Influence of GABA-acting drugs on morphine-induced hyperthermia in rats.

A major inhibitory neurotransmitter of the nervous system, GABA (gamma-aminobutyric acid), is involved in mammalian thermoregulation. The present study investigated the influence of GABAergic neurotransmission-enhancing drugs, in a model of morphine-induced hyperthermia in conscious rats. We used body temperature assays to examine the effects of GABA-acting drugs on morphine-induced hyperthermia. In rats, low doses of morphine injected i.p. produced significant hyperthermia in a body temperature assay that was significantly attenuated upon pretreatment with GABA-acting drugs. These results suggest the existence of opioidergic-GABAergic interactions in a complex process of thermoregulation.

Deep brain stimulation as a possible treatment of hyperthermia in patients with serotonin syndrome.

Maintaining a body temperature within a narrow range is vital for the survival of all mammals, including humans. With the help of optogenetics, a better understanding of the thermoregulatory organs and pathways is achieved. Optogenetic activation of the GABAergic neurons in the ventral part of the lateral preoptic nucleus (VLPO) leads to decrease in the body temperature. On the other hand, number of drugs could alter the thermoregulatory balance, leading to a hyperthermic state, such as serotonin syndrome (SS). SS is a potentially life-threatening clinical condition that occurs as a result of a drug-induced increase in the intrasynaptic serotonin (5-hydroxytryptamine, 5-HT) levels due to overdose of a single drug or due to interaction between two or more drugs with serotonergic mechanism of action. In this hypothesis, we propose a novel method for the treatment of hyperthermia, a core clinical sign of serotonin syndrome, through deep brain stimulation (DBS). An electrode is stereotactically placed in the VLPO, which may lead to reduction of the core body temperature. If proven effective, this technique should be left as a salvage method for reduction of hyperthermia, where the drug treatment is insufficient or ineffective. This technique could be used for the treatment of other syndromes, where hyperthermia takes a central place, including malignant hyperthermia, neuroleptic malignant syndrome, etc. DBS, on the other hand, could be used alone to induce hyperthermia in patients with malignant diseases. Hyperthermia improves the immune response, improves the drug penetration and stop the repair of already damaged tumor cells after chemotherapy or radiotherapy.

Eicosanoids in rat brain during ischemia and reperfusion--correlation to DC depolarization.

The effects of complete ischemia on cerebral arachidonic acid (AA) metabolism were investigated in the isolated perfused rat brain. During 12.5 min of ischemia, AA, 5-hydroxy-6,8,11,14-eicosatetraenoic acid, and 15-hydroxy-5,8,11,13-eicosatetraenoic acid increased 129-, 4-, and 10-fold, respectively, while subsequent reperfusion for 30 min resulted in normalized levels independently of the duration of preceding ischemia. Prostaglandin (PG) F2 alpha, PGE2, PGD2, 6-keto-PGF1 alpha, and thromboxane (Tx) B2 remained at preischemic levels during 12.5 min of complete ischemia. However, at the end of subsequent reperfusion for 30 min, the levels of the prostanoids PGF2 alpha, PGE2, PGD2, 6-keto-PGF1 alpha, and TxB2 increased according to the preceding ischemic time. The levels reached a maximum after 7.5 min of ischemia and were elevated by 7-, 14-, 48-, 3-, and 30-fold, respectively. A prolongation of ischemia of up to 12.5 min was not associated with further increases of prostanoids at the end of reperfusion. The mechanisms underlying the metabolism of eicosanoids are discussed in relation to the changes of cortical direct current potential.

Alzheimer's disease therapy - an update.

