Kaoru Chiba

l-Deprenyl prevents the cell hypoxia induced by dopaminergic neurotoxins, MPP+ and β-carbolinium: a microdialysis study in rats

N-Methyl-4-phenylpyridinium (MPP(+)) and 2,9-di-methyl-norharmanium (2,9-Me2NH(+)), which is a beta-carbolinium proposed as an endogenous MPP(+)-like toxin underlying Parkinsons disease, are strong mitochondrial toxins. We have measured the extracellular lactate levels as a marker for the in vivo cell hypoxia in the striatum of freely moving rats. The perfusions with MPP(+) and 2,9-Me2NH(+) increased extracellular lactate levels in a dose-dependent manner. These increases in lactate levels were significantly prevented by the co-perfusion with 10 microM L-deprenyl, a selective monoamine oxidase (MAO)-B inhibitor, but not by pargyline, a non-specific MAO inhibitor. The increase in extracellular lactate levels was considered to be the reflection of the cell damage resulted from the impairment of mitochondrial function. The present results suggested that L-deprenyl would rescue nerve cells from these toxins through the direct influence on the mitochondrial electron transport.

Tandospirone, a 5-HT1A agonist, ameliorates movement disorder via non-dopaminergic systems in rats with unilateral 6-hydroxydopamine-generated lesions.

Serotonin 1A (5-HT1A) receptors are distributed throughout the brain with their highest concentrations in the frontal cortex, subthalamic nucleus and entopeduncular nucleus as well as the dorsal and median raphe nucleus. There is growing evidence that 5-HT1A receptor agonists have an antidepressant effect in individuals with major depressive disorders. Recent clinical studies suggest that tandospirone, a highly potent and selective 5-HT1A receptor agonist used clinically as an antidepressant in Japan and China, may act as an antiparkinsonian drug. In the present study, we investigated the effect of tandospirone on contralateral rotational behavior in a unilateral hemiparkinsonian rat model produced with 6-hydroxydopamine (6-OHDA). Tandospirone, as well as 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT), significantly increased contralateral turnings in a dose-dependent manner (0.5-10 mg/kg). Tandospirone also remarkably potentiated the contralateral turning induced by 0.025 mg/kg of apomorphine. Pretreatment with WAY-100635, a 5-HT1A receptor antagonist, almost completely blocked the contralateral turning behavior evoked by tandospirone and 8-OHDPAT, but not that by apomorphine. SCH-23390, a selective dopamine D1 receptor antagonist, did not affect on the tandospirone-induced rotational behavior. These results suggested that tandospirone could act on postsynaptic 5-HT1A receptors and modulate excitatory amino acid pathways in the basal ganglia. Thus, tandospirone could have therapeutic potential for the treatment of Parkinsons disease by modulating neuronal activities of non-dopaminergic pathways.

Cefoselis, a β-lactam antibiotic, easily penetrates the blood-brain barrier and causes seizure independently by glutamate release

Summary.Cefoselis is a widely used β-lactam antibiotic, but occasionally induces seizures and convulsion in elder and renal failure patients. However, β-lactams are known not to pass through the blood-brain barrier (BBB). In this study, we examined the BBB penetration of cefoselis in normal and renal failure rats by means of brain microdialysis. Cefoselis was dose-dependently appeared in brain extracellular fluid in proportion to its blood level. The elimination constant from brain extracellular fluid (apparent) was slightly lower than that from blood. These results indicated that cefoselis might penetrate the BBB or be discharged by a certain transport system. In contrast to the result of cefoselis, cefazolin, a leading drug of cephalosporins, could not be detected in the brain extracellular fluid after an intravenous injection. In renal dysfunction rats, the elimination half-lives of cefoselis from both blood and brain were extensively prolonged. This would be one of responsible factors inducing seizures seen in patients. However, the additional factor, such as decrease in brain function related to aging, would be involved in seizures in patient received cefoselis, because an extremely high dose was required to induce seizures even in renal failure rats. A local administration of cefoselis into the hippocampus through the microdialysis probe caused a striking elevation of extracellular glutamate, with a minimum increase in γ-aminobutyric acid (GABA). However, a systematic cefoselis administration via the tail vein did not elevate extracellular glutamate and GABA concentrations in the hippocampus of renal failure rats that exhibited marked seizures. These results suggested that not the stimulation of glutamate release, but the blockade of GABA receptors might be responsible for the seizure induced by cefoselis.

