{Beta}2-adrenergic receptor agonists inhibit the proliferation of 1321N1 astrocytoma cells.

Astrocytomas and glioblastomas have been particularly difficult to treat and refractory to chemotherapy. However, significant evidence has been presented that demonstrates a decrease in astrocytoma cell proliferation subsequent to an increase in cAMP levels. The 1321N1 astrocytoma cell line, as well as other astrocytomas and glioblastomas, expresses ß(2)-adrenergic receptors (ß(2)-ARs) that are coupled to G(s) activation and consequent cAMP production. Experiments were conducted to determine whether the ß(2)-AR agonist (R,R')-fenoterol and other ß(2)-AR agonists could attenuate mitogenesis and, if so, by what mechanism. Receptor binding studies were conducted to characterize ß(2)-AR found in 1321N1 and U118 cell membranes. In addition, cells were incubated with (R,R')-fenoterol and analogs to determine their ability to stimulate intracellular cAMP accumulation and inhibit [(3)H]thymidine incorporation into the cells. 1321N1 cells contain significant levels of ß(2)-AR as determined by receptor binding. (R,R')-fenoterol and other ß(2)-AR agonists, as well as forskolin, stimulated cAMP accumulation in a dose-dependent manner. Accumulation of cAMP induced a decrease in [(3)H]thymidine incorporation. There was a correlation between concentration required to stimulate cAMP accumulation and inhibit [(3)H]thymidine incorporation. U118 cells have a reduced number of ß(2)-ARs and a concomitant reduction in the ability of ß(2)-AR agonists to inhibit cell proliferation. These studies demonstrate the efficacy of ß(2)-AR agonists for inhibition of growth of the astrocytoma cell lines. Because a significant portion of brain tumors contain ß(2)-ARs to a greater extent than whole brain, (R,R')-fenoterol, or some analog, may be useful in the treatment of brain tumors after biopsy to determine ß(2)-AR expression.

Inotropic and chronotropic actions of Ilex latifolia inhibition of adenosine-5 '-triphosphatases as a possible mechanism.

Ilex latifolia is widely used as an ingredient to prepare traditional beverage drinks in southern China. In fact, various Ilex species have been used in Chinese folk medicine to treat coronary heart diseases. The mode of action is believed to be mediated by their coronary vasodilative effects. In this study, the water extract of the leaves of Ilex latifolia (IK-TP) was shown to increase the contractility and decrease the frequency of contraction in an isolated rat heart perfusion system. IK-TP was found to inhibit Na+/K+-ATPase activities in rat heart sarcolemma, rat brain microsomes and a purified enzyme from porcine cerebral cortex. IK-TP also inhibited Ca2+-dependent ATPase at a similar dose. Following exposure of the isolated rat heart to IK-TP at a dose that produces pronounced cardiac effects, inhibition of Na+/K+-ATPase activity can be readily detected in the heart. This study suggests the presence of ATPase inhibitory compounds in Ilex latifolia with specificities different from that of ouabain.

Inhibition of rat brain monoamine oxidase activities by psoralen and isopsoralen: implications for the treatment of affective disorders.

Psoralen and isopsoralen, furocoumarins isolated from the plant Psoralea corylifolia L., were demonstrated to exhibit in vitro inhibitory actions on monoamine oxidase (MAO) activities in rat brain mitochondria, preferentially inhibiting MAO-A activity over MAO-B activity. This inhibition of enzyme activities was found to be dose-dependent and reversible. For MAO-A, the IC50 values are 15.2 +/- 1.3 microM psoralen and 9.0 +/- 0.6 microM isopsoralen. For MAO-B, the IC50 values are 61.8 +/- 4.3 microM psoralen and 12.8 +/- 0.5 microM isopsoralen. Lineweaver-Burk transformation of the inhibition data indicates that inhibition by both psoralen and isopsoralen is non-competitive for MAO-A. The Ki values were calculated to be 14.0 microM for psoralen and 6.5 microM for isopsoralen. On the other hand, inhibition by both psoralen and isopsoralen is competitive for MAO-B. The Ki values were calculated to be 58.1 microM for psoralen and 10.8 microM for isopsoralen. These inhibitory actions of psoralen and isopsoralen on rat brain mitochondrial MAO activities are discussed in relation to their toxicities and their potential applications to treat affective disorders.