Learning behaviour and cerebral protein kinase C, antioxidant status, lipid composition in senescence-accelerated mouse: influence of a phosphatidylcholine-vitamin B12 diet.

Our objective was to determine whether dietary supplementation with phosphatidylcholine (PC) plus vitamin B12 could afford beneficial effects on biochemical and biophysical events in the brain of senescence-accelerated mouse (SAM) substrain SAMP8. We measured learning behaviour, hippocampal protein kinase C (PKC) activity, cerebral antioxidant status, phospholipid composition and fatty acid composition in 6-month-old SAMP8 and in age-matched controls (SAM substrain SAMR1). In comparison with SAMR1, SAMP8 showed a significant elevation in total grading score of senescence and a significant decline in acquisition SAMP8 had a lower hippocampal PKC activity and cerebral PKC-beta mRNA abundance than SAMR1. SAMP8 had increased cerebral lipid peroxide levels and proportion of sphingomyelin, and a lower proportion of 20 : 4n-6 and 22 : 6n-3 in cerebral phosphtidylethanolamine than SAMR1. SAMP8 fed the PC combined with vitamin B12 diet had an increased PKC activity and a higher proportion of 22 : 6n-3 than SAMP8 fed the control diet. These results indicate the potential benefit of PC combined with vitamin B12 as a dietary supplement.

Ibotenic acid-induced lesions of the medial septum increase hippocampal membrane associated protein kinase c activity and reduce acetylcholine synthesis: prevention by a phosphatidylcholine/vitamin B12 diet.

Ibotenic acid infusion into the medial septum (MS) results in biochemical alterations in the hippocampus. The biochemical events involved in this neuronal lesion are poorly understood. We investigated the effect of a purified diet supplemented with egg phosphatidylcholine (PC) and vitamin B(12) on ibotenic acid-medicated biochemical changes in the rat hippocampus and crude synaptosomal membranes. Male Wistar rats with this MS lesion were fed a purified diet (control diet) or a purified diet supplemented with 5.7 g PC and 125 microg vitamin B(12) per 100 g (experimental diet) for 18 days. Sham-operated rats were fed the control diet. Compared with the sham-operated rats, MS-lesioned rats fed the control diet showed increased activity of membrane-bound protein kinase C (PKC), decreased activity of choline acetyltransferase, and decreased concentrations of acetylcholine in the hippocampus. The ratio of cholesterol to phospholipid in the crude synaptic membrane was lower in the lesioned rats than in the sham-operated rats, but this was not accompanied by any alteration in membrane lipid fluidity. MS-lesioned rats fed the experimental diet showed lowered PKC activity and elevated acetylcholine concentrations than did rats fed the control diet, but there were no significant effects on choline acetyltransferase activity and the lipid ratio. The ibotenic acid-mediated elevation of PKC activity was observed as early as 2 days postinjury in the control diet-fed rats but not in the experimental diet-fed rats. We propose that ibotenic acid mediates pathophysiologic actions through the activation of PKC and that PC combined with vitamin B(12) ameliorates the second messenger-mediated injury.

Antianginal effects of YM-16151-4 in various experimental angina models.

The antianginal effects of YM-16151-4, a combined calcium entry blocking and beta 1-adrenoceptor blocking agent, were evaluated in various experimental angina models and compared with those of nifedipine and propranolol. In anesthetized dogs, YM-16151-4 (0.3 and 1 mg/kg intravenously, i.v.) increased coronary blood flow and reduced myocardial oxygen consumption (MVO2). In isolated dog coronary arteries, YM-16151-4 concentration-dependently inhibited 3,4-diaminopyridine-induced rhythmic contractions with an IC50 value of 91 nM. In anesthetized rats, YM-16151-4 also inhibited the ST-segment depression induced by vasopressin (0.5 U/kg i.v.) with an ED50 value of 29 mg/kg orally, (p.o.). Nifedipine was also effective in these models, but propranolol was not. In addition, YM-16151-4 (0.3 mg/kg i.v.) inhibited the ST-segment elevation in the epicardial ECG induced by coronary artery occlusion in anesthetized dogs. Propranolol (1 mg/kg i.v.) also inhibited this elevation, but nifedipine (0.003 mg/kg i.v.) did not. In anesthetized dogs, furthermore, the prolongation of PQ-interval induced by YM-16151-4 was almost the same as that induced by propranolol. These results demonstrate that YM-16151-4, in contrast to nifedipine and propranolol, is fully effective in these various types of angina models. Thus, YM-16151-4 is expected to prove a valuable antianginal agent in treatment of various types of angina pectoris, with these antianginal effects resulting from the sum of its calcium entry blocking and beta 1-adrenoceptor blocking activities.