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

Recent studies have demonstrated the neuroprotective properties of the novel imidazoquinoline benzodiazepine receptor partial agonist, PNU-101017, in the gerbil forebrain ischemia model. The compound effectively reduces delayed post-ischemic (5 min bilateral carotid occlusion) hippocampal CA1 neuronal degeneration even when its administration is withheld until 4 h after reperfusion and the effect is unrelated to hypothermia. The purpose of the present study was to determine the comparative abilities of PNU-101017 versus the full agonist diazepam to attenuate post-ischemic CA1 damage. Male gerbils were treated either 30 min before ischemia induction or immediately after reperfusion with an initial dose of PNU-101017 (30 mg/kg i.p.) or diazepam (10 mg/kg i.p.) with a second dose being given at 2 h after reperfusion. Possible hypothermic effects of either compound were prevented by external heating. In vehicle (0.05 N HCl)-treated gerbils, the loss of hippocampal CA1 neurons at 5 days was 85%. PNU-101017 pretreatment reduced the loss to 50% (p<0.05 vs. vehicle) whereas pretreatment with diazepam attenuated damage to only 17% (p<0.001 vs. vehicle). Delaying treatment with PNU-101017 until just after reperfusion still resulted in a reduction in CA1 degeneration statistically that was indistinguishable from that seen with pretreatment. In contrast, diazepam post-treatment did not significantly decrease CA1 neuronal loss. These results suggest that a benzodiazepine receptor partial agonist may have greater neuroprotective practicality than a full agonist for the treatment of global cerebral ischemia. The mechanistic basis for this difference may relate to the partially pro-excitatory neuronal response to endogenous GABA before and after neuronal insult.
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PMID:Comparative neuroprotective properties of the benzodiazepine receptor full agonist diazepam and the partial agonist PNU-101017 in the gerbil forebrain ischemia model. 966 60

Glutapyrone, a disodium salt of 2-(2,6-dimethyl-3,5-diethoxycarbonyl-1,4-dihydropyridine-4-carboxamido)- glutaric acid, is a representative of a novel 'class' of amino acid-containing 1,4-dihydropyridine (DHP) compounds developed at the Latvian Institute of Organic Synthesis, Riga, Latvia. Conceptually, the glutapyrone molecule can be regarded as a dipeptide-mimicking structure formed by the "free" amino acid (glutamate) moiety and "crypto" (built into the DHP cycle) amino acid ("GABA") elements. Both of these amino acids are joined by the peptide bond. This compound unlike classical DHPs lacks calcium antagonistic or agonistic properties. Our previous studies revealed a profound and long-term anticonvulsant, stress-protective and neurodeficit-preventive activities of glutapyrone. In view of structural properties the role of glutamatergic mechanisms in the mediation of central effects of glutapyrone was considered. In the present study glutapyrone at the concentration range of 1 microM(-1) mM failed to effect both NMDA ([3H]TCP) and non-NMDA ([3H]KA and [3H]AMPA) receptor ligand binding in the rat cortical membranes in vitro. The compound markedly enhanced motor hyperactivity induced by the NMDA antagonist PCP and the dopamine releasing compound D-amphetamine in the rats. Glutapyrone displayed activity in a variety of animal models relevant for affective/depressive disorders in humans i.e. reserpine-induced ptosis and hypothermia, forced swimming test and open field test. These data indicate that the unusually "broad" pharmacological spectrum of glutapyrone might involve concomitant actions on multiple neurotransmitter systems, particularly, GABA-ergic and the catecholamines. It is discussed whether these functional properties are secondary to action on intracellular events, predominantly, G protein-related since glutapyrone appears to lack direct interactions with a number of receptors including ionotropic glutamate and GABA(A)/Bzd receptors.
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PMID:"Atypical" neuromodulatory profile of glutapyrone, a representative of a novel 'class' of amino acid-containing dipeptide-mimicking 1,4-dihydropyridine (DHP) compounds: in vitro and in vivo studies. 992 26

A 2 day old foal was presented with central nervous depression (coma) after moxidectin overdose. Moxidectin belongs to the milbemycin anthelmintics which elicit their working mechanism through a GABA (gamma-aminobutyric acid)-stimulatory mode of action. The foal developed profound hypothermia, bradycardia and hypoventilation. Absence of urine voiding and mild abdominal distension suggested a ruptured bladder, which was confirmed by transabdominal ultrasound and clinical-pathologic parameters. Repeat auscultation of the ventral lung parts and the occurrence of gastric reflux were suggestive of an aspiration pneumonia. The foal underwent surgical bladder repair, however, did succumb due to mixed acidosis and early signs of sepsis postoperatively. The findings in this foal are suggestive for moxidectin overdosing. The GABAergic working mechanism of moxidectin does explain the development of profound central nervous depression and its sequels hypothermia, bradycardia, hypoventilation and paralytic ileus. Dyssynergia was unexpected, however, has to be related to a central nervous problem, rather than a peripheral nervous problem.
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PMID:[Moxidectin poisoning in a foal?]. 1041 82

