The ovarian hormone progesterone is neuroprotective in some animal models of neurodegeneration. Progesterone actions in the brain may partly be mediated by the locally produced metabolites 5alpha-dihydroprogesterone and 3alpha,5alpha-tetrahydroprogesterone. The neuroprotective effects of these two metabolites of progesterone were assessed in this study. Ovariectomized Wistar rats were injected with kainic acid, to induce excitotoxic neuronal death in the hippocampus, and with different doses of 5alpha-dihydroprogesterone and 3alpha,5alpha-tetrahydroprogesterone. The number of surviving neurones in the hilus of the dentate gyrus of the hippocampus was assessed with the optical disector method. The administration of kainic acid resulted in a significant decrease in the number of hilar neurones and in the induction of vimentin expression in reactive astrocytes, a sign of neural damage. Low doses of 5alpha-dihydroprogesterone (0.25 and 0.5 mg/kg body weight, b.w.) prevented the loss of hilar neurones and the appearance of vimentin immunoreactivity in astrocytes. Higher doses (1-2 mg/kg b.w.) were not neuroprotective. By contrast, low doses of 3alpha,5alpha-tetrahydroprogesterone (0.25-1 mg/kg b.w.) were unable to protect the hilus from kainic acid while higher doses (2-4 mg/kg b.w.) were protective. The different optimal neuroprotective doses of 5alpha-dihydroprogesterone and 3alpha,5alpha-tetrahydroprogesterone suggest that these two steroids may protect neurones using different mechanisms. The neuroprotective effects of 3alpha,5alpha-tetrahydroprogesterone may be exerted by the inhibition of neuronal activity via the GABAA receptor. This latter possibility is supported by the observation that 3beta,5alpha-tetrahydroprogesterone, an isomer of 3alpha,5alpha-tetrahydroprogesterone that does not bind to GABAA receptor, was not neuroprotective. In summary, our findings suggest that progesterone neuroprotective effects may be, at least in part, mediated by its reduced metabolites 5alpha-dihydroprogesterone and 3alpha,5alpha-tetrahydroprogesterone.

The ovarian hormone progesterone is neuroprotective in different experimental models of neurodegeneration. In the nervous system, progesterone is metabolized to 5alpha-dihydroprogesterone (DHP) by the enzyme 5alpha-reductase. DHP is subsequently reduced to 3alpha,5alpha-tetrahydroprogesterone (THP) by a reversible reaction catalyzed by the enzyme 3alpha-hydroxysteroid dehydrogenase. In this study we have analyzed whether progesterone metabolism is involved in the neuroprotective effect of the hormone in the hilus of the hippocampus of ovariectomized rats injected with kainic acid, an experimental model of excitotoxic cell death. Progesterone increased the levels of DHP and THP in plasma and hippocampus and prevented kainic-acid-induced neuronal loss. In contrast to progesterone, the synthetic progestin medroxyprogesterone acetate (MPA, Provera) did not increase DHP and THP levels and did not prevent kainic-acid-induced neuronal loss. The administration of the 5alpha-reductase inhibitor finasteride prevented the increase in the levels of DHP and THP in plasma and hippocampus as a result of progesterone administration and abolished the neuroprotective effect of progesterone. Both DHP and THP were neuroprotective against kainic acid. However, the administration of indomethacin, a 3alpha-hydroxysteroid dehydrogenase inhibitor, blocked the neuroprotective effect of both DHP and THP, suggesting that both metabolites are necessary for the neuroprotective effect of progesterone. In conclusion, our findings indicate that progesterone is neuroprotective against kainic acid excitotoxicity in vivo while the synthetic progestin MPA is not and suggest that progesterone metabolism to its reduced derivatives DHP and THP is necessary for the neuroprotective effect of the hormone.