The 5th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy focused on new therapeutic approaches for the treatment of Alzheimer 's disease (AD) based on the latest basic science data. The two major pharmacological principles of cholinergic therapy are 1) reduction of acetylcholine hydrolysis by means of acetylcholinesterase (AChE) inhibitors; and 2) direct stimulation of nicotinic or muscarinic receptors with selective agonists. Currently used AChE inhibitors are tacrine, donepezil hydrochloride, rivastigmine and metrifonate. In the area of muscarinic and nicotinic receptor modulation, studies were presented on AF-102B and AF-150(S), BIBN-99, CI-1017, RJR-2403, ABT-418, ABT-089, GTS-21 and SIB-1553A. Based on evidence of inflammatory mechanisms in the pathogenesis of AD, selective COX-2 inhibitors for the prevention and treatment of AD are a target of several pharmaceutical companies. Concerning known antiinflammatory drugs, results from controlled trials are expected soon. Estrogen replacement has been reported to produce cognitive and affective improvement in women with AD, and results from a number of studies were presented. Age-associated increases in oxidative stress may play a role in AD and thus antioxidants may also have a place in the therapy of this disease. The antioxidants vitamin E and selegiline are being investigated. Other drugs under investigation are propentofylline, Cerebrolysin, citicoline sodium, CDP-choline, memantine, Egb-761, calagualine and AIT-082. Iododoxorubicin may represent a new class of compounds able to interfere with the beta-amyloid cascade in AD and other brain amyloid diseases. Future preventive strategies in AD include genotype analysis and screening, presymptomatic diagnosis and avoidance of environmental risk factors.

Endothelin-1 exacerbates focal cerebral ischemia without exerting neurotoxic action in vitro.

In a model of focal cerebral ischemia in mice, intracisternal injection of 5 and 10 pmol/mouse endothelin-1 significantly increased the infarcted surface area by 15.5% and by 23.5%, respectively. Endothelin-1 (0.01, 1, and 100 nmol/l) added to the primary neuronal cultures of chick embryo cerebral hemispheres for 1 h and 24 h did not influence the viability of the neurons or the protein content of the cultures. When applied simultaneously with 1 mmol/l sodium cyanide for 30 min, endothelin-1 (0.01, 1, and 100 nM) did not modify the hypoxia-induced changes. The results show that exogenously applied endothelin-1 could exacerbate cerebral ischemia, probably due to its vasoconstrictive properties and not to a direct neurotoxic effect.

The effect of papaverine on local tissue PO2 and microflow in cat brain cortex.

The effect of intracarotid and intravenous administration of papaverine on local tissue PO2 and microflow in the cat's brain surface was studied. Local tissue PO2 was measured with a multiwire surface electrode polarographically, and microflow by local hydrogen clearance method. The intracarotid infusions were made for 1, 2 and 5 min with doses of 0.1, 0.2 and 0.5 mg/kg/min papaverine, and the intravenous ones for 5 min with doses of 0.2, 0.5 and 1 mg/kg/min. The continuous intracarotid infusions showed that papaverine in the doses used distinctly increased local tissue PO2 and microcirculation of the brain surface. With the doses applied, systemic arterial pressure (SAP) changed little. It slightly decreased only during the 5 min infusions containing 0.5 mg/kg/min. The duration of the effect increased with increases in the duration of the infusion and of the dose. The maximum duration was observed with 5 min infusions and lasted for 10--15 min after drug administration was discontinued. During the i.v. infusions, tissue PO2 and microflow rose less than with intracarotid ones. No redistribution of capillary flow was observed.

Arachidonic acid cascade and anti-hypoxic drugs.

The anti-hypoxic effect of drugs that inhibit different steps of arachidonic acid metabolism was studied using an experimental model of acute hypobaric hypoxia in mice. The drugs investigated were chloroquine, betamethasone, chlorpromazine (phospholipase A2 inhibitors), ketoprofen (cyclo-oxygenase inhibitor) and imidazole (TxA2 synthetase inhibitor). Prostacyclin (PGI2) and PGF2 alpha were also studied. The results show that all the inhibitors of arachidonic acid metabolism manifest an anti-hypoxic effect of a various degree. PGF2 alpha had a deleterious effect, and PGI2 showed a marked anti-hypoxic effect. The results suggest that it is advantageous to search for anti-hypoxic drugs among the blockers of arachidonic acid cascade.

Inhibition of phospholipase A2 in vitro by some anti-hypoxic drugs.

The effect of the anti-hypoxic drugs piracetam, nicergoline, papaverine, cinnarizine and aligeron on the activity of bee venom phospholipase A2 was studied in experiments in vitro. The pH-stat titration method of Grossmann et al. was used. All the drugs studied inhibited to a various degree the activity of phospholipase A2 in vitro. The most potent drug was nicergoline and the least potent was papaverine. Taking into account that the activity of phospholipase A2 is stimulated in hypoxia, the results make us believe that the inhibition of phospholipase A2 might play a certain role in the anti-hypoxic effect of the drugs studied.