We sought to prolong the window for stroke treatment using synergistic combinatorial therapy. We used the intraluminal filament occlusion model in rats to cause focal cerebral ischemia and a quantal bioassay to measure efficacy. The GABA agonist muscimol and the glutamate antagonist MK-801 were used alone and in combination at various times after ischemia onset. At progressively longer treatment delay intervals (30, 60, 75, 120, 240, and 360 min), higher doses of the single drugs were required to achieve neuroprotection. In contrast, the combination 1.0 mg/kg muscimol plus 0.5 mg/kg MK-801 was effective at all delay intervals studied except the longest (P < 0.05 at each time). After 240 min from ischemia onset, the combination was more effective than either single agent (P < 0.05 for each drug dose), suggesting synergism. The neuroprotective effect could not be demonstrated using morphometry. The treatment effects were probably not due to hypothermia because brain temperatures recorded in awake, unregulated subjects remained normo- or slightly hyperthermic following all treatments. Awake subjects kept on a heating pad exhibited mild brain hyperthermia. The combination caused a drop and MK-801 caused a significant increase in mean arterial blood pressure (main effects F(5,172) = 29, P < 0.0001). The combination of a GABA agonist and glutamate antagonist appears to possess synergistic neuroprotective effects when treatment is delayed up to 240 min following the onset of cerebral ischemia. Temperature regulation causes hyperthermia in awake subjects. The quantal bioassay is one method suitable for studies of synergistic stroke therapy.
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PMID:Synergistic combinatorial stroke therapy: A quantal bioassay of a GABA agonist and a glutamate antagonist. 1083 23

The action of diazepam (0.0, 1.0, and 2.0 mg/kg) and the serotonergic compounds buspirone (0.0, 2.5, and 5.0 mg/kg) and 8-OH-DPAT (0.0, 0.1, and 1.0 mg/kg) on maternal behavior and aggression were studied. An activity test was made after these treatments to control for unspecific actions due to motor impairment. Diazepam and buspirone dose-dependently inhibited the expression of maternal aggression and the active components of maternal behavior such as retrieving and nest building. 8-OH-DPAT did not affect these behaviors. 8-OH-DPAT (1.0 mg/kg) provoked the serotonergic syndrome and hypothermia; however, ovariectomized animals showed more signs of the syndrome and a decrease in body temperature after 8-OH-DPAT than lactating rats. Buspirone, but not the other anxiolytics, reduced motor activity. The role of drugs acting at the serotonergic, dopaminergic, and GABA-benzodiazepine systems in the control of maternal behavior and aggression is discussed.
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PMID:Inhibitory effect of buspirone and diazepam, but not of 8-OH-DPAT, on maternal behavior and aggression. 1088 Jun 95

GABA(B) (gamma-aminobutyric acid type B) receptors are important for keeping neuronal excitability under control. Cloned GABA(B) receptors do not show the expected pharmacological diversity of native receptors and it is unknown whether they contribute to pre- as well as postsynaptic functions. Here, we demonstrate that Balb/c mice lacking the GABA(B(1)) subunit are viable, exhibit spontaneous seizures, hyperalgesia, hyperlocomotor activity, and memory impairment. Upon GABA(B) agonist application, null mutant mice show neither the typical muscle relaxation, hypothermia, or delta EEG waves. These behavioral findings are paralleled by a loss of all biochemical and electrophysiological GABA(B) responses in null mutant mice. This demonstrates that GABA(B(1)) is an essential component of pre- and postsynaptic GABA(B) receptors and casts doubt on the existence of proposed receptor subtypes.
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PMID:Epilepsy, hyperalgesia, impaired memory, and loss of pre- and postsynaptic GABA(B) responses in mice lacking GABA(B(1)). 1149 50

There is large body of evidences on the role of taurine in the central mechanisms of thermoregulation in mammals, but it is not clear, whether the hypothermic effect of taurine depends on its interaction with GABA receptors or with a specific receptor. In order to answer this question, we have performed a structure-activity relationship study by using both in vitro and in vivo preparations. MicroM amounts of taurine or each of 20 analogues were injected intracerebroventricularly in conscious, restrained rabbits while rectal temperature was recorded. Receptor-binding studies, with synaptic membrane preparations from rabbit brain were used to determine the affinities of these compounds for GABA(A) and GABA(B) receptors. Furthermore, the interaction with presynaptic GABA and taurine uptake systems was studied using crude synaptosomal preparations from rabbit brain. Among the compounds tested, (+/-)-cis-2-aminocyclohexanesulfonic acid, induced hypothermia, but did not interact with GABA(A) and GABA(B) receptors neither did it affect GABA and taurine uptake, thus suggesting that its effect on body temperature is not mediated by the central GABAergic system. Interestingly, the trans-isomer was devoid of effects either in vivo or in vitro. In order to explain (+/-)-cis-2-aminocyclohexanesulfonic acid-induced hypothermia, a stereoscopic model was produced showing its possible interactions with a putative taurine brain receptor.
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PMID:Effects of taurine and some structurally related analogues on the central mechanism of thermoregulation: a structure-activity relationship study. 1178 8

