Calcium in Ischemic Cell Death

Abstract

Background-This review article deals with the role of calcium in ischemic cell death. A calcium-related mechanism was proposed more than two decades ago to explain cell necrosis incurred in cardiac ischemia and muscular dystrophy. In fact, an excitotoxic hypothesis was advanced to explain the acetylcholine-related death of muscle end plates. A similar hypothesis was proposed to explain selective neuronal damage in the brain in ischemia, hypoglycemic coma, and status epilepticus. Summary of Review-The original concepts encompass the hypothesis that cell damage in ischemia-reperfusion is due to enhanced activity of phospholipases and proteases, leading to release of free fatty acids and their breakdown products and to degradation of cytoskeletal proteins. It is equally clear that a coupling exists between influx of calcium into cells and their production of reactive oxygen species, such as ⅐O 2 Ϫ , H 2 O 2 , and ⅐OH. Recent results have underscored the role of calcium in ischemic cell death. A coupling has been demonstrated among glutamate release, calcium influx, and enhanced production of reactive metabolites such as ⅐O 2 Ϫ , ⅐OH, and nitric oxide. It has become equally clear that the combination of ⅐O 2 Ϫ and nitric oxide can yield peroxynitrate, a metabolite with potentially devastating effects. The mitochondria have again come into the focus of interest. This is because certain conditions, notably mitochondrial calcium accumulation and oxidative stress, can trigger the assembly (opening) of a high-conductance pore in the inner mitochondrial membrane. The mitochondrial permeability transition (MPT) pore leads to a collapse of the electrochemical potential for H ϩ , thereby arresting ATP production and triggering production of reactive oxygen species. The occurrence of an MPT in vivo is suggested by the dramatic anti-ischemic effect of cyclosporin A, a virtually specific blocker of the MPT in vitro in transient forebrain ischemia. However, cyclosporin A has limited effect on the cell damage incurred as a result of 2 hours of focal cerebral ischemia, suggesting that factors other than MPT play a role. It is discussed whether this could reflect the operation of phospholipase A 2 activity and degradation of the lipid skeleton of the inner mitochondrial membrane. Conclusions-Calcium is one of the triggers involved in ischemic cell death, whatever the mechanism. (Stroke.1998;29:705-718.)Key Words: calcium Ⅲ cerebral ischemia Ⅲ free radicals Ⅲ mitochondria T he calcium hypothesis of ischemic cell death was originally launched to explain the relationship between excessive calcium influx and the cell damage that is incurred in myocardial ischemia 1 as well as in muscle dystrophy. 2 In fact, studies conducted at that time led to the formulation of an excitotoxic hypothesis, predicting that excessive release of acetylcholine at the motor end plate was what caused damage to skeletal muscle. 3,4 The work performed at that time on ischemic muscle damage was almost visionary since it forestalled the pivotal role of release o...

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

“…The major cause of cell death in the ischemic tissue is an uncontrolled elevation of intracellular [Ca 2+ ] [6][7][8]. In the core, levels of extracellular Ca 2+ drop from ~2 mM to 0.05-0.08 mM, reflecting major Ca 2+ movement into the intracellular space.…”

Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells

“…Specifically, it has been reported that glutamate-induced neurotoxicity depends on mitochondrial Ca 2+ uptake ([Ca 2+ ] m ) [9,12]. Under stress conditions, there is an early increase in [Ca 2+ ] m that may contribute to mitochondrial dysfunction [13,14] and MPTP opening, a point-of-no-return step in the intrinsic pathway of apoptotic cell death [15,16].…”

Tf-lipoplex-mediated NGF gene transfer to the CNS: neuronal protection and recovery in an excitotoxic model of brain injury

“…Kainic acid is known to cause an increase in the levels of extracellular glutamate, [47][48][49] and the excitotoxicity of this amino acid is commonly related to the neuronal death observed for both neurodegenerative disorders and acute brain injuries. 45,46 Owing to its neuroprotective effects, biologically delivered NGF has been reported to counteract the death of striatal neurons, caused by excitotoxic insults. [60][61][62] In this work, we investigated the potential of Tf-lipoplexes (prepared at the 8/1 (+/À) lipid/DNA charge ratio) to mediate both neuronal protection and regeneration upon delivery of the NGF gene.…”

“…[42][43][44] Neuronal cell death is thought to be due, at least in part, to the massive influx of calcium induced by overactivation of glutamate receptors. 45,46 Kainic acid, an agonist of AMPA receptors, is responsible for the initiation of an excitotoxic cascade, which results in the accumulation of excitatory amino acids, such as glutamate, and thus in the increase of intracellular calcium concentration. [47][48][49] Therefore, kainic acid has commonly been used to elicit a selective neurodegeneration, both in vitro 48 and in vivo.…”