogenase (LDH) release in the hippocampal cell cultures. Raloxifene and DIM inhibited the hypoxia-induced LDH release by 10–51% and 9–61%, respectively. DIM inhibited also the hypoxia-induced caspase-3 activity by 2–18%, but raloxifene did not affect the hypoxia-induced apoptotic parameter. In our model of hypoxia, estrogen receptor alpha (ER alpha) antagonist MPP (0.01 µM) did not reverse raloxifene-mediated neuroprotection. However, a high-affinity estrogen receptor beta (ER beta) antagonist, PHTPP (0.01 μM), and G-protein coupled receptor 30 antagonist (GPR30), G-15 (0.01 µM), enhanced the neuroprotective effects of raloxifene, which point to neurotoxic potential of ER beta and GPR30 activation in hypoxia. Selective antagonist of aryl hydrocarbon receptors (AhR) alpha-naphthoflavone (1 µM) did not influence neuroprotective action of DIM, thus suggesting AhR-independent effect. These data demonstrated strong neuroprotective potential of raloxifene and DIM which may represent novel therapeutic tools for brain exposed to hypoxic insults. This study was supported by the Polish National Center of Science grant No 2011/01/N/NZ3/04786
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