sodium-oxybate and Brain-Ischemia

Gamma-hydroxybutyric acid (GHB) as a natural component of the mammalian brain was first introduced in clinical anaesthetic practice more than 30 years ago. Although GHB induced a reliable state of sedation and anaesthesia without depressing either respiratory or cardiocirculatory parameters or liver and kidney function, the drug was nearly displaced from clinical practice because of its prolonged duration of action. The results of recent clinical studies indicate a re-evaluation of GHB in emergency and critical care medicine. GHB is regarded as a natural neuronal transmitter with circuits which synthesise, accumulate and release GHB. Specific binding sites have also been demonstrated and identified. GHB is completely metabolized in the liver to the natural substrates carbon dioxide and water without accumulation in central or peripheral tissues. The reduction of energy metabolism and its possible properties as an "oxygen radical scavenger" may be of therapeutic benefit if tissues are exposed to hypoxia or reperfusion. Therefore, the application of GHB seems to be of advantage in states of traumatic brain injury with cerebral oedema or ischaemic lesions of brain or extraneural tissues. In hypovolaemic states or in patients with impaired cardiovascular function, the pressure effects of GHB may be beneficial for the prevention of tissue damage and may improve survival in the case of cardiocirculatory resuscitation. In the intensive care unit, GHB might be a favourable alternative to established sedative agents. Occurrence of side effects such as tolerance and withdrawal syndromes after the application of sedative drugs, an impaired metabolism with the accumulation of metabolites in the case of liver or kidney dysfunction as well as an insufficient regulation of natural sleep may be diminished by the application of GHB. The results of various clinical studies also suggest that GHB may be useful in the treatment of alcohol and opiate withdrawal syndrome. However, further studies are necessary to specify the proposed indications of GHB in anaesthesiology and critical care medicine.

Topics: Anesthesia, Intravenous; Anesthetics, Intravenous; Brain; Brain Injuries; Brain Ischemia; Cardiopulmonary Resuscitation; Conscious Sedation; Critical Care; Humans; Metabolic Clearance Rate; Sodium Oxybate

Hypothermia is a promising neuroprotective therapy. We studied the feasibility and safety of very prolonged moderate hypothermia for severe acute ischemic stroke.. Moderate hypothermia was induced within 24h after a severe ischemic stroke involving the middle cerebral artery. Hypothermia, with cooling blankets, reduced body-core temperature to 32-33°C, and was prolonged for up to 22 days until cerebral edema had significantly decreased (assessed by serial cerebral computed tomography) before slow rewarming (<1.5°C/day). Patients were mechanically ventilated and sedated with gamma-hydroxybutyrate (GHB), a naturally occurring metabolite of gamma-aminobutyric acid (GABA), which acts on the GABA(B) receptors. Outcomes and side effects at 12 months were recorded.. Nineteen patients (mean age: 52.6 years, mean National Institute of Health Stroke Scale (NIHSS) score 21) were enrolled. Cooling was achieved in all patients. The mean time to reach target temperature was 11.4 ± 8.6h and the mean duration of rewarming was 4.0 ± 1.1 days. For the 10 survivors (53%), the mean duration of hypothermia and rewarming was 22.6 ± 4.9 days. Five patients underwent a hemicraniectomy. All patients presented with hypotension, bradycardia, and hematological side effects. Eight patients had pneumonia (42%). At 12 months, the mean NIHSS score was 8.3 ± 2.7, the Barthel Index was 67 ± 18, and the modified Rankin scale was 3.2 ± 0.9.. This study shows the feasibility of very prolonged hypothermia beyond 3 weeks using GHB sedation in severe hemispheric infarcts.

Topics: Adult; Aged; Brain Ischemia; Cohort Studies; Feasibility Studies; Female; Humans; Hypothermia, Induced; Male; Middle Aged; Pilot Projects; Severity of Illness Index; Sodium Oxybate; Stroke; Time Factors

