Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020672 (hypothermia)
 17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxia-ischemia damages selected regions of the immature at different ages. Prior to 32 weeks gestation the periventricular white matter is selectively vulnerable but in the last trimester the basal ganglia become especially vulnerable to injury. Hypoxia-ischemia causes injury by activating a series of biochemical events that unfolds over a period of hours to days following the initial insult and we are investigating the ways in which age modifies these events. The cascade includes release of glutamate, overstimulation of excitatory amino acid receptors and raised intracellular levels of calcium. Clinically this series is manifested by hypoxic-ischemic encephalopathy (HIE), a syndrome that includes coma, seizures, a burst suppression EEG, respiratory depression and severe hypotonia. Clinical studies have established a relationship between the severity of neonatal encephalopathy and later manifestations of brain damage or cerebral palsy. Potential neuroprotective therapies need to be effective when given after the insult but the 'therapeutic time window' for most N-methyl-D-aspartate (NMDA) glutamate antagonists is limited after injury. Using a model of hypoxic-ischemic injury and neonatal rats and hypothermic-circulatory arrest in dogs, we found that immunohistochemical staining for neuronal nitric oxide synthase (nNOS) is markedly increased from 6 to 24 h after the insult in the basal ganglia and cortex. The induction of nNOS preceded the time of maximal neuronal necrosis and during the time when many apoptotic nuclei were appearing. We have also found that a brief period of 2 h of mild hypothermia (32 degrees C) following hypoxia-ischemia in neonatal rats delayed neuronal necrosis by more than a week. We are determining whether this delay is related to a change in nNOS activation. Induction of nNOS in the post-insult period may contribute to expression of injury and signs of encephalopathy following a hypoxic-ischemic insult.
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PMID:Hypoxic and ischemic disorders of infants and children. Lecture for 38th meeting of Japanese Society of Child Neurology, Tokyo, Japan, July 1996. 918 71

It has been demonstrated that nitric oxide (NO) has a thermoregulatory action, but very little is known about the mechanisms involved. In the present study we determined the effect of neuronal nitric oxide synthase (nNOS) inhibition on thermoregulation. We used 7-nitroindazole (7-NI, 1, 10 and 30 mg/kg body weight), a selective nNOS inhibitor, injected intraperitoneally into normothermic Wistar rats (200-250 g) and rats with fever induced by lipopolysaccharide (LPS) (100 microg/kg body weight) administration. It has been demonstrated that the effects of 30 mg/kg of 7-NI given intraperitoneally may inhibit 60% of nNOS activity in rats. In all experiments the colonic temperature of awake unrestrained rats was measured over a period of 5 h at 15-min intervals after intraperitoneal injection of 7-NI. We observed that the injection of 30 mg/kg of 7-NI induced a 1.5 degrees C drop in body temperature, which was statistically significant 1 h after injection (P<0.02). The coinjection of LPS and 7-NI was followed by a significant (P<0.02) hypothermia about 0.5 degrees C below baseline. These findings show that an nNOS isoform is required for thermoregulation and participates in the production of fever in rats.
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PMID:Effects of a neuronal nitric oxide synthase inhibitor on lipopolysaccharide-induced fever. 1055 39

Perinatal hypoxic-ischaemic encephalopathy(HIE) is being studied in laboratory models that allow the delayed cascade of events triggered by the energetic insult to be examined in detail. The concept of the 'excitotoxic cascade' provides a conceptual framework for thinking about the pathogenesis of HIE. Major events in the cascade triggered by hypoxia-ischaemia include overstimulation of N-methyl-D-aspartate type glutamate receptors, calcium entry into cells, activation of calcium-sensitive enzymes such as nitric oxide synthase, production of oxygen free radicals, injury to mitochondria, leading in turn to necrosis or apoptosis. New experimental approaches to salvaging brain tissue from the effects of HIE include inhibition of neuronal nitric oxide synthase, administration of neuronal growth factors, and inhibition of the caspase enzymes that execute apoptosis. Recent experimental work suggests that these approaches may be effective during a longer 'therapeutic window' after the insult, because they are acting on events that are relatively delayed. Application of modest hypothermia may allow these agents to be neuroprotective at even longer intervals after hypoxia-ischaemia.
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PMID:Novel treatments after experimental brain injury. 1080 52

Methamphetamine (METH)-induced dopaminergic neurotoxicity is associated with hyperthermia. We investigated the effect of several neuronal nitric oxide synthase (nNOS) inhibitors on METH-induced hyperthermia and striatal dopaminergic neurotoxicity. Administration of METH (5 mg/kg; q. 3 h x 3) to Swiss Webster mice produced marked hyperthermia and 50-60% depletion of striatal dopaminergic markers 72 h after METH administration. Pretreatment with the nNOS inhibitors S-methylthiocitrulline (SMTC; 10 mg/kg) or 3-bromo-7-nitroindazole (3-Br-7-NI; 20 mg/kg) before each METH injection did not affect the persistent hyperthermia produced by METH, but afforded protection against the depletion of dopaminergic markers. A low dose (25 mg/kg) of the nNOS inhibitor 7-nitroindazole (7-NI) did not affect METH-induced hyperthermia, but a high dose (50 mg/kg) produced significant hypothermia. These findings indicate that low dose of selective nNOS inhibitors protect against METH-induced neurotoxicity with no effect on body temperature and support the hypothesis that nitric oxide (NO) and peroxynitrite have a major role in METH-induced dopaminergic neurotoxicity.
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PMID:nNOS inhibitors attenuate methamphetamine-induced dopaminergic neurotoxicity but not hyperthermia in mice. 1100 70

