Gingerols and related analogues inhibit arachidonic acid-induced human platelet serotonin release and aggregation.

Gingerols, the active components of ginger (the rhizome of Zingiber officinale, Roscoe), represent a potential new class of platelet activation inhibitors. In this study, we examined the ability of a series of synthetic gingerols and related phenylalkanol analogues (G1-G7) to inhibit human platelet activation, compared to aspirin, by measuring their effects on arachidonic acid (AA)-induced platelet serotonin release and aggregation in vitro. The IC(50) for inhibition of AA-induced (at EC(50)=0.75 mM) serotonin release by aspirin was 23.4+/-3.6 microM. Gingerols and related analogues (G1-G7) inhibited the AA-induced platelet release reaction in a similar dose range as aspirin, with IC(50) values between 45.3 and 82.6 microM. G1-G7 were also effective inhibitors of AA-induced human platelet aggregation. Maximum inhibitory (IC(max)) values of 10.5+/-3.9 and 10.4+/-3.2 microM for G3 and G4, respectively, were approximately 2-fold greater than aspirin (IC(max)=6.0+/-1.0 microM). The remaining gingerols and related analogues maximally inhibited AA-induced platelet aggregation at approximately 20-25 microM. The mechanism underlying inhibition of the AA-induced platelet release reaction and aggregation by G1-G7 may be via an effect on cyclooxygenase (COX) activity in platelets because representative gingerols and related analogues (G3-G6) potently inhibited COX activity in rat basophilic leukemia (RBL-2H3) cells. These results provide a basis for the design of more potent synthetic gingerol analogues, with similar potencies to aspirin, as platelet activation inhibitors with potential value in cardiovascular disease.

Relative efficacy of the opioid antagonist, naltrexone, on the initiation and promotion phases of rat mammary carcinogenesis.

We have shown earlier that naltrexone, a long acting opioid antagonist, inhibits the development and growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumors. We extended these studies to determine the independent effects of naltrexone when fed at 75 mg/kg diet during the initiation (I), promotion (P), or initiation plus promotion (I+P) phases of DMBA-induced rat mammary carcinogenesis. The percentage of rats with palpable tumors as well as the number of tumors per rat were determined during the 130 day experiment. When fed during the 1, P, or I+P phases, mammary tumor incidence was significantly inhibited by 27%, 60% and 45% respectively, as compared to the control group. Similarly, tumor multiplicity was significantly reduced by naltrexone treatment. Tumor multiplicity was reduced by 40%, 73%, and 70% when fed naltrexone during I, P, and I+P respectively, as compared to the controls. These results indicate that naltrexone acts on the I and P phases, with the effects being maximal when fed during the P and I+P phases.

Methionine-enkephalin concentrations in discrete brain regions, spinal cord, pituitary gland and peripheral tissues of U-50,488H-tolerant and abstinent rats.

Effects were determined of chronic administration and withdrawal of a highly selective kappa-opioid receptor agonist, U-50,488H, on methionine-enkephalin levels in central and peripheral tissues of male Sprague-Dawley rats. Rats were rendered tolerant to and physically dependent on U-50,488H by twice daily injections of 25 mg/kg of this compound for 5 days. Rats deemed abstinent were injected with this drug for 4 days and sacrificed on 5th day. Methionine-enkephalin concentration increased in the hippocampus of U-50,488H-tolerant-dependent rats, whereas in abstinent rats, its level was elevated only in the hypothalamus. Levels of methionine-enkephalin in the pituitary gland of U-50,488H-tolerant-dependent or abstinent rats were unchanged. Among peripheral tissues, methionine-enkephalin concentration decreased in the adrenal gland of U-50,488H-tolerant-dependent rats. In the U-50,488H-abstinent rats, methionine-enkephalin concentration was elevated in the heart. In tissues of morphine- and U-50,488H-tolerant-dependent and abstinent rats methionine-enkephalin concentrations were affected differentially, suggesting inherent differences in mu- and kappa-opiate-mediated tolerance-dependence and abstinence processes.

beta-Endorphin-like immunoreactivity in discrete brain regions, spinal cord, pituitary gland and peripheral tissues of U-50,488H-tolerant and -abstinent rats.

