Hypothermia and Alzheimer's disease neuropathogenic pathways.

Alzheimer's disease (AD) remains a major health problem, and accounts for 50 to 60% of all cases of dementia. The two histopathological hallmarks of AD are senile plaques, composed of the ß-amyloid peptide (Aß), and intraneuronal neurofibrillary tangles composed of abnormally hyperphosphorylated tau protein. Only a small proportion of AD is due to mutations in the genome of patients, the large majority of cases being of late onset and sporadic in origin. The relative contribution of genetics and environment to the sporadic cases is unclear, but they are accepted to be of multifactorial origin. This means that genetic and environmental factors can interact together to induce or accelerate the disease. Among environmental factors, studies suggest that hypothermia may contribute to the development and exacerbation AD. Here, we review the preclinical data involving hypothermia with tau and Aß, as well as clinical evidence implicating hypothermia in the development of AD.

Dexmedetomidine decreases extracellular dopamine concentrations in the rat nucleus accumbens.

The effects of dexmedetomidine, a highly selective alpha(2)-adrenoceptor agonist, on extracellular dopamine (DA) concentrations in the nucleus accumbens of awake rats were collected via in vivo cerebral microdialysis and measured using HPLC with electrochemical detection. The administration of dexmedetomidine (DEX) at a low dose (2 microg/kg bolus i.v. over 2 min followed by a continuous infusion of 0.1 microg/kg per min) and a high dose (20 microg/kg bolus i.v. over 2 min followed by a continuous infusion of 1 microg/kg per min), significantly decreased extracellular dopamine concentrations in the nucleus accumbens. The observed decrease was dose-dependent, occurring sooner and to a greater magnitude in the rats receiving a high dose of DEX. This inhibitory modulation of accumbal dopamine was receptor-specific, as the decrease in extracellular DA produced by DEX was no longer evident following pre-treatment and co-infusion with the highly selective alpha(2)-adrenoceptor antagonist, atipamezole (ATZ). Thus, these data suggest that adrenoceptor agonists and antagonists may modulate dopaminergic neurotransmission via mechanisms that are specific to the alpha(2)-adrenoceptor.

Dose-related differences in the distribution of cocaine in the maternal-fetoplacental compartments in rats.

Our goals were to examine whether a high dose of cocaine to causing CNS toxic manifestations in the pregnant rats influences the delivery of cocaine to the fetus, and whether the non-placental compartments have a significant role in the distribution of cocaine to the fetal tissues. Either a low or high dose of cocaine was infused intravenously to near-term pregnant rats. Arterial blood pressure and heart rate were monitored. Cardiac output and uterine and placental blood flows were measured by using radiolabeled microspheres. Plasma and tissue samples were obtained from the mother, placenta, and fetus and analyzed for cocaine and its metabolites via capillary gas chromatography/mass spectrometry. A high dose of cocaine induced convulsions that were accompanied by increased arterial blood pressure and decreased uteroplacental blood flow. However, the distribution pattern of cocaine and metabolites in the mother and fetus were similar between the high and low dose groups. Considerable amounts of cocaine and its metabolites were in the placenta. Previously ignored non-placental tissues, such as the amnion and myometrium appear to be a significant source for cocaine accumulation in the fetus.

Disposition of bupivacaine and its metabolites in the maternal, placental, and fetal compartments in rats.

