Neuroscience
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The present study was designed to evaluate the possible neuroprotective effects of metabotropic glutamate receptor (mGluR7) allosteric agonist N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) on developmental sevoflurane neurotoxicity. To achieve the objective, hippocampal cultures (7 DIV, 7 day in vitro) were treated with different doses of L-(+)-2-amino-4-phosphonobutyric acid (L-AP4, an agonist of group III mGluRs), (RS)-α-Methylserine-O-phosphate (MSOP, an antagonist of group III mGluRs), AMN082 or cis-2-[[(3,5-dichlorophenyl)amino]carbonyl]cyclohexanecarboxylic acid (VU0155041, an agonist of mGluR4) before exposed to sevoflurane. Cell apoptosis were determined by flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL)-staining. ⋯ Finally, AMN082 improved the learning and memory defects caused by postnatal sevoflurane exposure without alternations in emotion or locomotor activity. These preliminary data indicate that AMN082 may protect immature brain against sevoflurane neurotoxicity, and the ERK1/2 MAP kinase signaling is likely to be involved. Further studies are needed to fully assess the neuroprotective role of mGluR7 agonist AMN082 in developmental anesthetic neurotoxicity.
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There is strong evidence that vascular risk factors play a role in the development of Alzheimer's disease (AD) or vascular dementia (vaD). Ethanol (EtOH) and cholesterol are such vascular risk factors, and we recently showed that hypercholesterolemia causes pathologies similar to AD [Ullrich et al. (2010) Mol Cell Neurosci 45, 408-417]. The aim of this study was to investigate the effects of long-term (12 months) EtOH treatment (20% v/v in drinking water) alone or long-term 5% cholesterol diet alone or a combination (mix) in adult Sprague-Dawley rats. ⋯ The effect of long-term hypercholesterolemia was similar. Combined long-term treatment of rats with 20% EtOH and 5% cholesterol (mix) did not potentiate treatment with EtOH alone, but instead counteracted some of the EtOH-associated effects. In conclusion, our data show that vascular risk factors EtOH and cholesterol play a role in cognitive impairment and possibly vaD.
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Delayed activation of tissue plasminogen activator (tPA) can lead to the disruption of the blood-brain barrier (BBB), resulting in hemorrhagic complications. In the present study, we focused on tight junction proteins (TJPs), occludin, zona occludens (ZO)-1, and claudin-5, which are important structural components of the BBB, and investigated whether inhibition of matrix metalloproteinases (MMPs) provides a protective effect against hemorrhagic complications induced by tPA. We subjected mice to 6-h filamental middle cerebral artery occlusion (MCAO) with vehicle, delayed tPA alone, or combined tPA (10 mg/kg, i.v.) plus GM6001 (100 mg/kg, i.p.), a broad-spectrum MMP inhibitor. ⋯ Furthermore, GM6001 treatment also significantly prevented cell damage, determined by release of lactase dehydrogenase (LDH) activity, and the decrease in transendothelial electrical resistance (TEER) induced by tPA. These findings indicate that GM6001 prevented the hemorrhagic complications and improved the behavioral abnormalities induced by tPA, partly via protection of TJPs. This suggests that GM6001 may be a useful candidate for combination therapy against the hemorrhagic complications induced by tPA.
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This study has investigated the role of hypothalamic and amygdalar type-1 cannabinoid (CB1) receptors in the emotional and neuroendocrine responses to stress. To do so, we used the Cre/loxP system to generate conditional mutant mice lacking the CB1 gene in neurons expressing the transcription factor single-minded 1 (Sim1). This choice was dictated by former evidence for Sim1-Cre transgenic mice bearing Cre activity in all areas expressing Sim1, which chiefly includes the hypothalamus (especially the paraventricular nucleus, the supraoptic nucleus, and the posterior hypothalamus) and the mediobasal amygdala. ⋯ The stimulatory influence of repeated social stress on body and adrenal weights, water intake, and sucrose preference was similar in the two genotypes. On the other hand, repeated social stress abolished the decrease in cued-fear conditioned expression that was observed in Sim1-CB1(-/-) mice, compared to Sim1-CB1(+/+) mice. This study suggests that CB1 receptors located on Sim1-expressing neurons exert a tonic control on locomotor reactivity, unconditioned anxiety, and cued-fear expression under basal conditions as well as after acute or repeated stress.
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The endocannabinoid (eCB) system is an important regulator of the stress response and mediates several stress-related behaviors, including anxiety. Despite anatomical evidence that eCBs interact with the principle stress peptide, corticotropin-releasing factor (CRF), few data exist that address functional interactions between these systems. Accordingly, we examined the effects of the CB1 receptor antagonist, AM251, on behavioral anxiety induced by (1) exogenous CRF, and (2) withdrawal from chronic cocaine exposure (mediated by CRF). ⋯ AM251 produced an anxiogenic response at the highest dose, but reversed the behavioral anxiety induced by CRF and withdrawal from chronic cocaine in a dose-dependent manner. AM251 also increased plasma corticosterone levels, but did so irrespective of CRF treatment or cocaine preexposure. Our findings suggest that the anxiogenic effects of CRF and cocaine withdrawal are mediated, at least in part, by CB1 receptor transmission, and provide evidence in support of eCB-CRF interactions that are independent of the hypothalamic-pituitary-adrenal axis.