UMLS:C0020672 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0020672 (hypothermia)
17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neuroprotective effects of U-101017, [7-chloro-5-[cis-3,5-dimethylpiperazine)carbonyl]-imidazole[1,5a]quinoli ne-3-carboxylate], a GABA(A) receptor partial agonist, were investigated in 3-acetylpyridine (3-AP) treated Wistar rats. A significant (P < 0.01) reduction in both cGMP and ATP in the cerebellum was observed at 96 h after treatment with 3-AP (500 micromol/kg i.p.). Oral administration of U-101017 before and after treatment with 3-AP significantly attenuated 3-AP-induced decreases in cGMP and ATP, and this effect was dose related. Consistent with the neurochemical effect, U-101017 prevented 3-AP-induced loss of motor coordination. Treatment with U-101017 partially, but significantly (P < 0.01) prevented the loss of inferior olivary neurons. U-101017 had no significant effect on body temperature. Thus, hypothermia was not involved in neuroprotective effects of U-101017. Co-administration of flumazenil with each treatment of U-101017 blocked the neuroprotective effect of U-101017, indicating that it mediated neuroprotection via the benzodiazepine binding sites on the GABA(A) receptor complex. Delayed administration of U-101017 at various time intervals after treatment with 3-AP demonstrated a significant neuroprotective effect even at 8 h, suggesting that this drug has a wide therapeutic window.
...
PMID:Neuroprotective effects of the GABA(A) receptor partial agonist U-101017 in 3-acetylpyridine-treated rats. 919 84

This study examined the effects of the GABA(A) agonist THIP on flash-evoked potentials (FEPs) recorded from the primary visual cortex (VC) and superior colliculus (SC) of chronically implanted hooded rats. Animals were given I.P. injections of saline, and of 8, 16, and 24 mg THIP/kg body weight on separate days. Evoked potentials were recorded at 5, 20, and 35 min following injection. Animals were tested at a standard (22.5 degrees C) room temperature. Most significant effects were observed at the 20- and 35-min recording intervals for both the 16 and 24 mg/kg doses, with effects at the 24 mg/kg dose the most pronounced. VC P1 amplitude remained unchanged, while N1 was reduced to such an extent that it became positive, ultimately blending into the rising phase of a positive component appearing between N1 and P2. This positive component had a latency of about 6 ms longer than N1, and became larger in amplitude than P1 at the 24 mg/kg dose. P2 amplitude was drastically reduced, becoming negative. In contrast, components N2 and P3 were augmented, while the amplitude of N3 was unchanged. In the SC, P1 was augmented while P3 was reduced in amplitude. A biphasic (increase/decrease) effect was observed in the N4 complex. In both the VC and SC, latencies of most components were increased, with the late components in the VC increased to the greatest extent. A mild hypothermia was observed at 16 and 24 mg/kg. The results suggest that the GABA(A) receptor plays an important role in the elaboration of the middle (N1-P2) components of FEPs recorded from the rat VC, and that GABAergic mechanisms can influence other components in the VC and SC as well.
...
PMID:THIP, a selective gamma-aminobutyric acid receptor agonist, alters flash-evoked potentials in rats. 940 97

Hypothermic newborn piglets have a depressed ventilatory response to hypoxia, and this may be due to an increase in CNS gamma-aminobutyric acid (GABA) levels. To evaluate the effects of GABA(A) receptor blockade on the ventilatory response to hypoxia in hypothermic piglets, 31 anesthetized paralyzed mechanically ventilated newborn piglets (2-7 d) were studied at a brain temperature of 38.5 +/- 0.5 degrees C [normothermia (NT), n = 15] or 34 +/- 0.5 degrees C [hypothermia (HT), n = 16]. The central respiratory output was evaluated by measuring burst frequency and moving time average area of phrenic nerve activity. Measurements of minute phrenic output (MPO), arterial blood pressure, heart rate, oxygen consumption, and arterial blood gases were obtained at room air and during 20 min of isocapnic hypoxia [fraction of expired oxygen (FiO2) = 0.10]. After 10 min of hypoxia, a bolus injection of 20 microL of bicuculline methiodide (BM; 10 microg) or Ringer's solution was administered into the cisterna magna over a 1-min period, and the piglets remained in hypoxia for an additional 10 min. There was an initial increase of 50 +/- 6% in MPO during the first minute of hypoxia followed by a decrease to values 24 +/- 8% above baseline at 10 min in the NT group. In contrast, in the HT group, the initial increase in MPO with hypoxia was eliminated, and, at 10 min, there was a decrease to a mean value 35 +/- 4% below baseline level (NT versus HT, p < 0.03). After administration of BM, a significant increase in MPO with hypoxia was observed in both groups compared with their placebo groups (p < 0.002 in NT-BM group, p < 0.0001 in HT-BM group). However, the magnitude of the increase in MPO during hypoxia was significantly greater in the HT group after administration of BM (NT versus HT, p < 0.0001). Changes in oxygen consumption, arterial blood pressure, heart rate, pH, partial pressure of oxygen (PaO2), and base excess with hypoxia were not different between NT and HT groups before and after the administration of BM. The cardiorespiratory response to hypoxia was not modified after administration of Ringer's solution to NT and HT placebo groups. These data suggest that the depression in hypoxic ventilatory response produced by HT is in part modulated by an increased CNS GABA concentration.
...
PMID:Effects of GABA receptor blockade on the ventilatory response to hypoxia in hypothermic newborn piglets. 1081 94

