Dexmedetomidine improves the acute stress reactivity of male rat through interventions of serum- and glucocorticoid-inducible kinase 1 and nNOS in the bed nucleus of the stria terminalis.

Moderate acute stress responses are beneficial for adaptation and maintenance of homeostasis. Exposure of male rat to stress induces effects in the bed nucleus of the stria terminalis (BNST), for it can be activated by the same stimuli that induce activation of the hypothalamic-pituitary-adrenal axis. However, the underlying mechanism of the BNST on male stress reactivity remains unclear. In this study, we explored whether systematic administration of dexmedetomidine (DEXM) altered the acute stress reactivity through its effect on the BNST. Male Sprague-Dawley rats in the stress (STRE) group, DEXM group, and the DEXM + GSK-650394 (GSK, an antagonist of serum- and glucocorticoid-inducible kinase 1 (SGK1)) group, except those in the vehicle (VEH) group, underwent 1-h restraint plus water-immersion (RPWI) exposure. All the rats proceeded the open field test (OFT) 24 h before RPWI and 1 h after RPWI. After the second OFT, the rats received VEH, DEXM (75 µg/kg i.p.), or were pretreated with GSK (2 µM i.p.) 0.5 h ahead of DEXM respectively. The third OFT was conducted 6 h after drug administration and then the rats were sacrificed. The rats that experienced RPWI showed dramatically elevated serum corticosterone (CORT), multiplied neuronal nitric oxide synthase (nNOS) and SGK1 in the BNST, and terrible OFT behavior. We discovered when the nNOS and SGK1 were decreased in the rat BNST through DEXM treatment, the serum CORT was reduced and the OFT manifestation was ameliorated, whereas these were restrained by GSK application. Our results reveal that modest interventions to SGK1 and nNOS in the BNST improve the male rat reactivity to acute stress, and DEXM was one modulator of these effects.

Isoflurane and Sevoflurane Induce Cognitive Impairment in Neonatal Rats by Inhibiting Neural Stem Cell Development Through Microglial Activation, Neuroinflammation, and Suppression of VEGFR2 Signaling Pathway.

Inhaled anesthetics are known to induce neurotoxicity in the developing brains of rodents, although the mechanisms are not well understood. The aim of this study was to elucidate the molecular mechanisms underlying anesthetics-induced neurodevelopmental toxicity by VEGF receptor 2 (VEGFR2) through the interaction between microglia and neural stem cells (NSCs) in postnatal day 7 (P7) rats. Cognitive function of P7 rats exposed to isoflurane and sevoflurane were assessed using Morris Water Maze and T maze tests. We also evaluated the expression levels of NSC biomarkers (Nestin and Sox2), microglia biomarker (CD11b or or IBA1), pro-inflammatory cytokines (IL-6 and TNF-α), and VEGFR2 using western blotting and immunohistochemistry in the brains of control and anesthesia-treated rats. We found spatial learning and working memory was impaired 2 weeks after anesthetics exposure in rats. Isoflurane induced stronger and more prolonged neurotoxicity than sevoflurane. However, cognitive functions were recovered 6 weeks after anesthesia. Isoflurane and sevoflurane decreased the levels of Nestin, Sox2, and p-VEGFR2, activated microglia, decreased the number of NSCs and reduced neurogenesis and the proliferation of NSCs, and increased the levels of IL-6, TNF-α, and CD11b. Our results suggested that isoflurane and sevoflurane induced cognitive impairment in rats by inhibiting NSC development and neurogenesis via microglial activation, neuroinflammation, and suppression of VEGFR2 signaling pathway.

Methyl tert-butyl ether inhibits pubertal development of Leydig cells in male rats by inducing mitophagy and apoptosis.

Methyl tert-butyl ether (MTBE) is a widely used gasoline additive. It is considered an endocrine-disrupting chemical. Whether MTBE affects the development of Leydig cells in late puberty of males and its underlying mechanism remains unclear. Twenty-four male Sprague-Dawley rats (35 days old) were randomly allocated into four groups and were orally given MTBE (0, 300, 600, and 1200 mg/kg/day) from postnatal day (PND) 35-56. MTBE markedly reduced serum testosterone levels at 300 mg/kg and higher doses without altering the serum levels of luteinizing hormone and follicle-stimulating hormone. It mainly inhibited cell proliferation, induced mitochondrial autophagy and apoptosis, and indirectly stimulated Sertoli cells to secrete anti-Müllerian hormones, thereby significantly reducing the number of Leydig cells at 1200 mg/kg. MTBE also markedly down-regulated the expression of mature Leydig cell biomarker Cyp11a1 and Hsd3b1 and their proteins, while up-regulating the expression of immature Leydig cell biomarker Akr1c14 and its protein at 600 mg/kg and higher. MTBE significantly down-regulated the expression of cell cycle gene Ccnd1, antioxidant gene Gpx1, and anti-apoptotic gene Bcl2, while increasing pro-apoptotic gene Bax level at 1200 mg/kg. In vitro study further confirmed that MTBE can inhibit testosterone synthesis by inducing reactive oxygen species (ROS) generation, mitophagy, and apoptosis at 200 and 300 mM. In conclusion, exposure to MTBE compromises the development of Leydig cells in late puberty in male rats.