Effect of prostaglandin F2 alpha and prostacyclin on asphyxic anoxia in cats.

The effects of exogenously applied prostaglandin F2 alpha (PGF2 alpha) and prostacyclin (PGI2) on asphyxic anoxia was studied in curarized and artificially ventilated cats. Anoxia was induced by stopping the ventilation and checking the changes in the EcoG. Cortical resistance (CRs) was evaluated as time between stopping the ventilation and the extinction of ECoG. Cortical recovery (CRc) was expressed as time between restitution of ventilation and reappearance of brain activity. Anoxia resistance index (ARI) was defined as the ratio between these two parameters (CRs/CRc). PGF2 alpha was applied by 5 minute i.v. and intracarotid (i.c.) infusion in a dose of 10 micrograms/kg/min, and PGI2 in a dose of 250 ng/kg/min for 15 minutes intracarotidly. The results show that both the i.c. and i.v. infusion with PGF2 alpha led to a significant decrease of CRs and prolongation of CRc resulting in decrease of ARI. The changes are more expressed at i.v. infusion, PGI2 does not improve the ECoG changes evoked by hypoxia. Suggestions for the possible mechanism of PGF2 alpha action and for the failure of PGI2 to protect the brain are made.

Protective effect of piracetam against PGF2 alpha-impaired cerebral resistance to hypoxia.

The protective effect of piracetam against PGF2 alpha-impaired cerebral resistance to hypoxia was investigated by EEG study in relaxed and artificially ventilated cats. Asphyxic anoxia was performed after 5 min of intracarotid (i.c.) or i.v. infusion of 10 micrograms/kg/min PGF2 alpha before and 30 min after piracetam (100 mg/kg i.v.). The following parameters were determined: cortical resistance (CRs)--as time between stopping the ventilation and the extinction of EEG; cortical recovery (CRc) - as time between restitution of ventilation and reappearance of brain activity; anoxia resistance index (ARI) - as the ratio between these two parameters (CRs/Crc). Both the i.c. and i.v. infusion of PGF2 alpha led to a significant decrease in CRs and lengthening of CRc which resulted in a decrease in ARI. Piracetam reverses the PGF2 alpha-induced changes in asphyxic anoxia. The possible mechanism of piracetam's effect and the probable therapeutic value of the latter are considered.

Rheoencephalographic and electroencephalographic studies on flunarizine.

The effect of flunarizine on the rheoncephalogram (REG) and on spontaneous electroencephalographic activity (EEG) was studied in acute experiments in cats. The following REG parameters were assayed: amplitude, anacrotic section of the curve and its relative part, and dicrotic index. EEG spectra were derived from 10-sec samples of EEG and the relative amplitudes were estimated at 2 Hz-intervals from 0-40 Hz. The REG study showed that flunarizine (2.5 and 5 mg/kg i.v.) caused an increase of the amplitude and a decrease of the anacrote, of its relative part, and the dicrotic index, changes indicating a lowering of the cerebrovascular resistance. EEG study showed a decrease of the amplitudes of the alpha-frequency band, and an increase of the fast-waves amplitudes, most pronounced at 5 mg/kg, changes showing enhancement of the activation processes in the brain cortex.

Study on the anti-hypoxic effect of some drugs used in the pharmacotherapy of cerebrovascular disease.

The anti-hypoxic effect of some agents used in the pharmacotherapy of cerebrovascular disease was studied using the following methods: incomplete ischemia by bilateral carotid ligation in rats, anoxic hypoxia by inhalation of argon in mice, and hemic hypoxia induced by injection of sodium nitrite (120 mg/kg s.c.) in rats. The following drugs were studied: piracetam, orotic acid, centrophenoxine, pentobarbital, vincamine, vinpocetine, cinnarizine, aligeron, xanthinol nicotinate and papaverine. The most pronounced anti-hypoxic effect was shown primarily with the metabolic acting drugs, such as orotic acid, centrophenoxine, piracetam and pentobarbital, followed by the preparations with combined metabolic and vasoactive properties (vincamine and vinpocetine). The predominantly vasoactive drugs were less effective in anoxic hypoxia, but showed more pronounced effect in incomplete ischemia.

Anti-hypoxic effect of indomethacin and its interaction with prostacyclin.

