Effects of chlorpromazine and some of its metabolites on the EEG and on dopamine metabolism of the isolated perfused rat brain.

Abstract The study concerned the effects of chlorpromazine (CPZ), monodesmethyl-chlorpromazine (NOR1-CPZ), didesmethyl-chlorpromazine (NOR2-CPZ), and chlorpromazine-N-oxide (CPZ-NO) on the EGG and on dopamine metabolism of the isolated perfused rat brain. Isolated brains were perfused with 100 ml of a perfusion medium containing 30% bovine red cells (v/v), 2 g bovine serum albumin, 14 mM glucose as well as one of the agents in a concentration of 10 μM. The main dopamine metabolite homovanillic acid (HVA) was measured fluorimetrically in the striatum of the isolated brain. The EGG was recorded by two symmetrical bipolar leads from the parietal regions at various times during the 30 min perfu…

Die Bindung einiger Phenothiazinderivate an Rinderserumalbumin

Cerebral toxicity of penicillins in relation to their hydrophobic character

The neurotoxic effects of ticarcillin, methicillin, phenthicillin, oxacillin, cloxacillin and dicloxacillin were studied in the conscious rabbit. During and after intravenous administration of 1.2 and 2.4 g/kg, resp., over 50 min the blood concentrations of the drugs were determined and the neurotoxicity assessed by continuous recording of the electroencephalogram. The hydrophobia of the penicillins was characterized by determination of their partition coefficients between isobutanol and buffer solution pH 7.4. The penicillins showed quite different neurotoxic properties. A close correlation (r = 0.928) was found between the neurotoxic potency of the penicillins and their partition coeffici…

Influence of therapeutic and toxic doses of neuroleptics and antidepressants on energy metabolism of the isolated perfused rat brain.

The isolated perfused rat brain was used for a comparative study of the effects of promazine, imipramine, monodesmethyl promazine and desipramine on cerebral energy metabolism. After perfusion for 30 min or 1 h the brain levels of the following substrates and metabolites were estimated: P-creatine, creatine, ATP, ADP, AMP, glycogen, glucose, glucose-6-P, fructose diphosphate, dihydroxyacetone-P, pyruvate, lactate, α-ketoglutarate, and ammonia. Drug concentrations of 5·10−6 M and 10−5 M in the perfusion medium caused a significant decrease of glucose-6-P alone. When the drug concentration was raised to a toxic range (10−4 M), reflected in the EEG by the pattern of secondary discharges, an ac…

Applicability of the isolated perfused rat brain for studying central cholinergic mechanisms.

The ACh content of the isolated perfused rat brain as well as that of the rat brain in vivo was determined by gas chromatography. After a perfusion period of 30 min the endogenous ACh content of the isolated brain was significantly higher than that of the brain in vivo. Physostigmine caused a rise in the ACh concentration of both the isolated brain and the brain in vivo. Oxotremorine produced an increase in the ACh content in the brain in vivo, but not in the isolated brain after appropriate dosage. The concentration of the drugs in the perfusion medium of the isolated brain was so that distinct EEG changes could be observed but spontaneous electrical activity could be maintained during the…

Long survival time of an isolated perfused rat brain

A two-circuit apparatus for the perfusion of the isolated rat brain.

A perfusion apparatus for the isolated rat brain is described which has two recirculating systems running synchronously. Instantaneous transfer from one circulating system to the other is possible by use of a 2-way stopcock, enabling different media to be perfused through the brain without interrupting the perfusion. The feasibility of the system is demonstrated experimentally.

Distribution of chlorpromazine in a simplified blood influenced by various drugs

The binding of chlorpromazine to erythrocytes and to albumin as influenced by other drugs was studied in a simplified blood (31.5±0.3% bovine erythrocytes, 4 g-% bovine serum albumin in 0.02 M phosphate buffer solution containing 0.15 M NaCl). the total concentration of chlorpromazine in the simplified blood was 10−4 M, the concentration of the displacing drugs was 10−3 M. After an incubation period of 3 h at 22° C the chlorpromazine concentration was determined in the albumin solution after centrifugation of the blood at 3000×g and in the aqueous phase after ultracentrifugation at 150000×g. Under control conditions 68.1±0.9% of chlorpromazine was bound to the erythrocytes, 28.5±0.9% was bo…