BACKGROUND: This study was designed to determine the disposition of bupivacaine and its metabolites in the maternal, placental, and fetal compartments, using multiple sampling time points in chronically prepared awake pregnant rats. METHODS: All animals received an intravenous infusion of bupivacaine at a rate of 0.33 mg. kg-1. min-1 over a period of 15 min. The fetuses were delivered either at the end of infusion or at 2 or 4 h after dosing. Maternal and fetal blood and tissue samples were obtained for the assays of bupivacaine and its metabolites using capillary gas chromatography-mass spectrometry. RESULTS: The elimination half-life of bupivacaine was 37.7 min. The major metabolite was 3'-hydroxybupivacaine. Bupivacaine and 3'-hydroxybupivacaine were present in all samples at the end of administration. The fetal to maternal concentration ratio of bupivacaine in plasma was 0.29, and in the placenta was 0.63. The amnion contained the highest bupivacaine concentration: threefold higher in the maternal and 11-fold higher than in the fetal plasma. At 4 h after dosing, bupivacaine was no longer detectable in any maternal and fetal samples, whereas 3'-hydroxybupivacaine was still present in all tissues except the fetal plasma and heart. CONCLUSIONS: These data indicate that a considerable amount of bupivacaine is taken up by both sides of the placenta, as well as the amnion and myometrium. 3'-Hydroxybupivacaine was present in all tissues except the fetal plasma and heart samples, even after the parent compound became no longer detectable. Whether this slow elimination of 3'-hydroxybupivacaine causes any adverse effects on the fetus-newborn needs to be explored.

The nitric oxide-cGMP system of the locus coeruleus and the hypnotic action of alpha-2 adrenergic agonists.

Dexmedetomidine (Dex), a potent, selective alpha-2 adrenergic agonist, injected bilaterally directly into the locus coeruleus (LC), 7 microgram/LC, or ip, 100 microgram/kg, produced a maximum decrease in LC cGMP (-38 and -46%, respectively). Atipamezole, a selective alpha-2 adrenergic antagonist, given into the LC, 10 microgram/LC, prevented the decrease in LC cGMP induced by Dex, given i.p. or into the LC. Dex produced a loss of righting reflex in about 80% of the animals, an effect which was prevented by pretreatment with atipamezole. The nitric oxide synthase antagonist L-Name injected bilaterally into the LC, 20 microgram/LC, produced by itself a maximum decrease in LC cGMP of 54.5%. Dex, 100 microgram/kg, ip, given after L-Name, did not further decrease LC cGMP. L-Name, by itself, did not produce a loss of righting reflex, while 6 out of 9 rats pretreated with L-Name lost their righting reflex in response to Dex. A role of the nitric oxide-cGMP system of the LC in the modulation of the hypnotic effect of alpha-2 adrenergic agonists remains uncertain.

The comparative toxicity of cocaine and its metabolites in conscious rats.

BACKGROUND: The metabolites of cocaine, benzoylecgonine and ecgonine methyl ester, have been considered pharmacologically inactive when administered systemically. However, recent in vitro studies suggest that this may not be true. The current study was designed to evaluate the systemic toxicity of cocaine and its metabolites when administered systemically to awake rats fitted with catheters for long-term monitoring. METHODS: Cocaine, norcocaine, cocaethylene, benzoylecgonine, and ecgonine methyl ester were infused intravenously to produce sequential behavioral alterations and central nervous system and cardiovascular toxic effects. Arterial blood pressure and heart rate were monitored continuously. Plasma and tissue samples were analyzed for all compounds by capillary gas chromatography-mass spectrometry. RESULTS: The dose of norcocaine necessary to produce toxic effects was smaller than that of cocaine and cocaethylene. Benzoylecgonine and ecgonine methyl ester did not produce toxic manifestations at infusion rates that produced toxicity in the cocaine, norcocaine, and cocaethylene groups. Furthermore, 30- and 60-fold higher doses of benzoylecgonine and ecgonine methyl ester, respectively, were necessary to produce only mild neurobehavioral changes. Benzoylecgonine was not lethal even at doses 100 times greater than cocaine. CONCLUSIONS: These results indicate that benzoylecgonine and ecgonine methyl ester are not as toxic as cocaine, norcocaine, or cocaethylene when administered intravenously to pharmacologically naive rats.

Role of gender in the toxicity of norcocaine.