Hallervorden-Spatz syndrome is an autosomal-recessive brain disorder with signs of extrapyramidal dysfunction and mental deterioration, which associate with iron accumulation in globus pallidus and substantia nigra pars reticulata. Studies of oxidant stress in parkinsonian animal models suggest a linkage of iron overload to axonal dystrophy. Redox cycling of iron complexes (i.e., ferrous citrate and hemoglobin) increases hydroxyl radicals, lipid peroxidation, axonal dystrophy, and necrotic or apoptotic cell death. An increase of oxidative stress in the basal ganglia because of redox cycling of iron complexes leads to dopamine overflow and psychomotor dysfunction. Iron overload-induced axonal dystrophy has been demonstrated consistently using in vitro and in vivo models with a prominent feature of lipid peroxidation. This iron-induced oxidative stress is often accentuated by ascorbate and oxidized glutathione, although it is suppressed by the following antioxidants: S-nitrosoglutathione or nitric oxide, MnSOD mimics, manganese, U-78517F, Trolox, and deferoxamine. Preconditioning induction of stress proteins (i.e., hemeoxygenase-1 and neuronal nitric oxide synthase) and hypothermia therapy suppress the generation of toxic reactive oxygen, lipid, and thiol species evoked by bioactive iron complexes in the brain. Finally, combined antioxidative therapeutics and gene induction procedures may prove to be useful for slowing progressive neurodegeneration caused by iron overload in the brain.
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PMID:Iron overload, oxidative stress, and axonal dystrophy in brain disorders. 1155 44

In the present study, we describe a new role of the neuronal nitric oxide synthase (nNOS) gene in the regulation of alcohol drinking behavior. Mice deficient in the nNOS gene (nNOS -/-) and wild-type control mice were submitted to a two-bottle free-choice procedure with either water or increasing concentrations of alcohol (2-16%) for 6 weeks. nNOS -/- mice did not differ in consumption and preference for low alcohol concentrations from wild-type animals; however, nNOS -/- mice consumed sixfold more alcohol from highly concentrated alcohol solutions than wild-type mice. Taste studies with either sucrose or quinine solutions revealed that alcohol intake in nNOS -/- and wild-type mice is associated, at least in part, with sweet solution intake but not with the taste of bitterness. When compared with wild-type mice, the nNOS -/- mice were found to be less sensitive to the sedative effects of ethanol as measured by shorter recovery time from ethanol-induced sleep and did not develop rapid tolerance to ethanol-induced hypothermia, although plasma ethanol concentrations were not significantly different from those of controls. Our findings contrast with previous reports that showed that nonselective NOS inhibitors decrease alcohol consumption. However, because alcohol consumption was suppressed in wild-type as well as nNOS -/- mice by the NOS inhibitor N(G)-nitro-L-arginine methyl ester, we conclude that the effect of nonselective NOS inhibitors on alcohol drinking is not mediated by nNOS. Other NOS isoforms, most likely in the periphery or other splice variants of the NOS gene, might contribute to the effect of nonselective NOS inhibitors on alcohol drinking. In summary, the nNOS gene is critically involved in the regulation of neurobehavioral effects of alcohol.
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PMID:The neuronal nitric oxide synthase gene is critically involved in neurobehavioral effects of alcohol. 1235 42

Previous studies have implicated a role for nitric oxide (NO) and peroxynitrite in methamphetamine-induced dopaminergic neurotoxicity. The present study was undertaken to investigate whether NO is involved in serotonergic neurotoxicity caused by fenfluramine. In the first experiment, the effect of the neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole (7-NI; 25 mg/kg x 4) on fenfluramine (25 mg/kg x 4)-induced serotonergic neurotoxicity in Swiss Webster mice was investigated. In the second experiment, the effect of fenfluramine (25 mg/kg x 4) on nNOS (-/-) and wild-type (WT) mice was investigated. Fenfluramine induced hypothermia in all three mouse strains, and 7-NI had no thermoregulatory effect. Selective depletion of 5-HT and 5-HT transporter binding sites in the striatum, frontal cortex and hippocampus in all three mouse strains was observed, with no evidence of dopaminergic neurotoxicity. In the first experiment, 7-NI did not attenuate serotonergic neurotoxicity in Swiss Webster mice. In the second experiment, nNOS(-/-) and WT mice were equally sensitive to serotonergic neurotoxicity. These findings suggest that NO and peroxynitrite do not mediate fenfluramine-induced serotonergic neurotoxicity, and that NO is a selective mediator of amphetamines-induced dopaminergic neurotoxicity.
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PMID:Fenfluramine-induced serotonergic neurotoxicity in mice: lack of neuroprotection by inhibition/ablation of nNOS. 1296 73