Ketamine Modulates Zic5 Expression via the Notch Signaling Pathway in Neural Crest Induction.

Ketamine is a potent dissociative anesthetic and the most commonly used illicit drug. Many addicts are women at childbearing age. Although ketamine has been extensively studied as a clinical anesthetic, its effects on embryonic development are poorly understood. Here, we applied the Xenopus model to study the effects of ketamine on development. We found that exposure to ketamine from pre-gastrulation (stage 7) to early neural plate (stage 13.5) resulted in disruption of neural crest (NC) derivatives. Ketamine exposure did not affect mesoderm development as indicated by the normal expression of Chordin, Xbra, Wnt8, and Fgf8. However, ketamine treatment significantly inhibited Zic5 and Slug expression at early neural plate stage. Overexpression of Zic5 rescued ketamine-induced Slug inhibition, suggesting the blockage of NC induction was mediated by Zic5. Furthermore, we found Notch signaling was altered by ketamine. Ketamine inhibited the expression of Notch targeted genes including Hes5.2a, Hes5.2b, and ESR1 and ketamine-treated embryos exhibited Notch-deficient somite phenotypes. A 15 bp core binding element upstream of Zic5 was induced by Notch signaling and caused transcriptional activation. These results demonstrated that Zic5 works as a downstream target gene of Notch signaling in Xenopus NC induction. Our study provides a novel teratogenic mechanism whereby ketamine disrupts NC induction via targeting a Notch-Zic5 signaling pathway.

Nutritional Deficiency in Early Life Facilitates Aging-Associated Cognitive Decline.

BACKGROUND: Nutrition is important for the fetal developmental programming. Nutritional deficiency in early life could increase the susceptibility to many aging-related disorders including cognitive decline. OBJECTIVE: Our study aims to investigate the effect of early famine exposure on aging-associated cognitive function. METHODS: We recruited 6790 subjects born between 1956 to 1964 during which the Great Chinese Famine occurred (1959-1961). Cognitive function of these subjects were evaluated using the Mini-Mental State Examination (MMSE), the Activities of Daily Living scale (ADL), the Instrumental Activities of Daily Living scale (IADL) and the Clinical Dementia Rating (CDR). RESULTS: Our study identified that early exposure to the famine significantly increased the risk of cognitive impairments in later life, leading to higher prevalence of Mild Cognitive Impairment (MCI) and dementia. We also found the sex and rural-urban differences in this malnutrition-induced effect. Illiteracy, history of stroke or diabetes mellitus are great risk factors to facilitate the cognitive decline. CONCLUSION: These findings demonstrate that exposure to famine during early life including prenatal period and early childhood facilitates aging-associated cognitive deficits.

Association of Apolipoprotein E (ApoE) Polymorphism with Alzheimer's Disease in Chinese Population.

Apolipoprotein E (ApoE) plays a vital role in cholesterol metabolism and its allele polymorphisms have been associated with several diseases including Alzheimer's disease (AD). There are few systematic studies on ApoE polymorphism and its association with AD in Chinese population. To examine this issue, participants included 4251 subjects and 404 AD patients with 390 healthy elderly residing in Chongqing city were genotyped. The results showed that the ε3 allele presented the highest frequency (82%), followed by ε4 (6.25%) and ε2 (11.75%) in general population. ε3/ε3 genotype carriers are the most common ones (64.19%) and the ε4/ε4 had the lowest frequency (0.59%). The frequency of ApoEε4 allele frequency in AD (15.35%) was significantly higher than control (10.00%). Those carriers of two ε4 allele have five time higher risk to develop AD. Our study demonstrate that ApoEε4 allele is a risk factor of AD for Chinese population.

5-Mehtyltetrahydrofolate rescues alcohol-induced neural crest cell migration abnormalities.

BACKGROUND: Alcohol is detrimental to early development. Fetal alcohol spectrum disorders (FASD) due to maternal alcohol abuse results in a series of developmental abnormalities including cranial facial dysmorphology, ocular anomalies, congenital heart defects, microcephaly and intellectual disabilities. Previous studies have been shown that ethanol exposure causes neural crest (NC) apoptosis and perturbation of neural crest migration. However, the underlying mechanism remains elusive. In this report we investigated the fetal effect of alcohol on the process of neural crest development in the Xenopus leavis. RESULTS: Pre-gastrulation exposure of 2-4% alcohol induces apoptosis in Xenopus embryo whereas 1% alcohol specifically impairs neural crest migration without observing discernible apoptosis. Additionally, 1% alcohol treatment considerably increased the phenotype of small head (43.4% ± 4.4%, total embryo n = 234), and 1.5% and 2.0% dramatically augment the deformation to 81.2% ± 6.5% (n = 205) and 91.6% ± 3.0% (n = 235), respectively (P < 0.05). Significant accumulation of Homocysteine was caused by alcohol treatment in embryos and 5-mehtyltetrahydrofolate restores neural crest migration and alleviates homocysteine accumulation, resulting in inhibition of the alcohol-induced neurocristopathies. CONCLUSIONS: Our study demonstrates that prenatal alcohol exposure causes neural crest cell migration abnormality and 5-mehtyltetrahydrofolate could be beneficial for treating FASD.