Gender differences may significantly influence the toxicity of cocaine in mammals. In this study, the influence of gender on the toxicity of norcocaine, a pharmacologically active metabolite of cocaine, was compared with its parent compound in adult male and female rats. In addition, the plasma and tissue norcocaine concentrations were evaluated after the administration of norcocaine and cocaine. Norcocaine or cocaine was administered intravenously at a rate of 2 mg/kg/min until circulatory collapse. Arterial blood samples as well as heart, liver, and brain tissues were obtained at circulatory collapse for the measurement of concentrations of norcocaine as well as cocaine and its major metabolites. There were no gender-related differences in the doses of norcocaine required to produce circulatory collapse; however, there were significant gender-related differences in the norcocaine tissue-to-plasma concentration ratios (T:P ratios). After the administration of norcocaine, T:P ratios for heart, liver, and brain tissue were significantly greater in males. Furthermore, after cocaine administration, the hepatic norcocaine T:P ratio was approximately 3-fold greater in the male rats than in the female rats. In contrast, female rats had a greater percentage of norcocaine in the plasma at circulatory collapse after acute cocaine administration. Although no gender differences in the lethality of norcocaine were observed, it remains to be seen whether the gender differences in the distribution and uptake of norcocaine play a role in the hepatotoxicity of the drug, particularly after chronic exposure.

The disposition of cocaethylene in rat maternal, placental, and fetal compartments.

OBJECTIVE: The aim of this project was to examine the disposition of maternally administered cocaethylene in the fetus. STUDY DESIGN: Pregnant rats with long-term catheter placement received an intravenous infusion of cocaethylene during a period of 30 minutes. At either the completion of the infusion or 6 hours after the infusion the fetuses were delivered by hysterotomy. Maternal and fetal blood and major tissue samples were obtained for assays of cocaethylene and its metabolites. RESULTS: Cocaethylene was present in all samples obtained at the end of the infusion, but after 6 hours it was no longer detectable in the maternal and fetal systemic circulations. However, a substantial amount of cocaethylene was still present in the placenta on both the maternal and fetal sides, with the concentration on the maternal side being higher, indicating that the placenta stores cocaethylene. At the end of the infusion benzoylecgonine was found in all samples and the maternal concentrations were higher than the corresponding fetal concentrations. This order was reversed 6 hours after infusion. Extremely high concentrations of cocaethylene and benzoylecgonine were found in the amnion. CONCLUSIONS: These results suggest that the placenta limits the transfer of cocaethylene to the fetus. The high affinity of this compound for extraplacental sites cannot be ignored.

Interaction of the alpha-2 adrenergic- and opioid receptor with the cGMP system in the mouse cerebellum.

The alpha-2 adrenergic agonist dexmedetomidine (Dex), 3-300 microg/kg, i.p., decreased cerebellar cGMP in a dose-dependent manner. Fentanyl (F), an opioid agonist, increased cerebellar cGMP at 0.3 mg/kg, s.c., and decreased it at doses >/=1 mg/kg. The inhibitory effect was receptor specific, that of Dex being blocked by the alpha-2 adrenergic antagonist yohimbine, 5 mg/kg, i.p.; that of F by the opioid antagonist naloxone, 5 mg/kg, i.p. In contrast the stimulatory effect of F was blocked by both naloxone and yohimbine. Yohimbine also enhanced the inhibitory effect of F. In mice pretreated with pertussis toxin, 2 microgram/mouse, given i.c.v. 72 h before the agonists, the decrease in cGMP induced by Dex or F was not affected, while the stimulatory effect of F was reversed to an inhibitory effect. When inhibiting doses of F and Dex were administered together, the cGMP response was smaller than the sum of the individual responses. Dex attenuated in a dose-dependent manner the decrease in cGMP induced by F, and unmasked or enhanced the stimulatory effect of F. These results show that the alpha-2 adrenergic- and opioid-receptors are coupled to the cGMP effector system and suggest that the two pathways converge at a common post-receptor site in the cascade of events transducing the receptor signal to cGMP regulation.