Tests of ethanol effects in PKCgamma null mutant mice have indicated that PKCgamma plays a role in initial sensitivity to ethanol-induced sedation, hypothermia, and GABA(A) receptor function and impacts neurochemical pathways mediating anxiety. The present study was undertaken to evaluate whether the decreased sensitivity to ethanol previously observed in these mice generalized to the anxiolytic effects of ethanol. PKCgamma null mutant mice and wild-type controls were tested in the elevated-plus maze, the black/white box, and the mirrored chamber after ethanol (0, 1.0, 1.25, 1.5 g/kg) or flunitrazepam (FNZ) (0, 0.015, 0.03, 0.06 mg/kg). Results indicated that although both genotypes exhibited anxiolytic responses to ethanol in the elevated plus-maze, null mutant mice were less sensitive than wild-type control mice; however, in the black/white box, PKCgamma null mutants were more sensitive than controls to the anxiolytic effects of FNZ. Neither ethanol nor FNZ produced anxiolytic responses in the mirrored chamber for either genotype. These results suggest that PKCgamma differentially mediates anxiolytic responses to ethanol and FNZ and that this relationship interacts with each drug's efficacy in reducing anxiety-related behaviors specific to each of the three mazes.
...
PMID:Differential sensitivity to the anxiolytic effects of ethanol and flunitrazepam in PKCgamma null mutant mice. 1142 74

1. Activation of GABA(B) receptors evokes hypothermia in wildtype (GABA(B(1))+/+) but not in GABA(B) receptor knockout (GABA(B(1))-/-) mice. The aim of the present study was to determine the hypothermic and behavioural effects of the putative GABA(B) receptor agonist gamma-hydroxybutyrate (GHB), and of the GABA(A) receptor agonist muscimol. In addition, basal body temperature was determined in GABA(B(1))+/+, GABA(B(1))+/- and GABA(B(1))-/- mice. 2. GABA(B(1))-/- mice were generated by homologous recombination in embryonic stem cells. Correct gene targeting was assessed by Southern blotting, PCR and Western blotting. GABA(B) receptor-binding sites were quantified with radioligand binding. Measurement of body temperature was done using subcutaneous temperature-sensitive chips, and behavioural changes after drug administration were scored according to a semiquantitative scale. 3. GABA(B(1))-/- mice had a short lifespan, probably caused by generalised seizure activity. No histopathological or blood chemistry changes were seen, but the expression of GABA(B(2)) receptor protein was below the detection limit in brains from GABA(B(1))-/- mice, in the absence of changes in mRNA levels. 4. GABA(B) receptor-binding sites were absent in brain membranes from GABA(B(1))-/- mice. 5. GABA(B(1))-/- mice were hypothermic by approximately 1 degrees C compared to GABA(B(1))+/+ and GABA(B(1))+/- mice. 6. Injection of baclofen (9.6 mg kg-1) produced a large reduction in body temperature and behavioural effects in GABA(B(1))+/+ and in GABA(B(1))+/- mice, but GABA(B(1))-/- mice were unaffected. The same pattern was seen after administration of GHB (400 mg kg-1). The GABA(A) receptor agonist muscimol (2 mg kg-1), on the other hand, produced a more pronounced hypothermia in GABA(B(1))-/-mice. In GABA(B(1))+/+ and GABA(B(1))+/- mice, muscimol induced sedation and reduced locomotor activity. However, when given to GABA(B(1))-/- mice, muscimol triggered periods of intense jumping and wild running. 7. It is concluded that hypothermia should be added to the characteristics of the GABAB(1)-/-phenotype. Using this model, GHB was shown to be a selective GABAB receptor agonist. In addition, GABAB(1)-/- mice are hypersensitive to GABAA receptor stimulation, indicating that GABAB tone normally balances GABAA-mediated effects.
...
PMID:Effects of GABA agonists on body temperature regulation in GABA(B(1))-/- mice. 1297 75

