Due to the many similarities in mechanisms of action, targets and effects, progesterone, estrogen and neurotrophins have been implicated in synaptic plasticity as well as in neuroprotection and neurodegeneration. In this study, we examined the interactions between 17-β-estradiol (E2) and progesterone (P4) and BDNF on both plasticity and excitotoxicity in rat cultured hippocampal slices. First, we evaluated the neuroprotective effects of E2 and P4 against NMDA toxicity in cultured rat hippocampal slices. As previously reported, pretreatment with 10 nM E2 (24 h) was neuroprotective against NMDA toxicity. However, progesterone (10 nM) added 20 h after E2 treatment for 4 h, reversed its protective effect. In addition, the same E2 treatment resulted in an increase in BDNF protein levels as well as in activation of its receptor, TrkB, while addition of P4 attenuated E2-mediated increase in BDNF and TrkB levels. Furthermore, E2-mediated neuroprotection was eliminated by a BDNF scavenger, TrkB-Fc. Our results indicate that E2 neuroprotective effects are mediated through the BDNF pathway, and that, under certain conditions, P4 antagonizes the protective effect of estrogen.

17β-estradiol and progesterone exert a number of physiological effects throughout the brain due to interactions with several types of receptors belonging to the traditional family of intracellular hormonal receptors as well as to membrane-bound receptors. In particular, both hormones elicit rapid modifications of neuronal excitability that have been postulated to underlie their effects on synaptic plasticity and learning and memory. Likewise, both hormones have been shown to be neuroprotective under certain conditions, possibly due to the activation of pro-survival pathways and the inhibition of pro-apoptotic cascades. Because of the similarities in their cellular effects, there have been a number of questions raised by numerous observations that progesterone inhibits the effects of estrogen. In this manuscript, we first review the interactions between 17β-estradiol (E2) and progesterone (P4) in synaptic plasticity, and conclude that, while E2 exerts a clear and important role in long-term potentiation of synaptic transmission in hippocampal neurons, the role of P4 is much less clear, and could be accounted by the direct or indirect regulation of GABAA receptors. We then discuss the neuroprotective roles of both hormones, in particular against excitotoxicity. In this case, the neuroprotective effects of these hormones are very similar to those of the neurotrophic factor BDNF. Interestingly, P4 antagonizes the effects of E2, possibly through the regulation of estrogen receptors or of proteins associated with the receptors or interactions with signaling pathways activated by E2. Overall, this review emphasizes the existence of common molecules and pathways that participate in the regulation of both synaptic plasticity and neurodegeneration.

Arginase I (AI), the fifth and final enzyme of the urea cycle, detoxifies ammonia as part of the urea cycle. In previous studies from others, AI was not found in extrahepatic tissues except in primate blood cells, and its roles outside the urea cycle have not been well recognized. In this study we undertook an extensive analysis of arginase expression in postnatal mouse tissues by in situ hybridization (ISH) and RT-PCR. We also compared arginase expression patterns with those of ornithine decarboxylase (ODC) and ornithine aminotransferase (OAT). We found that, outside of liver, AI was expressed in many tissues and cells such as the salivary gland, esophagus, stomach, pancreas, thymus, leukocytes, skin, preputial gland, uterus and sympathetic ganglia. The expression was much wider than that of arginase II, which was highly expressed only in the intestine and kidney. Several co-localization patterns of AI, ODC, and OAT have been found: (a) AI was co-localized with ODC alone in some tissues; (b) AI was co-localized with both OAT and ODC in a few tissues; (c) AI was not co-localized with OAT alone in any of the tissues examined; and (d) AI was not co-localized with either ODC or OAT in some tissues. In contrast, AII was not co-localized with either ODC or OAT alone in any of the tissues studied, and co-localization of AII with ODC and OAT was found only in the small intestine. The co-localization patterns of arginase, ODC, and OAT suggested that AI plays different roles in different tissues. The main roles of AI are regulation of arginine concentration by degrading arginine and production of ornithine for polyamine biosynthesis, but AI may not be the principal enzyme for regulating glutamate biosynthesis in tissues and cells.

J. Neurochem. (2010) 115, 1277–1287. Abstract While both 17β‐estradiol (E2) and progesterone (P4) are neuroprotective in several experimental paradigms, P4 also counteracts E2 neuroprotective effects. We recently reported that a 4‐h treatment of cultured hippocampal slices with P4 following a prolonged (20 h) treatment with E2 eliminated estrogenic neuroprotection against NMDA toxicity and induction of brain‐derived neurotrophic factor (BDNF) expression. In the present study, we evaluated the effects of the same treatment on levels of estrogen receptors, ERα and ERβ, and BDNF using a similar paradigm. E2 treatment resulted in elevated ERβ mRNA and protein levels, did not modify ERα mRNA, but increased ERα protein levels, and increased BDNF mRNA levels. P4 reversed E2‐elicited increases in ERβ mRNA and protein levels, in ERα protein levels, and in BDNF mRNA levels. Experiments with an ERβ‐specific antagonist, PHTPP, and specific agonists of ERα and ERβ, propylpyrazoletriol and diarylpropionitrile, respectively, indicated that E2‐mediated neuroprotection against NMDA toxicity was, at least in part, mediated via ERβ receptor. In support of this conclusion, E2 did not protect against NMDA toxicity in cultured hippocampal slices from ERβ−/− mice. Thus, E2‐mediated neuroprotection against NMDA toxicity may be because of estrogenic induction of BDNF via its ERβ receptor, and P4‐mediated inhibition of E2 neuroprotective effects treatment to P4‐induced down‐regulation of ERβ and BDNF.

The molecular basis of complex neuropsychiatric disorders most likely involves many genes. In recent years, specific genetic variations influencing risk for schizophrenia and other neuropsychiatric disorders have been reported. We have used custom DNA microarrays and qPCR to investigate the expression of putative schizophrenia susceptibility genes and related genes of interest in the normal human brain. Expression of 31 genes was measured in Brodmann's area 10 (BA10) in the prefrontal cortex of 72 postmortem brain samples spanning half a century of human aging (18-67 years), each without history of neuropsychiatric illness, neurological disease, or drug abuse. Examination of expression across age allowed the identification of genes whose expression patterns correlate with age, as well as genes that share common expression patterns and that possibly participate in common cellular mechanisms related to the emergence of schizophrenia in early adult life. The expression of GRM3 and RGS4 decreased across the entire age range surveyed, while that of PRODH and DARPP-32 was shown to increase with age. NRG1, ERBB3, and NGFR show expression changes during the years of greatest risk for the development of schizophrenia. Expression of FEZ1, GAD1, and RGS4 showed especially high correlation with one another, in addition to the strongest mean levels of absolute correlation with all other genes studied here. All microarray data are available at NCBI's Gene Expression Omnibus: GEO Series accession number GSE11546 (http://www.ncbi.nlm.nih.gov/geo) [corrected]