F.S. Messiha

Angiogenesis : modulation with opioids

1. The effect of beta-endorphin (beta-EP) and morphine sulfate (MS), in presence and absence of naloxone (NX), on chicken chorioallantoic membrane was studied as a function of blood vessel proliferation. 2. A 50% reduction in blood vessel proliferation occurred by 10 micrograms of beta-EP or by 5 micrograms of MS per egg compared to controls. 3. An individual dose, i.e. 5 micrograms of beta-EP, did not significantly inhibit blood vessel counts after initial 24 hr period of the drug application when given alone compared to inhibition occurring with combined use of NX. 4. NX (1 microgram) did not significantly reverse the angiostatic effects of MS (10 micrograms) or of beta-EP (5 micrograms). 5. The observed modulation of angiogenesis by opioids suggests involvement of beta-EP and MS in the proliferation of vascular endothelial cells. 6. This may be due to an effect of beta-EP and MS on cell-mediated immunity factors such as interferons, interleukins and prostaglandin E2.

Voluntary drinking of ethanol by the rat: Biogenic amines and possible underlying mechanism

The present study evaluates the possible relationship between certain biogenic amine metabolites-produced changes in voluntary drinking of ethyl alcohol (ET) solution by the rat and their in vivo effects on the enzymes primarily involved in the hepatic metabolism of ET, i.e., liver alcohol-(L-ADH) and aldehyde dehydrogenase (L-ALDH). In experiments on voluntary intake of ET solution by the rat, compounds selected were injected, 0.5 mM/kg, IP. Administration of vanillylmandelic acid (VMA) and 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) markedly reduced ET drinking. Similar significant effects were seen after administration of the neutral metabolites of the biogenic amines tested, after injection of metanephrine or 3-methoxy-4-hydroxyphenylpyruvic acid. Threodihydroxyphenylserine but not L-dopa reduced ET intake by the rat. Treatment with peripheral decarboxylase inhibitors, i.e., carbidopa, 50 mg/kg, IP, significantly reduced ET drinking as contrasted with nonsignificant decline in ET consumption following benserazide, 500 mg/kg, IP. In the biochemical study, short-term administration of the compounds selected produced varied effects on L-ADH and L-ADH. It is suggested that alteration of hepatic ADH by the compounds tested might account for the observation reduced ET drinking thereby, indicating the contribution of peripheral sources rather than central factors in mediating the behavioral effects studied.

Blockade of 5-HTP reduction of ethanol drinking with the decarboxylase inhibitor, Ro 4-4602

5-Hydroxytryptophan (5-HTP) reduced ethanol intake in laboratory rats. The reduction of ethanol intake was blocked when Ro 4-4602, the decarboxylase inhibitor, was given in combination with the 5-hydroxytryptophan. These observations provide further support for the involvement of brain serotonin in voluntary ethanol drinking by the rat.

Antagonism of ethanol-evoked responses by amantadine: A possible clinical application

The behavioral and biochemical effects of amantadine hydrochloride (ATD) on some ethanol (ETOH) mediated responses in rats and mice were studied. Administration of ATD, 0.5 mM/kg IP, prior to a narcotic dose of ETOH significantly decreased the central depressant action of ETOH, as measured by the duration of ETOH-produced narcosis in mice. The time required for the onset of ETOH-narcosis was significantly delayed in ATD-treated mice compared to controls. Analyses of whole blood and brain ETOH concentrations showed that ATD-treatment prior to ETOH significantly reduced brain content of ETOH from saline-pretreated mice at the time of onset of ETOH narcosis as well as 30 min after ETOH injection without concomitant change in blood ETOH concentrations at the respective time intervals. Administration of ATD 0.5mM/kg IP, reduced voluntary intake of ETOH by rats voluntarily selecting 5% ETOH solution over water as the drinking fluid. There were no changes in cytoplasmic rat liver alcohol dehydrogenase (L-ADH) and mitochondrial aldehyde dehydrogenase (L-ALDH) activities in rats maintained on water or 5% ETOH as the drinking fluid and administered ATD, 0.5 mM/kg IP, once or identical dose once daily for six consecutive days. However, ATD produced in vitro non-competitive inhibiton of both L-ADH and L-ALDH at a concentration range between 10(-3) M and 3 x 10(-3) M assay mixture. The results indicate the potency of ATD in negating ETOH-mediated responses measured and suggest for a possible clinical trial for ATD in the management of alcoholic patients provided it is devoid of disulfiram-like reaction in man.