The anti-hypoxic effect of indomethacin (1-10 mg/kg) was studied using the following experimental methods: asphyxic anoxia in cats, hypobaric and anoxic hypoxia in mice, incomplete ischemia by bilateral carotid occlusion and hemic hypoxia in rats. In hypobaric and anoxic hypoxia the interaction of indomethacin with the effect of prostacyclin (PCl2) was investigated. Indomethacin showed an anti-hypoxic effect in all the methods used: it enhanced anoxia resistance index in asphyxic anoxia and significantly increased survival of rats and mice subjected to experimental hypoxia. Indomethacin potentiated the effect of PGl2, shifting the anti-hypoxic dose-response curve of PGl2 to the left. The possible mechanism of action of indomethacin in relation to cyclo-oxygenase inhibition is discussed.

Effect of prostacyclin (PGI2) on the mechanical activity of isolated longitudinal and circular muscle strips of guinea-pig stomach.

Muscle strips isolated in longitudinal and circular directions from the fundus, corpus and antrum, and from the pyloric sphincter of the guinea-pig stomach were placed in organ baths for recording their spontaneous contractility. Concentrations of the order of 10(-9) to 10(-6) M of prostacyclin (PGI2) were tested and compared with the effect of PGE1, PGE2, PGF2 alpha and acetylcholine. Furthermore, a modification of PGI2 effect was studied in the presence of adrenergic and cholinergic blocking agents, tetrodotoxin, indomethacin and the PG antagonist SC-19220. Like PGE1, PGE2, PGF2 alpha and acetylcholine, PGI2 increased the tone of the longitudinal strips from fundus, corpus and antrum, its effect being less potent than the effects of PGE1 and PGE2 and more potent than the effects of PGF2 alpha and acetylcholine. All the PGs inhibited the phasic contractions of the circular muscle of antrum and pyloric sphincter in a dose-dependent manner. These effects were not significantly changed in the presence of adrenergic and cholinergic blocking agents, nor in the presence of tetrodotoxin, and could therefore be interpreted as being myogenic in nature. Indomethacin exerted effects opposite to those of PGI2. It shifted the log concentration-effect curve for PGI2 to the right suppressing the maximum response of PGI2 by about 50%. SC-19220 reversibly inhibited the spontaneous tone and the excitatory responses of the gastric muscle to PGI2. The concentration-effect curves for PGI2 were shifted to the right in the presence of SC-19220. Analysis of the data gave the pA2 value for PGI2 5.3, the slope of Schild plot being 1.23, which suggests that SC-19220 is a competitive antagonist.

Effect of piracetam on the electrocorticogram after traumatic brain oedema in cats.

The effect of piracetam on the electrocorticogram changes caused by experimentally-induced traumatic brain oedema in cats has been studied. The trauma was evoked by sticking a needle through the parietal associative cortical area. The electrocorticogram amplitude and frequency depression of the injured cortical area was eliminated and the bioelectrical activity restored to a normal pattern 22.4 +/- 10.3 min after a single dose of piracetam (100 mg/kg i.v.). The results indicate that piracetam recovered the cortical bioelectrical activity disturbed by experimentally-induced traumatic oedema. The beneficial effect of piracetam is probably due to an optimization of the functional state of the brain since piracetam acts as a nonspecific activator of brain excitability.

Anti-hypoxic effect of piracetam and its interaction with prostacyclin.

The anti-hypoxic effect of piracetam was studied using the following experimental methods: hypobaric and anoxic hypoxia in mice, complete ischemia by decapitation in mice, incomplete ischemia by bilateral carotid occlusion in rats and hemic hypoxia in rats. Cinnarizine and vinpocetine were used as reference drugs. In hypobaric hypoxia, anoxic hypoxia, and complete ischemia by decapitation the interaction of piracetam with the effect of prostacyclin (PGI2) was investigated. Piracetam showed anti-hypoxic effect in all the methods used. Its effect was greater than that of cinnarizine and similar to that of vinpocetine. Piracetam potentiated the effect of PGI2 shifting the anti-hypoxic dose-response curve of PGI2 to the left.

Study on the anti-hypoxic effect of cinnarizine and its interaction with prostacyclin.