Mechanism, onset and duration of tolerance development to clomethiazole-induced hypothermia were investigated in rats using telemetry. The hypothermic effect of clomethiazole was completely abolished for 10 days after an s.c. injection of 300 micromol/kg and the effect returned to approximately 50% in 32 days. The gamma-aminobutyric acidA (GABA(A)) receptor agonist muscimol induced hypothermia at 88 micromol/kg without any (cross-) tolerance. GABA(A) receptor antagonists, bicuculline (5.4 micromol/kg) and picrotoxin (3.3 micromol/kg), did not inhibit clomethiazole-induced hypothermia nor the tolerance. The noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, dizocilpine, counteracted clomethiazole-induced hypothermia at 3 micromol/kg but not the tolerance. Tolerance to the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor agonist R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT)-induced hypothermia was blocked by dizocilpine and clomethiazole but not vice versa. No pharmacokinetic interaction was observed. In conclusion, long-lasting tolerance to clomethiazole-induced hypothermia does not involve GABA(A) or 5-HT(1A) receptor functions. Glutamate via NMDA receptors may be involved in the hypothermic response but not in the tolerance.
...
PMID:Rapid and long-lasting tolerance to clomethiazole-induced hypothermia in the rat. 1584 Mar 98

The effects of the novel GABA analogue (2R)-(3-amino-2-fluoropropyl)sulphinic acid (AFPSiA) on transient lower oesophageal sphincter relaxations (TLOSRs) were studied in the dog. In addition, the GABA(A)/GABA(B) selectivity was determined in vitro and in vivo, and the pharmacokinetics and the metabolism of the compound were studied in the dog and rat. TLOSRs were reduced by 55 +/- 8% after intragastric administration of AFPSiA at 14 mumol kg(-1) and did not decrease further at higher doses. When evaluated 2 and 4 h after administration, the effect declined to 37 +/- 6 and 16 +/- 9%, respectively. Spontaneous swallowing was only significantly inhibited at 100 micromol kg(-1). The oral availability of AFPSiA was 52 +/- 17 and 71 +/- 4% in the dog and rat, respectively. A fraction of AFPSiA was oxidised to the corresponding sulphonate, (2R)-(3-amino-2-fluoropropyl)sulphonic acid (AFPSoA) after oral administration to the rat and dog. In rat brain membranes, AFPSiA was found to have ten times higher affinity for rat brain GABA(B) (K(i) =47 +/- 4.4 nM) compared to GABA(A) (K(i) = 430 +/- 46 nM) binding sites. The compound was a full agonist at human recombinant GABA(B(1a,2)) receptors (EC(50) = 130 +/- 10 nM). In contrast, the metabolite AFPSoA was considerably more selective for binding to rat brain GABA(A) (K(i) = 37 +/- 3.1 nM) vs GABA(B) (K(i) = 6800 +/- 280 nM) receptors. In the mouse, high doses (1-8 mmol kg(-1)) of AFPSiA induced a rapid and mild hypothermia followed by a profound and sustained hypothermia at the higher doses tested (6 and 8 mmol kg(-1)). This effect was unaffected by the selective GABA(B) receptor antagonist CGP62349. AFPSoA (1 and 2 mmol kg(-1)) produced transient and moderate hypothermia while the hypothermic response was considerably larger at 4 mmol kg(-1).It is concluded that AFPSiA inhibits but does not abolish TLOSRs in the dog. High doses of the compound induce hypothermia in the mouse, which probably is attributable to activation of the GABA(A) receptor. The latter effect may be caused both by AFPSiA and its oxidised sulphonic acid metabolite AFPSoA.
...
PMID:Effects of (2R)-(3-amino-2-fluoropropyl)sulphinic acid (AFPSiA) on transient lower oesophageal sphincter relaxation in dogs and mechanism of hypothermic effects in mice. 1598 Aug 75