�ber die Neurotoxizit�t von Carbenicillin

Die neurotoxische Wirkung von Carbenicillin wurde am wachen Kaninchen untersucht. Die Neurotoxizitat wurde bestimmt anhand von EEG-Veranderungen wie Spikes, Polyspikes and Spike-wave-Paroxysmen. Den Tieren wurden 2,4 g/kg Carbenicillin uber 50 min intravenos infundiert. Bis 2 Std nach Infusionsbeginn wurden zu bestimmten Zeitpunkten die Carbenicillinblutspiegel gemessen. Spikes als erstes neurotoxisches Symptom waren regelmasig bei Blutspiegeln von 3252±186 µg/ml zu beobachten. Nach Carbenicillin waren die toxischen Veranderungen wesentlich ausgepragter als nach Ampicillin, jedoch deutlich geringer als nach Penicillin G. Diese Ergebnisse stehen im Einklang mit den in klinischen Fallberichte…

Suitability of the isolated perfused rat brain for studying effects on cerebral metabolism

The concentrations of P-creatine, creatine, ATP, ADP, AMP, glycogen, glucose, glucose-6-P, fructose diphosphate, dihydroxyacetone-P, α-glycero-P, lactate and pyruvate were measured in the isolated perfused rat brain as well as in rat brain in vivo. Similar levels were observed in the isolated brain and in intact animals, and the values measured were in good accordance with those described in the literature. Only the pyruvate and lactate content were significantly higher in the isolated brain but the lactate/pyruvate ratio remained unchanged. An anesthetic or ischemia caused just the same effects on energy metabolism of the isolated rat brain as described for intact animals. Thus, 1.5 mM phe…

Comparative study on the inhibition of Na+, K+-activated ATPase activity by chlorpromazine, promazine, imipramine, and their monodesmethyl metabolites

The inhibition of the sodium- and potassium-activated adenosine triphosphatase (Na-K-ATPase, EC 3.6.1.3) activity by chlorpromazine, promazine and imipramine was compared with that by the monodesmethyl metabolites of these drugs. The experiments were performed with a deoxycholate- and sodium iodide-treated microsomal enzyme preparation from rat brain. It was shown in dose-response curves as well as in double-reciprocal Lineweaver-Burk plots of Na-K-ATPase activity against KCl concentration that the monodesmethyl metabolites were stronger inhibitors than their parent compounds. The results obtained with the desmethyl metabolites and imipramine as inhibitors indicate competitive inhibition wh…

Comparative study of the effects of chloral hydrate and trichloroethanol on cerebral metabolism

The isolated perfused rat brain was used for a comparative study of the effects of chloral hydrate and trichloroethanol on cerebral energy metabolism. After a perfusion period of 30 min the brain levels of the following substrates and metabolites were measured spectrophotometrically: P-creatine, creatine, ATP, ADP, AMP, glycogen, glucose, glucose-6-P, fructose diphosphate, α-glycero-P, dihydroxyacetone-P, pyruvate, lactate, glutamate, α-ketoglutarate and ammonia. Furthermore, the concentration of chloral hydrate and trichloroethanol in the isolated brain and in the perfusion medium was measured colorimetrically. Little more than 10% of chloral hydrate in the isolated brain and in the perfus…

Dephosphorylation of Centrins by Protein Phosphatase 2C α and β.

In the present study, we identified protein phosphatases dephosphorylating centrins previously phosphorylated by protein kinase CK2. The following phosphatases known to be present in the retina were tested: PP1, PP2A, PP2B, PP2C, PP5, and alkaline phosphatase. PP2C 𝛼 and 𝛽 were capable of dephosphorylating P-Thr138-centrin1 most efficiently. PP2C𝛿 was inactive and the other retinal phosphatases also had much less or no effect. Similar results were observed for centrins 2 and 4. Centrin3 was not a substrate for CK2. The results suggest PP2C 𝛼 and 𝛽 to play a significant role in regulating the phosphorylation status of centrins in vivo.

�ber die Bedeutung der Eiwei�bindung f�r die Aufnahme von Promazin in die Leber

Comparison of the effects of chloral hydrate and trichlorethanol on the EEG of the isolated perfused rat brain.

An isolated perfused rat brain preparation was used to compare the effects of chloral hydrate and its metabolite trichloroethanol on the EEG. The concentrations of chloral hydrate and trichloroethanol in the perfusion medium ranged from 1.5 to 5.5 mM. 5, 10, 15, and 30 min after the beginning of the perfusions EEG-recordings were taken. The recordings were evaluated both by a descriptive method and by a simple quantitative appraoch, counting the waves with an amplitude greater than 50 microvolts and averaging this value for a period of 1 sec. The following results were obtained: Both drugs exhibited CNS depressant activity. Between 5 and 10 min of perfusion the effect of trichloroethanol wa…