The anti-hypoxic effect of cinnarizine was studied using the following experimental methods: hypobaric and anoxic hypoxia in mice, complete ischemia by decapitation in mice and hemic hypoxia in rats. Papaverine, xanthinol nicotinate and naftidrofuryl were used as reference drugs. In hypobaric and anoxic hypoxia the interaction of cinnarizine with the effect of prostacyclin (PGI2) was investigated. Cinnarizine showed an anti-hypoxic effect in all the methods used. It was more effective in hypobaric and anoxic hypoxia, in incomplete ischemia by decapitation, and less effective in hemic hypoxia. Cinnarizine potentiated the effect of PGI2 shifting the anti-hypoxic dose-response curve of PGI2 to the left. Suggestions as to the possible mechanism of anti-hypoxic action of cinnarizine are made.

Effects of intracerebroventricular endothelin-1 on CNS and cerebral hypoxia/ischemia and their modification by cinnarizine.

The central effects of endothelin-1 (ET-1) and their modification by the calcium entry blocker cinnarizine have been investigated using CNS and hypoxia/ischemia tests. CNS tests comprised behavior, horizontal and vertical motor activity and hot plate test. Hypoxia/ischemia tests used were hypobaric hypoxia and complete ischemia by decapitation. ET-1 was injected intracerebroventricularly (i.c.v.) in a volume of 0.01 ml at doses of 1.25, 2.5 and 5 pmol/mouse 15 min before the tests. Cinnarizine (10 mg/kg, i.p.) was administered 60 min prior to ET-1. The i.c.v. ET-1 at all the doses used decreased horizontal and vertical motor activity and produced barrel-rolling. Survival/gasping time of mice subjected to hypoxia/ischemia increased dose-dependently. ET-1 showed an antinociceptive effect. Cinnarizine attenuated the appearance of barrel-rolling, did not antagonize disturbances in motor activity and reversed the antinociceptive effect of ET-1. In hypobaric hypoxia and decapitation cinnarizine antagonized the effects of 5 pmol/mouse ET-1 and potentiated that of 1.25 pmol/mouse. The pharmacological modification of the ET-1 effects by cinnarizine strongly suggests that the CNS actions of ET-1 might be due to multiple mechanisms triggered by an increased influx of extracellular Ca2+ into the brain cells.

Study on the cerebral effects of sabeluzole.

The cerebral effects of subeluzole have been studied using the following methods: hypobaric hypoxia in mice, complete ischemia by decapitation in mice, anoxic hypoxia in mice, hemic hypoxia in rats, incomplete ischemia by bilateral carotid ligation in rats, anoxic hypoxia in rats and asphyxic hypoxia in cats. Sabeluzole was active in all the models used: it increased the survival time in hypobaric hypoxia (maximum at 40 mg/kg--by 92.0%, p less than 0.001), survival time in anoxic hypoxia in mice (maximum at 40 mg/kg--by 27.2%, p less than 0.001), gasping in decapitation model (maximum at 20 mg/kg--by 155.4%, p less than 0.001) and survival in hemic hypoxia (maximum at 2.5 mg/kg--by 21.1%, p less than 0.05). The duration of the effect as evaluated in the decapitation model was about 6 h. In incomplete ischemia in rats, however, it showed a weak effect. In anoxic hypoxia in rats, sabeluzole (5 mg/kg i.v.) increased the time latency between onset of anoxia and negative DC-shift by 20.5% and the K+e-threshold by 25.7%. In asphyxic hypoxia in cats, sabeluzole (0.5 mg/kg i.v.) counteracted the hypoxia-induced decrease of the fast-wave amplitudes during the cortical resistance period and the hypoxia-induced decrease of the slow-wave and increase of the fast wave amplitudes during the cortical recovery period.

L-NAME augments the antinociceptive effects of intracerebroventricularly applied ET-1 and ET-3.

The interaction between endothelin-1 (ET-1) (5 pmol/mouse, i.c.v.) and endothelin-3 (ET-3) (5 pmol/mouse, i.c.v.) with NG-nitro-L-arginine methyl ester (L-NAME) (5 mg/kg i.p., 30 min pretreatment) was investigated in mice by the use of two experimental procedures: hot plate and tail flick tests in mice. L-NAME showed slight insignificant antinociceptive action, but augmented significantly the antinociceptive effects of i.c.v. administered ET-1 and ET-3 in both experimental tests.