Effects of tilisolol on ischemic myocardial metabolism in dogs

The effects of tilisolol on ischemic myocardial energy and carbohydrate metabolism were examined, and compared with those of propranolol. Ischemia was induced by ligating the left anterior descending coronary artery for 3 or 30 min in anesthetized open-chest dogs, 5 min after saline, tilisolol (0.2 mg.kg-1, i.v.), or propranolol (1 mg.kg-1, i.v.) injection. During ischemia, the myocardial energy stores were depleted, and the levels of glycolytic intermediates were altered, associated with ST segment elevation and TQ segment depression of the epicardial electrocardiogram. Tilisolol prevented the myocardial energy depletion and alterations of carbohydrate metabolism caused by 3 min of ischemia, to the same extent as did propranolol. Even 30 min after ischemia, the prevention of these ischemic changes was sustained by tilisolol, but not by propranolol. Tilisolol briefly reduced the ST segment elevation and TQ segment depression induced by ischemia. These results suggest that the protective effects of tilisolol on the ischemic myocardium are more potent and long-lasting than those of propranolol.

Effect of Nipradilol on Myocardial Energy Metabolism in the Dog Ischaemic Heart

Abstract— The effect of nipradilol, a newly developed β‐adrenoceptor blocking agent with a vasodilatory action, on myocardial energy metabolism has been examined in the dog ischaemic heart, and compared with that of propranolol. Ischaemia was induced by ligating the left anterior descending coronary artery. Either saline, nipradilol (0.3 mg kg1), or propranolol (1 mg kg−1) was injected intravenously 5 min before coronary ligation. After 3 or 30 min of coronary ligation, the ischaemic region of the myocardium was removed, and the endocardial portion used to determine the levels of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), creatine phosphate (CrP) and lactate. Ischaemia decreased the levels of ATP and CrP, and increased the levels of ADP, AMP and lactate. Immediately after the injection of nipradilol, rapid falls in blood pressure and heart rate were observed. Pretreatment with nipradilol lessened the decreases in the levels of ATP and CrP and the increases in the levels of AMP and lactate, caused by 3 min of ischaemia, to the same extent as propranolol. However, after 30 min of ishchaemia, nipradilol had no effect on myocardial metabolism unlike propranolol. These results indicate that nipradilol can reduce ischaemic influences on myocardial metabolism as well as propranolol, but only in the early stages of ischaemia.

Questionnaire on Hospital Pharmaceuticals Prepared (Proposed) Through Clinical Pharmacy Services.

Hospital pharmaceutical preparations (HPP) are used in patients whose complications are not well controlled by the commercially available drugs or injections. The use of HPP is effective when HPP are proposed through clinical pharmacy services. A questionnaire was developed to evaluate the use of HPP and then was sent to 49 hospital pharmacies who belong to the Hokkaido Association for Hospital Pharmaceuticals.As a result, 32 institutions replied to questionnaire, thus indicating a recovery rate of 65%. HPP, including mixtures of injectable drugs, were used at 30 out of 32 institutions. According to the questionnaires, 11 hospitals manufactured 24 HPP which were used during clinical pharmacy services. Half of these preparations were used to care for adverse symptoms, such as stomatitis, induced by the cancer chemotherapy.The use of HPP prepared by clinical pharmacy services is closely related to patients symptoms. The practical use of HPP is not only considered to improve drug compliance and the QOL of patients, but are also thought to enhance the general capabilities of pharmacists in clinical pharmaceutical practice.