We examined neuroprotective effects of ␤-estradiol, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S) against N-methyl-D-aspartate (NMDA)-induced neurotoxicity in primary cultured rat hippocampal neurons. All three steroids demonstrated neuroprotective effects. Time-course studies revealed that steroid cotreatment for only 15 min at the same time as exposure to NMDA, but neither pretreatment nor addition of steroids for 24 h after NMDA-mediated neuroprotective effects. This indicates that short-term actions of these steroids are critical for this process. Acute treatment with ␤-estradiol dose dependently inhibited NMDA-induced intracellular Ca 2ϩ increases, which strongly correlated with its neuroprotective effect via L-type voltage-gated calcium channels. Acute treatment with DHEA, but not with DHEA-S, significantly inhibited nitric oxide (NO) production and Ca 2ϩ -sensitive NO synthase (NOS) activity caused by NMDA stimulation. An NOS inhibitor, N G -monomethyl-L-arginine acetate was also protective against NMDA-induced neurotoxicity. These data indicate that ␤-estradiol may exert neuroprotective effects mainly by reducing Ca 2ϩ increases but that DHEA may act by inhibiting NOS activity. Treatment with the -1 receptor (Sig-1R) antagonists rimcazole or BD1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine dihydrochloride) partially, but significantly, reversed the neuroprotective effect of DHEA-S against NMDAinduced neurotoxicity, whereas muscimol, a GABA-A-receptor agonist, did not. This suggests that the neuroprotective effect of DHEA-S may be mediated via Sig-1R, at least in part. Together, our data suggest that the neurosteroid family members ␤-estradiol, DHEA, and DHEA-S exert neuroprotective effects through different nongenomic mechanisms.

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BackgroundFor patients starting treatment for depression, current guidelines recommend titrating the antidepressant dosage to the maximum of the licenced range if tolerated. When patients do not achieve remission within several weeks, recommendations include adding or switching to another antidepressant. However, the relative merits of these guideline strategies remain unestablished.MethodsThis multi-centre, open-label, assessor-blinded, pragmatic trial involved two steps. Step 1 used open-cluster randomisation, allocating clinics into those titrating sertraline up to 50 mg/day or 100 mg/day by week 3. Step 2 used central randomisation to allocate patients who did not remit after 3 weeks of treatment to continue sertraline, to add mirtazapine or to switch to mirtazapine. The primary outcome was depression severity measured with the Patient Health Questionnaire-9 (PHQ-9) (scores between 0 and 27; higher scores, greater depression) at week 9. We applied mixed-model repeated-measures analysis adjusted for key baseline covariates.ResultsBetween December 2010 and March 2015, we recruited 2011 participants with hitherto untreated major depression at 48 clinics in Japan. In step 1, 970 participants were allocated to the 50 mg/day and 1041 to the 100 mg/day arms; 1927 (95.8%) provided primary outcomes. There was no statistically significant difference in the adjusted PHQ-9 score at week 9 between the 50 mg/day arm and the 100 mg/day arm (0.25 point, 95% confidence interval (CI), − 0.58 to 1.07, P = 0.55). Other outcomes proved similar in the two groups.In step 2, 1646 participants not remitted by week 3 were randomised to continue sertraline (n = 551), to add mirtazapine (n = 537) or to switch to mirtazapine (n = 558): 1613 (98.0%) provided primary outcomes. At week 9, adding mirtazapine achieved a reduction in PHQ-9 scores of 0.99 point (0.43 to 1.55, P = 0.0012); switching achieved a reduction of 1.01 points (0.46 to 1.56, P = 0.0012), both relative to continuing sertraline. Combination increased the percentage of remission by 12.4% (6.1 to 19.0%) and switching by 8.4% (2.5 to 14.8%). There were no differences in adverse effects.ConclusionsIn patients with new onset depression, we found no advantage of titrating sertraline to 100 mg vs 50 mg. Patients unremitted by week 3 gained a small benefit in reduction of depressive symptoms at week 9 by switching sertraline to mirtazapine or by adding mirtazapine.Trial registrationClinicalTrials.gov, NCT01109693. Registered on 23 April 2010.Electronic supplementary materialThe online version of this article (10.1186/s12916-018-1096-5) contains supplementary material, which is available to authorized users.

We investigated the effects of antidepressants on the intracellular Ca²⁺ concentration ([Ca²⁺]_i) increases induced by γ-aminobutyric acid (GABA) or N-methyl-D-aspartate (NMDA) in primary cultured rat cortical neurons using fluorescence imaging. Acute treatment with imipramine inhibited GABA- and NMDA-induced increases in [Ca²⁺]_i in a concentration-dependent manner. Doses of 30 μM clomipramine, desipramine, amoxapine and maprotiline also inhibited both the GABA- and NMDA-induced [Ca²⁺]_i increases significantly. Both inhibitory effects of the five major antidepressants on the GABA- or the NMDA-induced [Ca²⁺]_i increases were well-correlated. Imipramine could inhibit significantly high-K⁺-induced [Ca²⁺]_i increases. Our previous study has already shown that the GABA-induced [Ca²⁺]_i increase involves a similar pathway to high-K⁺-induced Ca²⁺ influx. In conclusion, imipramine and several other antidepressants have acute inhibitory effects on the GABA-, NMDA- and high-K⁺-induced [Ca²⁺]_i increases, suggesting that these inhibitory effects are not related to specific receptors. One possibility is that these effects may be commonly mediated via part of the high-K⁺-induced [Ca²⁺]_i pathway.

From previous findings that the physiological responses of buffaloes to hot conditions were characterized by an increase in blood volume, a decrease in hematocrit (Ht) and an increase in skin temperature, we hypothesized that an increase in blood volume in buffaloes contributes to heat transportation from the body core (rectum) to the surface (skin). As a result, the rectal-skin temperature difference in buffaloes was small with the decrease in Ht value and was large with the increase in Ht value. From these results, it was concluded that an increase in blood volume in buffaloes was rapidly caused by the exposure to hot conditions and contributed to reduce the rectal-skin temperature difference and to increase the temperature difference between skin and environment. These characteristics of buffaloes may be advantageous to increase sensible heat loss from the skin surface during a wallowing.