Neuroprotective effects of estradiol are well characterized in animal experimental models. However, in humans, the outcome of estrogen treatment for cognitive function and neurological diseases is very controversial. Selective estrogen receptor modulators (SERMs) may represent an alternative to estrogen for the treatment or the prevention of neurodegenerative disorders. SERMs interact with the estrogen receptors and have tissue-specific effects distinct from those of estradiol, acting as estrogen agonists in some tissues and as antagonists in others. In this study we have assessed the effect of tamoxifen, raloxifene, lasofoxifene (CP-336,156), bazedoxifene (TSE-424), and 17beta-estradiol on the hippocampus of adult ovariectomized rats, after the administration of the excitotoxin kainic acid. Administration of kainic acid induced the expression of vimentin in reactive astroglia and a significant neuronal loss in the hilus. SERMs did not affect vimentin immunoreactivity in the hilus, while 17beta-estradiol significantly reduced the surface density of vimentin immunoreactive profiles. Estradiol, tamoxifen (0.4-2 mg/kg), raloxifene (0.4-2 mg/kg), and bazedoxifene (2 mg/kg) prevented neuronal loss in the hilus after the administration of kainic acid. Lasofoxifene (0.4-2 mg/kg) was not neuroprotective. These findings indicate that SERMs present different dose-dependent neuroprotective effects. Furthermore, the mechanisms of neuroprotection by SERMs and estradiol are not identical, because SERMs do not significantly affect reactive gliosis while neuroprotection by estradiol is associated with a strong down-regulation of reactive astroglia.

IMPORTANCE Although an emergency coronary angiogram (CAG) is recommended for patients who experience an out-of-hospital cardiac arrest (OHCA) with ST-segment elevation on the postresuscitation electrocardiogram (ECG), this strategy is still debated in patients without ST-segment elevation. OBJECTIVE To assess the 180-day survival rate with Cerebral Performance Category (CPC) 1 or 2 of patients who experience an OHCA without ST-segment elevation on ECG and undergo emergency CAG vs delayed CAG. DESIGN, SETTING, AND PARTICIPANTS The Emergency vs Delayed Coronary Angiogram in Survivors of Out-of-Hospital Cardiac Arrest (EMERGE) trial randomly assigned survivors of an OHCA without ST-segment elevation on ECG to either emergency or delayed (48 to 96 hours) CAG in 22 French centers.

Estradiol (E 2 ) modulates affective and socio-sexual behavior of female rodents. E 2 's functional effects may involve actions through a and b isoforms of estrogen receptor (ERs). The importance of E 2 's actions at these isoforms for anxiety (open field, elevated plus maze), depression (forced swim test), and sexual behavior (lordosis) was investigated using an antisense oligonucleotide (AS-ODN) strategy. If ERb is required for anti-anxiety and antidepressant-like effects, and ERa is required for sexual receptivity, of E 2 , then intracerebroventricular administration of AS-ODNs against these ERs should attenuate these effects and reduce immunoreactivity of ERs in brain regions that mediate these behaviors, such as the hippocampus and ventral medial hypothalamus (VMH). Ovariectomized rats were primed with 17b-E 2 (10 mg) 48 h before testing (hour 0). At hours 0, 24, and 47.5, rats were infused with saline vehicle, scrambled control AS-ODNs, or AS-ODNs targeted against ERa and/or ERb, and were tested at hour 48. Rats infused with ERb AS-ODNs, alone, or with ERa AS-ODNs had significantly decreased open field central entries, decreased plus maze open arm time and entries, increased time spent immobile, and decreased time spent swimming in the forced swim test, and decreased ERb immunoreactivity in the brain than did rats administered ERa AS-ODNs, vehicle, or scrambled AS-ODNs. Rats that were administered ERa AS-ODNs, alone, or with ERb AS-ODNs had significantly decreased lordosis and decreased ERa immunoreactivity in the brain compared to rats administered ERb AS-ODNs, vehicle, or scrambled AS-ODNs. Thus, ERb and ERa may be required for E 2 's modulation of affective and sexual behavior, respectively.