MONOCYTIC CELL LINE

The Regulation of C2 Expression Examined In Human Monocytic Cell Line Thp-1

ABSTRACT

Histamine affects homeostatic mechanisms, including food and water consumption, by acting on central nervous system (CNS) receptors. Presynaptic histamine H3 receptors regulate release of histamine and other neurotransmitters, and histamine H3 receptor antagonists enhance neurotransmitter release. A-331440 {4'-[3-(3(R)-(dimethylamino)-pyrrolidin-1-yl)-propoxy]-biphenyl-4-carbonitrile} is a histamine H3 receptor antagonist which binds potently and selectively to both human and rat histamine H3 receptors (Ki=25 nM). Mice were stabilized on a high-fat diet (45 kcal % lard) prior to 28-day oral b.i.d. dosing for measurement of obesity-related parameters. A-331440 administered at 0.5 mg/kg had no significant effect on weight, whereas 5 mg/kg decreased weight comparably to dexfenfluramine (10 mg/kg). A-331440 administered at 15 mg/kg reduced weight to a level comparable to mice on the low-fat diet. The two higher doses reduced body fat and the highest dose also normalized an insulin tolerance test. These data show that the histamine H3 receptor antagonist, A-331440, has potential as an antiobesity agent.

The Regulation of C2 Expression Examined In Human Monocytic Cell Line Thp-1

Introduction

A large percentage of people worldwide (in excess of 50% in the US and Russia, for example) are overweight, with a body mass index (BMI) between 25 and 29.9 kg m-2. Excess body weight has been linked to adverse cardiovascular events, diabetes and premature mortality. Of greater concern are more severe cases of excess weight, manifested as frank obesity (BMI>30 kg m-2), which is especially prevalent in the United States (over 90% of type 2 diabetics. Estimates suggest that one quarter to one-third of the population is obese. Moreover, the disease incidence is increasing throughout the world.

Historically, antiobesity treatments have included aminergic stimulant drugs, like amphetamine, although efficacy may diminish over time and abuse liabilities have been recognized. More recently, drugs acting through the serotonin system have been employed. The combination of dexfenfluramine and phentermine was highly efficacious in reducing body weight when part of a diet and weight control regimen, but the combination was linked to adverse cardiovascular effects resulting in clinical abandonment of the fen-phen combination. Currently available therapeutic modalities include the lipase inhibitor, orlistat and the centrally acting inhibitor of serotonin and norepinephrine uptake, sibutramine. However, the increasing prevalence of obesity has been predicted to lead to increasing drug therapy based on greater understanding of novel pharmacological principles. As a result, there is a medical need for more efficacious treatment modalities for obesity.

Several recent animal studies have indicated potential for a novel molecular approach via modulation of activity of histaminergic systems in the central nervous system (CNS). For example, it is known that blockade of postsynaptic histamine H1 receptors induces weight gain . Similarly, knockout mice lacking the histamine H1 receptor tend to exhibit a phenotype of inadequate modulation by the leptin system of appetite and of increased food consumption. Blockade of histamine synthesis has also been shown to cause increased weight gain, and obese Zucker rats have been shown to have low concentrations of hypothalamic ...