Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.8 (FAST)
 758 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Brain NMDA receptor responses and their sensitivity to ethanol in vitro were determined in replicate lines of FAST and SLOW mice, selectively bred for differences in sensitivity to the locomotor stimulant effects of a low dose of ethanol. L-Glutamate-stimulated increases in the intracellular free calcium concentration (Cai) were determined in microsacs, a cell-free brain membrane preparation, isolated from hippocampus or cerebral cortex. Previous work showed that L-glutamate-stimulated increases in Cai in microsacs are mediated by activation of NMDA receptors. The concentration response for L-glutamate-stimulated increases in Cai did not differ between the lines in either hippocampal or cerebrocortical microsacs. Ethanol produced a concentration-dependent decrease in L-glutamate-stimulated increases in Cai in hippocampal and cerebrocortical microsacs from SLOW mice, but this effect of ethanol was reduced or absent in microsacs isolated from FAST mice. Resting Cai and the ability of a high ethanol concentration to increase resting Cai did not differ between the lines. These results suggest that differences in the sensitivity of brain NMDA receptors to the effects of ethanol determine, at least in part, differences in the locomotor stimulant effects of low doses of ethanol in FAST and SLOW mice. These differences are not due to ethanol effects on resting Cai.
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PMID:Ethanol sensitivity of brain NMDA receptors in mice selectively bred for differences in response to the low-dose locomotor stimulant effects of ethanol. 769 47

FAST vs. SLOW selected mouse lines and C57BL/6J (B6) vs. DBA/2J (D2) inbred strains differ in their sensitivities to ethanol's locomotor stimulant effects, and provide two unique sets of genetic animal models to study neurophysiological substrates of this behavior. To determine whether NMDA receptor function mediates sensitivity to ethanol's stimulant effects, we assessed the effects of the noncompetitive NMDA antagonist, MK-801, on locomotor activity of naive and ethanol-treated FAST, SLOW, B6, and D2 mice. MK-801 (0.01-0.5 mg/kg, I.P.) had biphasic effects in all genotypes, with stimulation at moderate doses and decreased activation at the highest dose. FAST mice were more activated by MK-801 than SLOW mice, suggesting that selection differentially altered NMDA receptor function between the lines. B6 and D2 mice did not differ in locomotor responses following MK-801 administration. Stimulant doses of MK-801 decreased or blocked ethanol-stimulated locomotor activity in FAST and D2 mice, and potentiated the locomotor depressant actions of ethanol in SLOW and B6 mice. Potentiation of ethanol's activating properties was observed in one treatment group in D2 mice. These data suggest that NMDA receptors modulate ethanol's stimulant properties, by a more significant involvement in expression of ethanol's locomotor depressant properties.
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PMID:MK-801 potentiates ethanol's effects on locomotor activity in mice. 944 48

Treatments for spontaneous intracerebral, thrombolytic-induced and intraventricular hemorrhages (IVH) are still at the preclinical or early clinical investigational stages. There has been some renewed interest in the use of surgical evacuation surgery or thrombolytics to remove hematomas, but these techniques can be used only for specific types of brain bleeding. The STICH (Surgical Trial in Intracerebral Haemorrhage) clinical trials should provide some insight into the potential for such techniques to counteract hematoma-induced damage and subsequently, morbidity and mortality. More recently, clinical trials (ATACH [Antihypertensive Treatment in Acute Cerebral Hemorrhage] and INTERACT [Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial]) have begun testing whether or not regulating blood pressure affects the well-being of hemorrhage patients, but the findings thus far have not conclusively demonstrated a positive result. More promising trials, such as the early stage CHANT (Cerebral Hemorrhagic And NXY-059 Treatment) and the late stage FAST (Factor VIIa for Acute Hemorrhagic Stroke Treatment), have addressed whether or not manipulating oxidative stress and components of the blood coagulation cascade can achieve an improved prognosis following spontaneous hemorrhages. However, CHANT was halted prematurely because although it showed that the spin trap agent NXY-059 was safe, it also demonstrated that the drug was ineffective in treating acute ischemic stroke. In addition, the recombinant activated factor VII FAST trial recently concluded with only modestly positive results. Despite a beneficial effect on the primary end point of reducing hemorrhage volume, controlling the coagulation cascade with recombinant factor VIIa did not decrease the mortality rate. Consequently, Novo Nordisk has abandoned further development of the drug for the treatment of intracerebral hemorrhaging. Even though progress in hemorrhage therapy that successfully reduces the escalating morbidity and mortality rate associated with brain bleeding is slow, perseverance and applied translational drug development will eventually be productive. The urgent need for such therapy becomes more evident in light of concerns related to uncontrolled high blood pressure in the general population, increased use of blood thinners by the elderly (e.g., warfarin) and thrombolytics by acute ischemic stroke patients, respectively. The future of drug development for hemorrhage may require a multifaceted approach, such as combining drugs with diverse mechanisms of action. Because of the substantial benefit of factor VIIa in reducing hemorrhage volume, it should be considered as a prime drug candidate included in combination therapy as an off-label use if the FAST trial proves that the risk of thromboembolic events is not increased with drug administration. Other promising drugs that may be considered in combination include uncompetitive NMDA receptor antagonists (such as memantine), antioxidants, metalloprotease inhibitors, statins and erythropoietin analogs, all of which have been shown to reduce hemorrhage and behavioral deficits in one or more animal models.
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PMID:Advances in hemorrhagic stroke therapy: conventional and novel approaches. 1787 68