The effect was determined of trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzene- acetamide methane sulfonate (U-50,488H), a kappa opioid agonist, -induced tolerance dependence and abstinence on the levels of beta-endorphin in discrete brain regions, spinal cord, pituitary gland, plasma and peripheral tissues of male Sprague-Dawley rats. The brain regions examined were hypothalamus, hippocampus, amygdala, midbrain, corpus striatum, pons-medulla and cortex. The peripheral tissues included kidneys, spleen, adrenals and heart. Rats were made tolerant dependent on U-50,488H by intraperitoneal injections of the drug (25 mg/kg) twice a day for 4 days. Vehicle-injected rats served as controls. Rats that were labeled as tolerant dependent were injected with U-50,488H (25 mg/kg) on day 5 and killed 1 hr later, whereas those labeled as abstinent were killed without injection of the drug. Rats serving as controls were injected with the vehicle. Tolerance to the analgesic and hypothermic effects of U-50,488H developed, as evidenced by a decrease in the intensity of responses in chronic U-50,488H-treated compared with chronic vehicle-treated rats. In U-50,488H-tolerant rats, the concentration of beta-endorphin was increased in hippocampus, corpus striatum, pituitary gland, plasma, kidneys and adrenals compared with vehicle-injected controls. In U-50,488H-abstinent rats, the concentration of beta-endorphin was increased in pons-medulla and amygdala, whereas the concentration of beta-endorphin did not change in the pituitary gland, plasma and peripheral tissues. In general, chronic treatment with a kappa opioid agonist results in increases in the concentration of beta-endorphin in specific tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of U-50,488H tolerance-dependence and abstinence on the levels of dynorphin (1-13) in brain regions, spinal cord, pituitary gland and peripheral tissues of the rat.

Male Sprague-Dawley rats were rendered tolerant to and physically dependent on U-50,488H, a kappa-opiate agonist, by injecting 25 mg/kg of the drug intraperitoneally twice a day for 4 days. Two sets of rats were used. Rats labeled as tolerant-dependent were injected with U-50,488H (25 mg/kg) 1 h before sacrificing on day 5, whereas the abstinent rats were sacrificed on day 5 without the injection of U-50,488H. Of all the tissues on day 5 without the injection of U-50,488H. Of all the tissues examined, the pituitary gland had the highest level of dynorphin (1-13), whereas the heart had the lowest level. The levels of dynorphin (1-13) increased in the hypothalamus, hippocampus and pons/medulla of U-50,488H tolerant-dependent rats, whereas in abstinent rats the levels of dynorphin (1-13) were elevated only in the midbrain. The levels of dynorphin (1-13) in the pituitary gland of U-50,488H tolerant-dependent or abstinent rats were unchanged. In peripheral tissues, the levels of dynorphin (1-13) in the heart of U-50,488H tolerant-dependent rats were increased. In the abstinent rats they were elevated in the adrenals, spleen, and the heart but were decreased in the kidneys. Compared to morphine tolerant-dependent and abstinent rats, significant differences in the levels of dynorphin (1-13) in tissues of 50,488H tolerant-dependent and abstinent rats were observed and may explain many pharmacological differences in the mu- and kappa-opiate induced tolerance-dependence and abstinence processes.

The effect of morphine tolerance dependence and abstinence on immunoreactive dynorphin (1-13) levels in discrete brain regions, spinal cord, pituitary gland and peripheral tissues of the rat.

The effect of morphine tolerance dependence and protracted abstinence on the levels of dynorphin (1-13) in discrete brain regions, spinal cord, pituitary gland and peripheral tissues was determined in male Sprague-Dawley rats. Of all the tissues examined, the highest level of dynorphin (1-13) was found to be in the pituitary gland. Among the brain regions and spinal cord examined, the levels of dynorphin (1-13) in descending order were: hypothalamus, spinal cord, midbrain, pons and medulla, hippocampus, cortex, amygdala and striatum. The descending order for the levels of dynorphin (1-13) in peripheral tissues was: adrenals, heart and kidneys. In morphine tolerant rats, the levels of dynorphin (1-13) increased in amygdala but were decreased in pons and medulla. In morphine abstinent rats, the levels of dynorphin (1-13) were increased in amygdala, hypothalamus and hippocampus. The levels of dynorphin (1-13) were increased in pituitary but decreased in spinal cord and remained so even during protracted abstinence. The levels of dynorphin (1-13) in the peripheral tissues of morphine tolerant rats were unaffected. However, in the heart and kidneys of morphine abstinent rats, the levels of dynorphin (1-13) were increased significantly. It is concluded that both morphine tolerance and abstinence modify the levels of dynorphin (1-13) in pituitary, central and peripheral tissues. Morphine abstinence differed from non-abstinence process in that there were additional changes (increases) in the levels of dynorphin (1-13) in brain regions (hypothalamus and hippocampus) and peripheral tissues (heart and kidneys) and may contribute to the symptoms of the morphine abstinence syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of an automated human sperm quality system.

A computer-automated system, including hardware and software components, is developed for objective assessment of human sperm density and other characteristics, including morphological abnormalities and motility. The hardware component essentially consists of an IBM AT, a relatively low-cost image processing board and other inexpensive commercially available instruments. On the other hand, the software component is developed through the incorporation of image analysis, pattern recognition and modelling techniques with the knowledge of human reproduction from the available literature. The whole system is expected to produce a practical and cost-effective means for the routine assessment of human semen quality.