Clinically used anesthetics show amnestic, sedative, hypnotic and immobilizing properties. On a molecular level these drugs affect several receptors in the cell membrane of neurons. By using genetically engineered mice a linkage can now be made between actions on certain receptors and clinically desired and undesired effects. Experiments show that a certain GABA(A) receptor subtype mediates hypnosis and immobility, whereas another subtype is involved in side-effects like sedation and hypothermia. These findings form the basis for the development of new drugs, acting highly specific and with fewer side-effects.
...
PMID:[The GABA(A) receptor family: possibilities for the development of better anesthetics]. 1631 24

The stress-induced hyperthermia procedure, in which effects of drugs on basal (T(1)) and stress-induced body temperature (T(2)) are measured, predicts anxiolytic drug effect. Serotonergic drugs alter these responses and here, we studied the role of 5-HT(1A) receptors in stress-induced hyperthermia by using 5-HT(1A) receptor knockout mice. Three strains (129/Sv, Swiss Webster and C57Bl6) were used because genetic background can significantly modulate the null phenotype. We found that GABA-ergic drugs with an anxiolytic profile and stimulate alpha(2) subunit containing GABA(A) receptors, including diazepam and L838,417, result in reduced DeltaT (DeltaT=T(2)-T(1)). The alpha(1) subunit containing GABA(A) receptor was found to be primarily involved in regulation of basal body temperature T(1) and its stimulation can induce hypothermia. In addition, stimulation of 5-HT(1A) receptors by buspirone results in a reduced DeltaT, while stimulation of 5-HT(7) receptors primarily results in hypothermia. The null mutation of 5-HT(1A) receptors resulted in differences in drug-sensitivity that was further modulated by the genetic background. In particular, the null mutation on the SW and C57Bl6 backgrounds resulted in differential diazepam/L838,417 and 5-CT responses respectively. This indicates an interaction between the 5-HT(1A) receptor and genetic background and demonstrates the importance of selecting the background strain in a receptor knockout model.
...
PMID:Effects of genetic background and null mutation of 5-HT1A receptors on basal and stress-induced body temperature: modulation by serotonergic and GABAA-ergic drugs. 1702 70

The aim of the present investigation was to analyze the molecular mechanism(s) of diazepam neuroprotection in two models of selective neuronal death in CA1 sector of hippocampus: in vivo following transient gerbil brain ischemia and in vitro in rat hippocampal brain slices subjected to glutamatergic (100 microM NMDA) or oxidative (30 microM tertbutyl-hydroksyperoxide (TBH)) stress. In the in vivo model the diazepam treatment (two doses of 10mg/kg i.p. 30 and 90 min after the insult) resulted in more than 60% of CA1 hippocampal neurons surviving the insult comparing with 15% in untreated animals. To test whether the protective effect of diazepam was due to the postulated drug-induced hypothermia we followed the fluxes of body temperature during postischemic reperfusion: diazepam reduced temperature from 36.6+/-1 degrees C to 33.4+/-2 degrees C. Equivalent hypothermia induced and maintained in animals after ischemia did not prevent neuronal cell loss to the same extent as diazepam did (42.8+/-9.2% and 72.4+/-14.5% of live neurons, respectively). In vitro, under constant temperature conditions, diazepam exerted neuroprotective effects following a "U-shaped" dose-response curve, with concentration efficacy window of 0.5-10 microM. Five micro-molar diazepam showed significant protection by reducing over 50% the number of (dead) propidium iodide labeled cells even in the presence of GABA(A) receptor antagonist bicuculline. Next, we have shown that diazepam reduced the efflux of cytochrome c out of mitochondria both in compromised CA1 neurons in vitro and in isolated mitochondria treated with 30 microM THB. Our results suggest that the neuroprotective action of diazepam relies on additional mechanism(s) and not solely on its hypothermic effect. We suggest that diazepam evokes neuroprotection through its central receptors located on the GABA(A) receptor complex and, possibly, through its peripheral receptor, the translocator protein TSPO (previously called the peripheral benzodiazepine receptor) located in the outer mitochondrial membrane.
...
PMID:Diazepam neuroprotection in excitotoxic and oxidative stress involves a mitochondrial mechanism additional to the GABAAR and hypothermic effects. 1942 22

1 2 Next >>