gamma-Hydroxybutyrate (GHB), a natural metabolite of gamma-aminobutyric acid and a drug used in humans to promote slow-wave sleep and treat narcolepsy, has been suggested to protect against ischemic stroke at high doses. This study aimed to assess recovery-promoting effects of GHB at a low dose similar to that used in patients.. Adult mice, subjected to 30 min of intraluminal middle cerebral artery occlusion, were intraperitoneally treated with GHB (100 mg/kg, twice/day, 8 h apart) or saline for 10 days. Motor recovery was evaluated by the grip strength test. The brain lesion was assessed by cresyl violet and NeuN staining 5 weeks after stroke. Expression of neuroplasticity-related genes (GAP43, c-jun, neurocan and ephrin B1) was analyzed by Taqman real-time PCR.. GHB-treated mice regained their body weight faster and recovered grip strength (3 weeks after stroke) more quickly than saline-treated mice. This was noteworthy as GHB did not influence ischemia-induced brain injury, as revealed by cresyl violet and neuronal staining. The Taqman PCR assay revealed a decreased expression of c-jun and neurocan in the ischemic striatum of GHB-treated mice in comparison to saline-treated mice.. GHB at a low dose accelerates neurological recovery following ischemic stroke. Further studies are necessary to determine the potential relationship between GHB, neuroplasticity, sleep and stroke recovery.

Topics: Adjuvants, Anesthesia; Animals; Brain Ischemia; Disease Models, Animal; Ephrin-B1; Gene Expression; Infarction, Middle Cerebral Artery; JNK Mitogen-Activated Protein Kinases; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Neurocan; Neuronal Plasticity; Proteoglycans; Recovery of Function; Sodium Oxybate

Gamma-hydroxybutyrate (GHB) and its lactone, gamma-butyrolactone (GBL) have been previously shown to produce a protective effect in animal models of cerebral ischaemia/hypoxia, as well as in human conditions of head injury-induced coma. The aim of the present research was to study the effect of GHB in experimental conditions of focal cerebral damage, either induced by ischaemia or excitotoxicity. Under general anaesthesia, rats were injected into the right striatum with either endothelin-1 (ET-1, 0.43 nmol) or kainic acid (7.5 nmol) in a volume of 1 microl. Sham-lesioned rats received 1 microl of the solvent. Both ET-1- and kainic acid-lesioned rats were randomly assigned to one of the following intraperitoneal (i.p.) treatments: (i) and (ii) GHB, 100 or 300 mg kg(-1) 2 h after the lesion, followed by 50 or 100 mg kg(-1), respectively, every 12 h; (iii) saline, 2 ml kg(-1), same schedule. Sham animals were treated with saline, 2 ml kg(-1), same schedule. Treatments lasted for 10 days. The higher dose of GHB produced a significant protection against the ET-1-induced impairments in sensory-motor orientation and coordinated limb use (evaluated 24 and 42 days after the lesion) and in place learning and memory (Morris test, performed 19 and 39 days after the lesion). The same dose regimen reduced the circling behaviour induced by apomorphine in kainate-lesioned rats (10 days after the lesion), and limited or prevented at all the histological damage produced either by ET-1 or by kainic acid (evaluated 43 or 10 days after the lesion, respectively). These results show that GHB limits both histological and functional consequences of a focal ischaemic or excitotoxic insult of the brain, in rats, even if the treatment is started 2 h after the lesion.

Topics: Animals; Apomorphine; Brain; Brain Ischemia; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Kainic Acid; Learning; Male; Memory Disorders; Motor Activity; Nerve Degeneration; Neuroprotective Agents; Neurotoxins; Rats; Rats, Wistar; Sodium Oxybate

The effect of gamma-hydroxybutyrate on the histological and behavioral consequences of transient brain ischemia was studied in the four vessel occlusion rat model. In saline-treated animals, 30 min ischemia caused a massive loss of neurons in the hippocampal CA1 subfield (normal neurons: 14%, 5%, 23% and 30% on the 3rd, 10th, 15th and 65th day after ischemia, respectively). gamma-Hydroxybutyrate - 300 mg/kg intraperitoneally (i.p.) 30 min before or 10 min after arteries occlusion, followed by 100 mg/kg i.p. twice daily for the following 10 days - afforded a highly significant protection (normal neurons on the 3rd, 10th, 15th and 65th day after ischemia: 88% and 91%, 80% and 80%, 91% and 90%, 72% and 71% in rats receiving the first dose before or after arteries occlusion, respectively). The ischemia-induced sensory-motor impairment was significantly attenuated in rats receiving the first dose of gamma-hydroxybutyrate before arteries occlusion. Finally, the ischemia-induced impairment in spatial learning and memory, evaluated starting 27 days after the ischemic episode, was significantly attenuated by gamma-hydroxybutyrate, either injected first at 30 min before or 10 min after arteries occlusion. Lower doses of gamma-hydroxybutyrate had no significant effect. In conclusion, these results indicate that gamma-hydroxybutyrate provides significant protection against both histological and behavioral consequences of transient global cerebral ischemia in rats.