The effects of compounds that open the GABAA receptor-chloride channel complex on the rapidly developed tolerance to the 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide(8-OH-DPAT)-induced hypothermia in rats were examined. The test compound was injected 15 min. before 1 mg/kg subcutaneous 8-OH-DPAT or saline and 24 hr later a challenge dose of 0.1 mg/kg subcutaneous 8-OH-DPAT was given. The rectal temperature was measured before the challenge dose and 30, 60, 90 and 120 min. thereafter. The hypothermic effect was calculated as the area under the curve. It was found that all the GABAergic compounds examined significantly counteracted the 8-OH-DPAT-induced tolerance to the hypothermic response: muscimol at 3 mg/kg subcutaneous, diazepam at 1 - 3 mg/kg subcutaneous, pentobarbitone sodium at 20 mg/kg subcutaneous, and chlormethiazole at 40 mg/kg subcutaneous. Combined treatment of the rats with the GABAA receptor antagonist, bicucculine, or the GABAA receptor-chloride channel blocker, picrotoxin and diazepam, pentoparbitone sodium or chlormethiazole significantly antagonised this counteraction of the 8-OH-DPAT-induced tolerance. Depletion of 5-HT by pretreatment of the rats with the tryptophan hydroxylase inhibitor p-chlorophenylalanine did not counteract the 8-OH-DPAT-induced tolerance to the hypothermic response. Pretreatment of the rats with dexamethazone did not change the development of the tolerance to 8-OH-DPAT-induced hypothermic effect which seems to exclude the involvement of the hypothalamo-pituitary-adrenocortical axis in the tolerance development. It is concluded that the results support the hypothesis that GABA neurones beyond the 5-HT neurones are involved in the mechanism causing tolerance to the 5-HT1A receptor-mediated hypothermia in rats.
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PMID:Counteraction of the rapid tolerance to 8-hydroxy-2-(di-n-propylamino)tetralin-induced hypothermia in rats by activation of the GABAA receptor-chloride channel complex. 1200 7

GABAergic drugs can positively or negatively influence recovery of neurobehavioral function following brain injury. Direct potentiation of GABA-mediated inhibition at the post-synaptic receptor (i.e., via GABA, muscimol, diazepam, phenobarbital) after brain damage has been associated with impaired functional recovery. What remains unclear, however, is whether the mechanism of action by which GABA is augmented contributes to a drug's impact on the recovery process. Vigabatrin, a novel anti-convulsant that inhibits GABA-transaminase, was administered chronically after unilateral anteromedial cortex lesions and recovery from somatosensory deficits assessed. In contrast to the direct GABA receptor agonists, vigabatrin did not adversely impact (i.e., was neutral) recovery from neurobehavioral deficits at any of the anti-convulsant doses tested. Measurable secondary drug effects like sedation and hypothermia diminished over time and were reversible upon drug discontinuation. These results suggest that the degree to which a GABAergic agent impacts the recovery process after brain injury is dependent on the drug's mechanism of action.
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PMID:Impact of the novel anti-convulsant vigabatrin on functional recovery following brain lesion. 1267 Dec 69

(1) Taurine and GABA are recognized as endogenous cryogens. In a previous study, some structural analogues of taurine, namely 6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (TAG), 2-aminoethylarsonic (AEA), 2-hydroxyethanesulfonic (ISE) and (+/-)cis-2-aminocyclohexane sulfonic acids (CAHS) have been shown to displace [(3)H]taurine binding from rabbit brain synaptic membrane preparations, without interacting either with GABA-ergic systems, nor with taurine uptake mechanism, thus behaving like direct taurinergic agents. (2) To answer the question whether the role of taurine as an endogenous cryogen depends on the activation of GABA receptors or that of specific taurine receptor(s), taurine or the above structural analogues were injected intracerebroventricularly in conscious, restrained rabbits singularly or in combination and their effects on rectal (RT)- and ear-skin temperature and gross motor behavior (GMB) were monitored. (3) Taurine (1.2 x 10(-6)-4.8 x 10(-5) mol) induced a dose-related hypothermia, vasodilation at ear vascular bed and inhibition of GMB. CAHS, at the highest dose tested (4.8 x 10(-5) mol) induced a taurine-like effect either on RT or GMB. On the contrary ISE, injected at the same doses of taurine, induced a dose-related hyperthermia, vasoconstriction and excitation of GMB. AEA and TAG caused a dose-related hyperthermia, but at doses higher than 1.2 x 10(-7) mol caused death within 24 h after treatment. (4) CAHS (4.8 x 10(-5) mol) antagonized the hyperthermic effect induced by TAG (1.2 x 10(-6) mol), AEA (1.2 x 10(-8) mol) or ISE (4.8 x 10(-5) mol). (5) In conclusion, these findings may indicate the existence of a recognition site specific for taurine, responsible for its effects on thermoregulation.
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PMID:A specific taurine recognition site in the rabbit brain is responsible for taurine effects on thermoregulation. 1278 8


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