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1.
Kainate receptors (KARs) are a class of ionotropic glutamate receptors that are expressed throughout the central nervous system. The function and subcellular localization of KARs are tightly regulated by accessory proteins. We have previously identified the single-pass transmembrane proteins, Neto1 and Neto2, to be associated with native KARs. In the hippocampus, Neto1, but not Neto2, controls the abundance and modulates the kinetics of postsynaptic KARs. Here we evaluated whether Neto2 regulates synaptic KAR levels in the cerebellum where Neto1 expression is limited to the deep cerebellar nuclei. In the cerebellum, where Neto2 is present abundantly, we found a ∼40% decrease in GluK2-KARs at the postsynaptic density (PSD) of Neto2-null mice. No change, however, was observed in total level of GluK2-KARs, thereby suggesting a critical role of Neto2 on the synaptic localization of cerebellar KARs. The presence of a putative class II PDZ binding motif on Neto2 led us to also investigate whether it interacts with PDZ domain-containing proteins previously implicated in regulating synaptic abundance of KARs. We identified a PDZ-dependent interaction between Neto2 and the scaffolding protein GRIP. Furthermore, coexpression of Neto2 significantly increased the amount of GRIP associated with GluK2, suggesting that Neto2 may promote and/or stabilize GluK2:GRIP interactions. Our results demonstrate that Neto2, like Neto1, is an important auxiliary protein for modulating the synaptic levels of KARs. Moreover, we propose that the interactions of Neto1/2 with various scaffolding proteins is a critical mechanism by which KARs are stabilized at diverse synapses. 相似文献
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Effects of Δ8- and Δ9-tetrahydrocannabinol (Δ8- and Δ9-THC) on three experimentally induced seizure models, i.e., audiogenic seizure (AS) test, maximal electroshock seizure (MES) test and pentylenetetrazol (PTZ)-induced seizure test were determined in the audiogenic rat. Both tetrahydrocannabinols possess a dose-related anticonvulsant effect against AS, MES and PTZ-induced maximal seizure. Although anticonvulsant potencies do not significantly differ, Δ8THC is three times more neurotoxic than Δ9THC. In addition, both THC's are without effect on minimal seizure and lethality induced by PTZ. Furthermore, the low protective indexes (TD50/ED50) determined in this study suggest that Δ8 and Δ9 THC may have poor therapeutic potentials as antiepileptic drugs. 相似文献
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Jean L. Santos Paulo R. Yamasaki Chung Man Chin Célio H. Takashi Fernando R. Pavan Clarice Q.F. Leite 《Bioorganic & medicinal chemistry》2009,17(11):3795-3799
New phthalimide derivatives were easily prepared through condensation of phthalic anhydride and selected amines with variable yields (70–90%). All compounds (3a–l) were evaluated against Mycobacterium tuberculosis H37Rv using Alamar Blue susceptibility. The compounds 3c, 3i, and 3l have the minimum inhibitory concentrations (MICs) of 3.9, 7.8, and 5.0 μg/mL, respectively, and could be considered new lead compounds in the treatment of tuberculosis and multi-drug resistant tuberculosis. 相似文献
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Investigation into the association of insurance status with the outcomes of patients undergoing neurosurgical intervention has been limited: this is the first nationwide study to analyze the impact of primary payer on the outcomes of patients with aneurysmal subarachnoid hemorrhage who underwent endovascular coiling or microsurgical clipping. The Nationwide Inpatient Sample (2001–2010) was utilized to identify patients; those with both an ICD-9 diagnosis codes for subarachnoid hemorrhage and a procedure code for aneurysm repair (either via an endovascular or surgical approach) were included. Hierarchical multivariate regression analyses were utilized to evaluate the impact of primary payer on in-hospital mortality, hospital discharge disposition, and length of hospital stay with hospital as the random effects variable. Models were adjusted for patient age, sex, race, comorbidities, socioeconomic status, hospital region, location (urban versus rural), and teaching status, procedural volume, year of admission, and the proportion of patients who underwent ventriculostomy. Subsequent models were also adjusted for time to aneurysm repair and time to ventriculostomy; subgroup analyses evaluated for those who underwent endovascular and surgical procedures separately. 15,557 hospitalizations were included. In the initial model, the adjusted odds of in-hospital mortality were higher for Medicare (OR 1.23, p<0.001), Medicaid (OR 1.23, p<0.001), and uninsured patients (OR 1.49, p<0.001) compared to those with private insurance. After also adjusting for timing of intervention, Medicaid and uninsured patients had a reduced odds of non-routine discharge (OR 0.75, p<0.001 and OR 0.42, p<0.001) despite longer hospital stays (by 8.35 days, p<0.001 and 2.45 days, p = 0.005). Variations in outcomes by primary payer–including in-hospital post-procedural mortality–were more pronounced for patients of all insurance types who underwent microsurgical clipping. The observed differences by primary payer are likely multifactorial, attributable to varied socioeconomic factors and the complexities of the American healthcare delivery system. 相似文献
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d-Aspartate in Human Brain 总被引:3,自引:3,他引:0
Eugene H. Man George H. Fisher Iris L. Payan Rodolfo Cadilla-Perezrios Nancy M. Garcia Radhika Chemburkar Georgine Arends William H. Frey II 《Journal of neurochemistry》1987,48(2):510-515
The presence of the biologically uncommon D-aspartic acid (D-aspartate) in human brain white matter has been previously reported. The earlier study has now been expanded to include D/L-aspartate ratios from 67 normal brains. The data show that the D-aspartate content increases rapidly from 1 year to approximately 35 years of age, levels off in middle age, and then appears to decrease somewhat. The D-aspartate content in gray matter remains at a consistently low level (half of that found in white matter) throughout the human life span. Within the limitations of current analytical methods, there was no detectable difference in D/L-aspartate ratios in white and gray matter of brains with Alzheimer's disease and several other pathologies when compared with brains of normal subjects. However, the presence of a significant D-aspartate level in white matter during the adult life span may lead to changes in protein configuration related to dysfunctions associated with the aging brain. 相似文献
9.