Topics: Animals; Brain Ischemia; Hippocampus; Learning; Male; Memory; Neurons; Neuroprotective Agents; Psychomotor Performance; Rats; Rats, Wistar; Sodium Oxybate; Somatosensory Cortex; Spatial Behavior

Cerebral protection means prevention of cerebral neuronal damage. Severe brain damage extinguishes the very "human" functions such as speech, consciousness, intellectual capacity, and emotional integrity. Many pathologic conditions may inflict injuries to the brain, therefore the protection and salvage of cerebral neuronal function must be the top priorities in the care of critically ill patients. Brain tissue has unusually high energy requirements, its stores of energy metabolites are small and, as a result, the brain is totally dependent on a continuous supply of substrates and oxygen, via the circulation. In complete global ischemia (cardiac arrest) reperfusion is characterized by an immediate reactive hyperemia followed within 20-30 min by a delayed hypoperfusion state. It has been postulated that the latter contributes to the ultimate neurologic outcome. In focal ischemia (stroke) the primary focus of necrosis is encircled by an area (ischemic penumbra) that is underperfused and contains neurotoxic substances such as free radicals, prostaglandins, calcium, and excitatory neurotransmitters. The variety of therapeutic effort that have addressed the question of protecting the brain reflects their limited success. 1) Barbiturates. After an initial enthusiastic endorsement by many clinicians and years of vigorous controversy, it can now be unequivocally stated that there is no place for barbiturate therapy following resuscitation from cardiac arrest. One presumed explanation for this negative statement is that cerebral metabolic suppression by barbiturates (and other anesthetics) is impossible in the absence of an active EEG. Conversely, in the event of incomplete ischemia EEG activity in usually present (albeit altered) and metabolic suppression and hence possibly protection can be induced with barbiturates. Indeed, most of the animal studies led to a number of recommendations for barbiturate therapy in man for incomplete ischemia. 2) Isoflurane. From a cerebral metabolic standpoint, exposure to isoflurane at concentration of 2 MAC is credited with providing the same potential for protection as high dose barbiturate (isoelectric EEG). A possible major difference between barbiturates and isoflurane is the modest cerebral vasodilation induced by the latter while barbiturates are associated with decreased CBF. This suggests that in focal ischemia isoflurane may elicit an intracerebral steal. 3) Calcium entry blockers. Some calcium entry blockers with the di

Topics: Adrenal Cortex Hormones; Anesthetics; Barbiturates; Benzodiazepines; Brain Ischemia; Calcium Channel Blockers; Free Radical Scavengers; Heart Arrest; Humans; Hypoxia, Brain; Lidocaine; Phenytoin; Prostaglandin Antagonists; Receptors, N-Methyl-D-Aspartate; Sodium Oxybate

Cerebral ischemia in rats (both carotid arteries occlusion) during 30 min, 3 hours and recirculation (1 hour) after ischemia (30 min) stimulated diene conjugates and fluorescent products accumulation in brain tissue. Intraperitoneal injection of sodium hydroxybutyrate (100 mg/kg), bemitil (50 mg/kg), ethomersol (50 mg/kg) reduced brain lipid peroxidation and did not yield in this respect to emoxypin (5 mg/kg). In contrast to emoxypin, sodium hydroxybutyrate, bemitil and ethomersol had no antiradical activity.

Topics: Animals; Antioxidants; Arterial Occlusive Diseases; Benzimidazoles; Brain Ischemia; Carotid Artery Diseases; Picolines; Rats; Rats, Wistar; Sodium Oxybate

Influence of natrii hydroxybutyrate (100 mg/kg), ascorbate (100 mg/kg), cavinton (5 mg/kg), bemitil (50 mg/kg), ethomersol (50 mg/kg) on Hb-O2 affinity and cortex PO2 after both carotid artery occlusion in rats was investigated. Correlation (r-0.87; P less than 0.05) between lowering of Hb-O2 affinity and antihypoxic effect was demonstrated in the line of these drugs.

