Effect of cerebrocrast on body and organ weights, food and water intake, and urine output of normal rats.

Type 2 diabetes is associated with obesity, insulin resistance, hyperglycemia, hyperphagia, polyuria, body weight gain, excessive secretion of glucocorticoids (GCs), thymus involution, adrenal gland hypertrophy, diabetic nephropathy, etc. We examined the effect of cerebrocrast, a new antidiabetic agent (synthesized in the Latvian Institute of Organic Synthesis), on body weight, food and water intake, urine output, and on changes of organ weight: that is, kidney, thymus, adrenal gland of normal rats. Cerebrocrast was administered at doses of 0.05 and 0.5 mg kg(-1) per os (p.o.) once a day for three consecutive days, and its effects were observed from 3 to 27 days after the last administration. Cerebrocrast, during the experimental period, decreased body weight by an average of approximately 32.3%, food intake by about 10-15% at the beginning of the experiments and by 22.6% at the end of the experiments, especially at a dose of 0.5 mg kg(-1). Water intake and urine output in comparison with controls were decreased. The daily food intake decreased about 1.0 and 2.1 g by administering single cerebrocrast doses of 0.05 and 0.5 mg kg(-1) body weight (b.w.), respectively, but by administering for three consecutive days, food intake decreased by about 2.2 and 3.4 g, respectively. The weekly body weight gain decreased by administering a single dose of cerebrocrast by 2.61 and 2.51 g, respectively, and by triple administration it decreased by 4.36 and 3.07 g, respectively. Cerebrocrast has long-lasting effects on these parameters and on thymus and adrenal gland weight. As cerebrocrast decreased glucose levels in normal and streptozotocin (STZ)-induced diabetic rats, it also promoted glucose uptake by the brain, intensified insulin action and formation de novo of insulin receptors. We can conclude that cerebrocrast may regulate food intake and body weight through glucose sensing by proopiomelanocortin (POMC) neurons, that are involved in control of glucose homeostasis, stimulation of alpha-melanocyte-stimulating hormone (alpha-MSH) secretion, activation of MC4-Rs and inhibition of neuropeptide Y (NPY) in the ARC of the hypothalamus, affecting the kidney, and causing decreased urine output and water intake. Moreover, it could stimulate secretion of vasopressin. By administration of cerebrocrast thymus mass was increased, thereby preventing the action of GCs. As cerebrocrast inhibited L- and T-type calcium channels, it can prevent vasoconstriction of kidney arterioles and aldosterone secretion that have significant roles in the development of hypertension and diabetic nephropathy. These properties of cerebrocrast are important for treatment of Type 2 diabetes and its consequent development of hypertension and diabetic nephropathy.

Acute effect of antidiabetic 1,4-dihydropyridine compound cerebrocrast on cardiac function and glucose metabolism in the isolated, perfused normal rat heart.

Diabetes mellitus (DM) is an important cardiovascular risk factor and is associated with abnormalities in endothelial and vascular smooth muscle cell function, evoked by chronic hyperglycemia and hyperlipidemia. Chronic insulin deficiency or resistance is marked by decreases in the intensity of glucose transport, glucose phosphorylation, and glucose oxidation, plus decreases in ATP levels in cardiac myocytes. It is important to search for new agents that promote glucose consumption in the heart and partially inhibit extensive fatty acid beta-oxidation observed in diabetic, ischemia. When the oxygen supply for myocardium is decreased, the heart accumulates potentially toxic intermediates of fatty acid beta-oxidation, that is, long-chain acylcarnitine and long-chain acyl-CoA metabolites. Exogenous glucose and heart glycogen become an important compensatory source of energy. Therefore we studied the effect of the antidiabetic 1,4-dihydropyridine compound cerebrocrast at concentrations from 10(-10) M to 10(-7) M on isolated rat hearts using the method of Langendorff, on physiological parameters and energy metabolism. Cerebrocrast at concentrations from 10(-10) M to 10(-7) M has a negative inotropic effect on the rat heart. It inhibits L-type Ca(2+)channels thereby diminishing the cellular Ca(2+) supply, reducing contractile activity, and oxygen consumption, that normally favors enhanced glucose uptake, metabolism, and production of high-energy phosphates (ATP content) in myocardium. Cerebrocrast decreases heart rate and left ventricular (LV) systolic pressure; at concentrations of 10(-10) M and 10(-9) M it evokes short-term vasodilatation of coronary arteries. Increase of ATP content in the myocytes induced by cerebrocrast has a ubiquitous role. It can preserve the integrity of the cell plasma membranes, maintain normal cellular function, and inhibit release of lactate dehydrogenase (LDH) from cells that is associated with diabetes and heart ischemia. Administration of cerebrocrast together with insulin shows that both compounds only slightly enhance glucose uptake in myocardium, but significantly normalize the rate of contraction and relaxation ( +/- dp/dt). The effect of insulin on coronary flow is more pronounced by administration of insulin together with cerebrocrast at a concentration of 10(-7) M. Cerebrocrast may promote a shift of glucose consumption from aerobic to anerobic conditions (through the negative inotropic properties), and may be very significant in prevention of cardiac ischemic episodes.

Effect of new and known 1,4-dihydropyridine derivatives on blood glucose levels in normal and streptozotocin-induced diabetic rats.

Analysis of the effect of several 1,4-DHP Ca(2+) channel antagonists on experimental and clinical diabetes shows that structurally similar Ca(2+) channel antagonists can exert opposite effects on Ca(2+) influx, glucose homeostasis and insulin secretion. The influence of the Ca(2+) channel antagonists on pancreatic beta cell functions is dependent on lipophilicity, interactions with the cell membrane lipid bilayer, with SNAREs protein complexes in cell and vesicle membranes, with intracellular receptors, bioavailability and time of elimination from several organs and the bloodstream. In the present work we studied the effect at several doses of new compounds synthesized in the Latvian Institute of Organic Synthesis on blood glucose levels in normal and STZ-induced diabetic rats. The compounds tested were: 1,4-DHP derivatives cerebrocrast (1), etaftoron (2), OSI-1190 (3), OSI-3802 (4), OSI-2954 (5) and known 1,4-DHP derivatives: niludipine (6), nimodipine (7) and nicardipine (8) which possess different lipophilicities. Analysis of the structure-function relationships of the effect of 1,4-DHP derivatives on glucose metabolism showed that cerebrocrast could evoke qualitative differences in activity. Insertion of an OCHF(2) group in position 2 of the 4-phenylsubstituent and propoxyethylgroup R in ester moieties in positions 3 and 5 of the DHP structure, as well as an increase in the number of carbon atoms in the ester moiety, significantly modified the properties of the compound. Thereby cerebrocrast acquired high lipophilicity and membranotropic properties. Cerebrocrast, in a single administration at low doses (0.05 and 0.5 mg x kg(-1), p.o.), significantly decreased the plasma level of glucose in normal rats and in STZ-induced diabetic rats returned plasma glucose to basal levels. This effect was characterized by a slow onset and a powerful long-lasting influence on glucose metabolism, especially in STZ-induced diabetic rats.