Calcium Accumulation and Neuronal Damage in the Rat Hippocampus following Cerebral Ischemia

Abstract

Summary: The present study was undertaken to corre late calcium accumulation with the development of neu ronal necrosis following transient ischemia. After ) 0 min of forebrain ischemia in the rat-a period that leads to reproducible damage of CAl pyramidal celis-determi nation of calcium concentration and evaluation of mor phological signs of cell body necrosis in the dorsal hippo campus were performed at various recirculation times. Tissue calcium concentration was not different from con trol at the end of ischemic period and did not change after 3, 6, 12, or 24 h of recirculation. However, after 48 h, calcium content increased significantly, with a further inBased on data showing accumulation of calcium in irreversibly damaged tissue and on results dem onstrating massive sequestration of calcium by mitochondria, the hypothesis of calcium-related cell death was advanced for cardiac tissue (Fleck enstein, 1977;Borgers, 1981), skeletal muscle (Wrogemann and Pena, 1976; Leonard and Sal peter, 1979), and liver (Schanne et ai. , 1979). In these hypotheses, it was tacitly assumed that one major mechanism of cell death was mitochondrial calcium overload, with ensuing structural damage and secondary energy failure. However, it was rec ognized that the adverse effects of calcium encom passed activation of neutral proteases (Guroff, 1964) and of phospholipases (Sun and Su, 1979).In recent years, it has been realized that the loss of calcium hemostasis may be an important mecha nism of ischemic brain damage (Haas, 1981;Siesj6, 1981) cumulation of polyenoic free fatty acids (FFAs) and their oxidative conversion products, and by trig gering proteolysis, protein phosphorylation, and disaggregation of cytoskeletal components (for ref erences see Siesj6 and Wieloch, 1985). One inter esting feature of the hypothesis of calcium-related damage as applied to the brain relates to the fact that neurons differ in the density of calcium channels, with some pyramidal cells having a dense population of agonist-operated channels in their dendritic fields. As at least some of these cells could be identical to those reported to be selec tively vulnerable to several different insults (see Siesj6, 1981;Wieloch, 1985), one has the interesting possibility that the calcium overload could help to explain not only neuronal necrosis in general, but also selective neuronal vulnerability.It has been demonstrated that ischemic insults that lead to irreversible damage are accompanied by net accumulation of calcium in the tissue (Yana gihara and McCall, 1982; Hossmann et aI. , 1983;Dienel, 1984). However, published results give no indication of whether calcium accumulates before cell necrosis occurs or occurs as a secondary phe nomenon to an irreversible injury. One previous study, in which 45Ca autoradiography and tissue 90 1. K. DESHPANDE ET AL.sampling were employed, gives information on re sidual calcium accumulation following 30 min of forebrain ischemia in the rat (Dienel, 1984). As his topathological evolution of cell damage as a result of th...

Angiotensin II-Induced Pulmonary Edema in a Rabbit Model

“…The increase of cellular calcium ions is thought to be an important trig ger in ischemic cell death (20,21). Although auto radiographic studies indicate the existence of 5-HT2 binding sites in the hippocampus (22)(23)(24), their density is low in this region.…”

Inhibition of Poly(ADP-Ribose) Polymerase Suppresses Inflammation and Promotes Recovery after Ischemic Injury

“…A treatment approach for stroke that is effective within a 48-h time window would greatly increase the number of patients eligible for therapy. The stroke model used here, transient forebrain ischemia, was chosen because it induces extensive loss of hippocampal CA1 neurons (Deshpande et al, 1987;Smith et al, 1984), thus permitting the use of hippocampal neurogenesis and spatial memory as experimental outcome measures. An issue to be established in future studies is whether the beneficial effects of PARP inhibition after transient forebrain ischemia are also evident after focal ischemia, which is a more common clinical event.…”

Functional, Behavioral, and Histological Changes Induced by Transient Global Cerebral Ischemia in Rats: Effects of Cinnarizine and Flunarizine

“…In contrast, flunarizine provided far greater neuronal protection but with less obvious effects Cerebral ischemia induces both immediate and delayed neuronal death according to the selective vulnerability of the neurons, which in turn depends upon the inherent functional and metabolic charac teristics of the nerve cells and the blood supply to that particular brain area (Farder, 1981;Simon et al , 1984;Siesj6, 1988). Calcium overload is thought to be one of the main factors inducing neuronal death (Simon et al, 1984;Siesj6, 1988;Deshpande and Siesj6, 1987) and several studies have shown a close temporal relationship between the accumula tion of calcium and the progression to ischemic cell death in a number of experimental animal models (Hossmann et al , 1983;Dienel, 1984). Although the demonstration of increased cellular levels of cal cium ions in ischemic tissues does not, of itself, upon behavioral parameters.…”