Lithium, rubidium and cesium: cerebral pharmacokinetics and alcohol interactions.

The distribution of exogenously administered Li+, Rb+ and Cs+ in distinct mouse brain regions was studied as a function of time subsequent termination of a short-term daily treatment with these alkali metal salts. The resulting distribution profiles were compared with that obtained from the corresponding endogenous alkali metals. Endogenous Rb+ and Cs+ were readily measurable in all 6 brain regions studied compared to traces of measurable Li+. The Rb+ concentration was greater than that of Cs+. Short-term treatment with equal doses of the alkali metals studied showed greater brain accumulation of Rb+ and Cs+ than Li+ with a prolonged brain regions preference for Cs+ storages as a function of time. Duration of ethanol-mediated narcosis was reduced from saline controls by pretreatment with RbCl or CsCl as contrasted with prolongation by LiCl. The narcotic dosage of ethanol used reduced endogeneous Li+ and increased Cs+ levels in the cerebellum. This massive ethanol dosage exerted little effect on the distribution of exogenously administered Cs+ with exception of the striatum which continued to show a high content of Cs+. This may have contributed to partial antagonism of ethanol-depressant action and to restoring of motor function, i.e., rapid regaining of righting reflex. The results showed that Cs+ possessed longer biological life time in the brain than Rb+ or Li+ which may be of therapeutic value, i.e., in the use of Cs salts in treatment of brain tumors and in conjunction with psychoactive agents provided the respective chemotherapeutic and antidepressant properties of CsCl have been established.

Leu-enkephalin, tamoxifen and ethanol interactions: Effects on motility and hepatic ethanol metabolizing enzymes

1. Short-term treatment with tamoxifen (a nonsteroidal antiestrogen) decreased mouse spontaneous locomotor activity compared to controls. 2. Short-term pretreatment with tamoxifen prior to an acute sedative dose of ethanol potentiated ethanol-medicated behavioral depression in the mouse. 3. Injection of a small dose of Leu-enkephalin, which is devoid of effect on mouse motility, prior to an acute sedative dose of ethanol to tamoxifen pretreated female mice counteracted ethanol-produced suppression of motor activity. 4. Mouse liver aldehyde dehydrogenase was inhibited by the short-term administration of tamoxifen when given alone or preceding acute dosages of Leu-enkephalin. Concomitantly, there was an increase in blood plasma ethanol concentration from corresponding control. 5. The results of the behavioral performance test used suggest that tamoxifen possesses depressant property and exerts synergestic effect with Leu-enkephalin in antagonizing ethanol-produced behavioral depression in the mouse. 6. The enzymatic part of the study indicates an adverse metabolic influence by tamoxifen on hepatic metabolism of ethanol-derived acetaldehyde which could contribute to the potentiation of the sedative effect of ethanol.