Topics: Acute Disease; Animals; Antioxidants; Ascorbic Acid; Benzimidazoles; Brain Ischemia; Drug Evaluation, Preclinical; Hemoglobins; Hypoxia, Brain; Oxygen; Rats; Sodium Oxybate; Vasodilator Agents; Vinca Alkaloids

Brain ischemia in gerbils was induced by ligation of both common carotid arteries for 1 min or 10 min. Sham-operated animals served as controls. Intracerebral injection of [3H]inositol into gerbil brain 16 hr before ischemic insult resulted in equilibration of the label between inositol lipids and water-soluble inositol phosphate. A short ischemic period (1 min) resulted in a statistically significant increase in the radioactivity of inositol triphosphate (IP3) and inositol monophosphate (IP), by about 48% and 79%, respectively, with little change in that of the intermediate inositol biphosphate (IP2), which increased by about 16%. When the ischemic period was prolonged (10 min), an increase in the radioactivity of inositol monophosphate exclusively, by about 84%, was observed. The level of radioactivity in inositol phosphates IP2 and IP3 decreased by about 50%, probably as a consequence of phosphatase activation by the ischemic insult. The agonist of the cholinergic receptor, carbachol, injected intracerebrally (40 micrograms per animal) increased accumulation of radioactivity in all inositol phosphates. The level of radioactivity in IP3, IP2, and IP was elevated by about 40, 23, and 147%, respectively. The muscarinic cholinergic antagonist, atropine, injected intraperitoneally in doses of 100 mg/kg body wt. depressed phosphoinositide metabolism in control animals. The level of radioactivity in water-soluble inositol metabolites in the brain of animals pretreated with atropine was evidently about 32% lower than in untreated animals. Pretreatment with atropine decreased the radioactivity of all inositol phosphates in the brain of animals subjected to 1-min ischemia and the radioactivity of IP in the case of 10-min brain ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atropine; Brain Ischemia; Gerbillinae; Hydroxybutyrates; Inositol Phosphates; Sodium Oxybate; Solubility; Sugar Phosphates; Tritium; Water

The effect of gamma-hydroxybutyrate (GHB) on the reactivity of pial arteries to local metabolic factors was tested in chloralose-anesthetized cats before or after a period of transient ischemia induced by air embolism. The vascular reactions were determined during the perivascular microapplication of artificial CSFs with increasing concentrations of adenosine (10(-11)-10(-3) M), H+ (pH 5.1-7.6), or K+ (0-10 mM). During nonischemic conditions the pial arterial reactivity to adenosine and H+, but not to K+, was significantly increased by GHB (250 mg/kg i.v.) when compared with the control reactivity. After cerebral ischemia the reactivity to adenosine was abolished with and without the administration of GHB prior to air embolism. The reactivity to K+ was partly preserved but not increased by GHB when compared with previous results without GHB. In contrast GHB improved the postischemic reactivity to perivascular H+ that had been found to be abolished in previous experiments without GHB. The perivascular microapplication of GHB showed no influence of GHB on the vascular diameter. An important finding of the present study is the demonstration of an increase in cerebrovascular reactivity, which may give scope for therapeutic improvement of the regulation of CBF in pathophysiological conditions.

Topics: Adenosine; Animals; Arteries; Brain Ischemia; Cats; Cerebrovascular Circulation; Embolism, Air; Female; Hydroxybutyrates; Intracranial Embolism and Thrombosis; Male; Microinjections; Pia Mater; Sodium Oxybate

A study was made of energy metabolism and concentration of malonic dialdehyde (MDA) in cerebral tissue of mice given sodium hydroxybutyrate and lithium hydroxybutyrate 30 and 60 s after decapitation. Administration of lithium hydroxybutyrate brought about a more economic consumption of the glycogen pool as compared with "hypoxic" control. The differences were revealed in the action of both salts on ATP. The concentration of MDA declined after their administration, lithium hydroxybutyrate being more efficacious. The possible mechanisms of the action of lithium hydroxybutyrate are discussed.

Topics: Animals; Brain; Brain Ischemia; Energy Metabolism; Hydroxybutyrates; Lithium; Male; Malondialdehyde; Mice; Organometallic Compounds; Sodium Oxybate

The antihypoxic effects of gutimine, piracetam, sodium hydroxybutyrate and lithium hydroxybityrate were studied on different models of brain hypoxia. All the drugs under study produced a remarkable antihypoxic effect in experimental asphyxic hypoxia, increasing brain resistance to oxygen deficiency and rapidly restituting brain function. Drug pretreatment of the animals with carotid artery occlusion raised the number of animals which survived 24 h after the operation. GABA salts appeared the most effective. Sodium hydroxybutyrate increased the lifespan of rats under histotoxic hypoxia.

Topics: Animals; Asphyxia; Brain Ischemia; Disease Models, Animal; Drug Evaluation, Preclinical; Electrocardiography; Electroencephalography; Guanylthiourea; Hydroxybutyrates; Hypoxia, Brain; Lithium; Male; Organometallic Compounds; Piracetam; Rats; Sodium Nitrite; Sodium Oxybate