Our laboratory recently demonstrated that a drug combination of baclofen and L-NAME, a nonspecific nitric oxide synthase (NOS) inhibitor, evokes synergistic hypothermia in rats. These data are the first demonstration of synergy between a GABA agonist and NOS inhibitor. While the hypothermic synergy suggests a role for NOS in baclofen pharmacology, it is unclear whether the super-additive hypothermia is specific for baclofen and L-NAME or extends to drug combinations of baclofen and other NOS inhibitors. The site of action (central or peripheral) and isoforms of NOS that mediate the synergy are also unknown. Here, we confirm the hypothermic synergy with additional data and discuss potential mechanisms of the drug interaction. Baclofen (2.5, 3.5, 5 and 7.5 mg/kg, i.p.) was administered to rats by itself or with 7-nitroindazole (7-NI), a neuronal NOS inhibitor. 7-NI (10 mg/kg, i.p.) did not affect body temperature. For combined administration, 7-NI (10 mg/kg, i.p.) increased the relative potency of baclofen (F=18.9, P<0.05). The present data validate the hypothermic synergy caused by the drug combination of baclofen and L-NAME and implicate nNOS in the synergy. In a context broader than thermoregulation, NO production and transmission may play an important role in baclofen pharmacology.
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PMID:Baclofen and NOS inhibitors interact to evoke synergistic hypothermia in rats. 1613 4

Previously, we showed that treatment with resuscitative, post-ischaemic mild hypothermia (34 degrees C for 2 h) reduced apoptosis in the penumbra (cortex), but not in the core (striatum) of an endothelin-1 (Et-1)-induced focal cerebral infarct in the anaesthetized rat. Therefore, the purpose of this study was to investigate by which pathways resuscitative mild hypothermia exerts its neuroprotective effect in this model. The amino acids glutamate, serine, glutamine, alanine, taurine, arginine and the NO-related compound citrulline were sampled from the striatum and cortex of the ischaemic hemisphere using in vivo microdialysis. The in vivo salicylate trapping method was applied for monitoring hydroxyl radical formation via 2,3 dihydroxybenzoic acid (2,3 DHBA) detection. Caspase-3, neuronal nitric oxide synthase (nNOS) immunoreactivity and the volume of ischaemic damage were determined 24 h after the insult. In both the striatum and the cortex, Et-1-induced increases in glutamate, taurine and alanine were refractory to mild hypothermia. However, mild hypothermia significantly attenuated the ischaemia-induced 2,3 DHBA levels and the nNOS immunoreactivity in the cortex, but not in the striatum. These observations were associated with a decreased caspase-3 immunoreactivity. These results suggest that mild hypothermia exerts its neuroprotective effect in the penumbra partially by reducing nNOS activity and thereby preventing oxidative stress. Furthermore, we confirm our previous findings that the neuroprotective effect of resuscitative hypothermia is not mediated by changes in ischaemia-induced amino acid release as they could not be associated with the ischaemia-induced damage in the Et-1 rat model.
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PMID:Post-ischaemic mild hypothermia inhibits apoptosis in the penumbral region by reducing neuronal nitric oxide synthase activity and thereby preventing endothelin-1-induced hydroxyl radical formation. 1619 Aug 88

Perinatal hypoxic-ischemic injury of the basal ganglia is a significant cause of disability in premature infants. Prolonged, moderate cerebral hypothermia has been shown to be neuroprotective after experimental hypoxia-ischemia; however, it has not been tested in the preterm brain. We therefore examined the effects of severe hypoxia and the potential neuroprotective effects of delayed hypothermia on phenotypic striatal neurons. Preterm (0.7 gestation) fetal sheep received complete umbilical cord occlusion for 25 min followed by cerebral hypothermia (fetal extradural temperature reduced from 39.4+/-0.3 degrees C to 29.5+/-2.6 degrees C) from 90 min to 70 h after the end of occlusion. Hypothermia was associated with a significant overall reduction in striatal neuronal loss compared with normothermia-occlusion fetuses (mean+/-SEM, 5.5+/-1.2% vs. 38.1+/-6.5%, P<0.01). Immunohistochemical studies showed that occlusion resulted in a significant loss of calbindin-28 kd, glutamic acid decarboxylase isoform 67 and neuronal nitric oxide synthase-immunopositive neurons (n=7, P<0.05), but not choline acetyltransferase-positive neurons, compared with sham controls (n=7). Hypothermia (n=7) significantly reduced the loss of calbindin-28 kd and neuronal nitric oxide synthase, but not glutamic acid decarboxylase-immunopositive neurons. In conclusion, delayed, prolonged moderate head cooling was associated with selective protection of particular phenotypic striatal projection neurons after severe hypoxia in the preterm fetus. These findings suggest that head cooling may help reduce basal ganglia injury in some premature babies.
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PMID:Induced cerebral hypothermia reduces post-hypoxic loss of phenotypic striatal neurons in preterm fetal sheep. 1696 98


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