A H van den Meiracker P J Admiraal A J Man in 't Veld F H Derkx H J Ritsema van Eck P Mulder P van Brummelen M A Schalekamp 《BMJ (Clinical research ed.)》1990,301(6745):205-210
OBJECTIVE--To investigate the effects of a novel specific renin inhibitor, RO 42-5892, with high affinity for human renin (Ki = 0.5 x 10(-9) mol/l), on plasma renin activity and angiotensin II concentration and on 24 hour ambulatory blood pressure in essential hypertension. DESIGN--Exploratory study in which active treatment was preceded by placebo. SETTING--Inpatient unit of teaching hospital. PATIENTS--Nine men with uncomplicated essential hypertension who had a normal sodium intake. INTERVENTIONS--Two single intravenous doses of RO 42-5892 (100 and 1,000 micrograms/kg in 10 minutes) given to six patients and one single oral dose (600 mg) given to the three others as well as to three of the patients who also received the two intravenous doses. RESULTS--With both intravenous and oral doses renin activity fell in 10 minutes to undetectably low values, while angiotensin II concentration fell overall by 80-90% with intravenous dosing and by 30-40% after the oral dose. Angiotensin II concentration was back to baseline four hours after the low and six hours after the high intravenous dose and remained low for at least eight hours after the oral dose. Blood pressure fell rapidly both after low and high intravenous doses and after the oral dose and remained low for hours. With the high intravenous dose the daytime (0900-2230), night time (2300-0600), and next morning (0630-0830) systolic blood pressures were significantly (p less than 0.05) lowered by 12.5 (95% confidence interval 5.6 to 19.7), 12.2 (5.4 to 19.3), and 10.7 (3.2 to 18.5) mm Hg respectively, and daytime diastolic pressure was lowered by 9.3 (2.2 to 16.8) mmHg. With the oral dose daytime, night time, and next morning systolic blood pressures were lowered by 10.3 (5.5 to 15.4), 10.5 (4.2 to 17.2), and 9.7 (4.0 to 15.6) mm Hg, and daytime and night time diastolic pressures were lowered by 5.8 (0.9 to 11.0) and 6.0 (0.3-12) mm Hg respectively. CONCLUSIONS--The effect of the inhibitor on blood pressure was maintained over a longer period than its effect on angiotensin II. RO 42-5892 is orally active and has a prolonged antihypertensive effect in patients who did not have sodium depletion. This prolonged effect seems to be independent, at least in part, of the suppression of circulating angiotensin II. 相似文献
10.
The changes in met-enkephalin and beta-endorphin contents in the pituitary in PTU-induced hypothyroidism were studied in the rat. After 2 weeks of PTU-treatment, both IR-met-enkephalin and IR-beta-endorphin contents in the pituitary were significantly reduced. Gel filtration chromatography followed by radioimmunoassay showed that the immunoactivities in the peaks of precursors, met-enkephalin, beta-lipotropin and beta-endorphin were all lower in the pituitaries from the PTU-treated rats. In another experiment, some of the PTU-treated rats were injected daily with 500 micrograms T3/kg b.w. In the hypothyroid rats, IR-met-enkephalin and IR-beta-endorphin contents were decreased in both the anterior and neurointermediate lobes. Only the changes in the anterior lobe were reversed by T3 treatment. In conclusion, while the effects on the anterior lobe are probably due to a deficiency in thyroid hormones, the mechanism for the decrease of opioid peptide contents in the neurointermediate lobe is still unclear. 相似文献