Protective effect of cerebrocrast on rat brain ischaemia induced by occlusion of both common carotid arteries

Abstract

Diabetes mellitus is accompanied by several cardiovascular complications including atherosclerosis, cerebral ischaemia and stroke. We examined the neuroprotective effect of a 1,4-dihydropyridine derivative cerebrocrast (C, a new antidiabetic agent, synthesized in the Latvian Institute of Organic Synthesis) on the level of ATP in the brain, and on changes of the EEG and ECG, as well as blood pressure parameters in anaesthetized Wistar male rats before and during 10-min occlusion of both common carotid arteries. Cerebrocrast was administered i.v. at doses of 1.0 and 10 microg/kg in the v. femoralis 20 min prior to ischaemia. After 10-min ischaemia animals were decapitated and the brain was immediately frozen in liquid nitrogen and subsequently used for analysis of changes of ATP contention. Cerebrocrast, administered at doses of 1.0 and 10 microg/kg 20 min prior to occlusion of both common carotid arteries, completely prevented a fall in the ATP content of brain compared with the control rats. In control rats the content of ATP in brain during ischaemia decreased from 2.77 +/- 0.22 (basal level) to 1.74 +/- 0.20 micromol/g as a result of ischaemia. By administration of cerebrocrast 20 min before occlusion of the arteries, the content of ATP in the brain remained at the level of preischaemia (1.0 microg/kg C + ischaemia 2.82 +/- 0.36; 10 microg/kg C + ischaemia 2.42 +/- 0.22 micromol/g). Analysis of EEG parameters both before and during 10 min of occlusion showed that at a C dose of 1.0 microg/kg before occlusion produced a regular alpha rhythm during ischaemia and prevented cerebral bioelectric activity from significant changes. The depression of basal rhythm was observed at a C dose of 10 microg/kg during ischaemia in two rats out of six as well as an increase in the ECG ST segment above the isoelectric line. Blood pressure was decreased by about 10-20 mm Hg. We propose that pretreatment of rats with cerebrocrast at doses of 1.0 or 10 microg/kg 20 min prior to ischaemia can prevent ischaemic damage of rat brain, maintain necessary energy consumption, promote ATP production in brain cells, and prevent significant changes in EEG and ECG parameters. These properties are important in diabetes mellitus and its evoked cardiovascular complications as stroke, ischaemia, etc.

Perindopril Attenuates Lipopolysaccharide-Induced Amyloidogenesis and Memory Impairment by Suppression of Oxidative Stress and RAGE Activation

“…In addition, we also observed a decreased ATP level in LPS-treated SHRs and NWRs (Figure D), demonstrating reduced brain energy metabolism during hypoperfusion. In support of this observation, a decreased ATP level has been reported in a rat model of chronic cerebral hypoperfusion . ACE inhibition by perindopril improved endothelial functions and hypoperfusion, suggesting that the beneficial effects of an ACE inhibitor might be mediated by the reduction in the formation of Ang II.…”

Methylene Blue Preserves Cytochrome Oxidase Activity and Prevents Neurodegeneration and Memory Impairment in Rats With Chronic Cerebral Hypoperfusion

“…Cytochrome oxidase (CO)−a transmembrane protein localized in the inner mitochondrial membrane-is the terminal enzyme of the electron transport chain (Wong-Riley, 1989). It is well-known that chronic cerebral hypoperfusion results in impaired ATP synthesis (Plaschke, 2005;Brīede and Duburs, 2007), mitochondrial dysfunction and a reduction in CO activity (de la Torre et al, 1997;Cada et al, 2000). There is also evidence that this mitochondrial dysfunction is paralleled by deficits in learning and memory (de la Torre et al, 1997;Cada et al, 2000).…”

“…A key determinant of necrosis vs. apoptosis is the presence of intracellular ATP. In the weeks following 2VO surgery, there is a rapid depletion of ATP (Plaschke, 2005;Brīede and Duburs, 2007). This may lead to an induction of necrotic mechanisms in cells more vulnerable to ATP depletion.…”

New 1,4‐Dihydropyridines Down‐regulate Nitric Oxide in Animals with Streptozotocin‐induced Diabetes Mellitus and Protect Deoxyribonucleic Acid against Peroxynitrite Action

“…None of them produce hypotonic effect when administered in the way it was done in our study; therefore, we did not monitor blood pressure in our experiments. In the single report where some blood pressure‐lowering effect was observed for cerebrocrast , it was administered as a bolus injection in a very low dose, and the effect was observed immediately.…”