Cesium and rubidium salts: Effects on voluntary intake of ethanol by the rat

The effects of RbCl and CsCl on voluntary intake of ethanol solution by rats preferring ethanol solution 5% (w/w) over water as the drinking fluid was studied as a function of the dose given and the vehicle injected. Administration of RbCl or CsCl, 0.5 mEq/kg/day or 1.5 mEq/kg/day for three consecutive days, did not alter amounts of ethanol consumed. Repeated administration of RbCl or CsCl, 3.0 mEq/kg/day for three days, produced some moderate reduction in ethanol consumption. Simultaneous injection of RbCl (1.5 mEq/kg) and CsCl (1.5 mEq/kg) resulted in greater and profound lasting decrease in ethanol drinking. The later treatment did not alter specific activities of rat liver alcohol- and aldehyde dehydrogenase from saline treated controls. In general, dissolving the chloride salt of the alkali metals in saline resulted in greater effects on ethanol drinking than that determined after identical dose injected with water as the vehicle. The possible mechanism(s) underlying the effects of alkali metal salts used are suggested.

EFFECT OF GOSSYPOL ON KINETICS OF MOUSE LIVER ALCOHOL AND ALDEHYDE DEHYDROGENASE

1. Gossypol, an antifertility ingredient of the cotton plant, altered specific activity of mouse liver alcohol dehydrogenase (L-ADH) and subcellular aldehyde dehydrogenase (L-ALDH) in mice of both sexes. 2. Intraperitoneal injection of a single gossypol dose, 50 mg/kg, inhibited both male and female L-ADH and cytoplasmic L-ALDH from saline controls 21 hr after drug treatment. 3. Gossypol inhibited female but not male mouse mitochondrial L-ALDH isoenzymes. 4. Gossypol-produced enzyme inhibition was determined as noncompetitive. 5. The results suggest gender-dependent sensitivity of mitochondrial L-ALDH to the gossypol inhibition. A toxic metabolic interaction between ethanol and gossypol has been indicated which suggests the contraindication of alcoholic beverages during gossypol use.

Cyclobenzaprine and ethanol interaction

The effects of cyclobenzaprine, a tricyclic compound, on the central depressant action of ethanol and on hepatic ethanol metabolizing enzymes were studied in rodents. Administration of cyclobenzaprine, 5 mg/kg, IP, 30 min prior to a narcotic dose of ethanol solution, 5 g/kg, IP, enhanced ethanol-produced narcosis in mice. This effect was greater in male than in female mice. Cyclobenzaprine inhibited endogenous rat liver alcohol dehydrogenase in vitro in the concentration range between 10(-5) M and 10(-6)M. Cyclobenzaprine exerted little effect on hepatic aldehyde dehydrogenase in vitro. The results suggest that cyclobenzaprine possesses depressant properties and inhibition of liver alcohol dehydrogenase may underlie the observed behavioral response studied. It is concluded that alteration of endogenous liver alcohol dehydrogenase by certain tricyclic antidepressant drugs may be involved in the mechanism(s) of their toxic interaction with ethanol.

Effect of cesium and ethanol on tumor bearing rats

The effect of separate and combined administration of 15% ethanol and 0.2% CsCl solution on life span of rats with Novikoff hepatoma implants was studied as a function of time of initiation of treatment. Pretreatment with CsCl alone or combined with ethanol resulted in earlier onset on morbidity compared to the ethanol-treatment or to controls. As high as 87.5% of Cs-treated animals died 16 days post tumor implantation compared to 33% of rats receiving CsCl and ethanol combined. This protective action of ethanol against Cs-evoked toxicity in tumor-bearing rats persisted through the experiment. Animals subjected to drug treatment immediately after tumor transplantation displayed delayed onset of morbidity compared to drug pretreated rats. In both cases the Cs-treatment enhanced morbidity by approximately 2 folds from corresponding controls. Animals sacrificed 18 days post tumor inoculation showed an induction of hepatic alcohol dehydrogenase and an increase in Vmax without changes in the apparent Km by the Cs-treatment. There was an increase in liver mitochondrial aldehyde dehydrogenase of hepatoma-bearing rats from tumor-free controls which was associated with an increase in the apparent Km value. The results indicate potentiation of the hepatoma toxicity by CsCl which may be minimized by ethanol. A role for hepatic enzymes determined in the pathogenesis of tumor line studied and/or their use as a biochemical correlate is suggested.