The Role of Calcium in Ischemic Brain Damage: By: Christian Stork

1977; Nicholson et al: This research group showed that anoxia triggers rapid translocation of calcium from extra to intracellular spaces in neural tissue. This work prompted speculation about why certain neurons are selectively more sensitive to ischemia, namely because of a higher density of calcium channels in their plasma membranes.

Theory: The Neurotoxic Cascade In 1990 Steven Rothman observed that neurons which were over-exposed to glutamate produced swelling and began degeneration in hippocampal cell cultures. Upon this Rothman predicated that glutamate toxicity was mediating an uncontrolled calcium and sodium influx into post-syn. neurons during hypoxia.

Early explanations: John Werth proposed that most current flow occurs in extracellular space. Tissue resistance was found to be inversely related to interstitial volume. So if the tissue swells, then resistance is elevated in the tissue. Hence, inflammation is implicated as a damage mediator. Werth’s real mark was made by demonstrating the capacity of MK-801 to delay and diminish cell swelling, by preventing ion influx, which decreased resistance in tissues (and halted inflammation).

The Theoretical Synthesis: A Mechanism of Ischemic Damage A blood vessel is blocked. (Ischemia) Downstream neurons release excess glutamate. Glutamate binds NMDA receptors, triggering the excessive influx of Ca, and Na ions. This uncontrolled influx of ions poisons post- synaptic neurons which release even more glutamate which spreads and amplifies the vicious cycle of neuronal death and destruction.

What about delayed Neuronal Death? 3 schemes have been presented: –1. Sustained perturbation of the signal path continues with changes in kinase and phosphatase activities, then ends with altered gene and protein expression. –2. Cell death is due to sustained perturbation of cell calcium metabolism, leading to a slow rise in intra-Ca, and eventual mitochondrial calcium overload. –3. This third theory also predicts that ultimate cell damage is due to mitochondrial failure, but through a different mechanism. The idea is that mitochondrial movement is along the cytoskeletons is halted when the cytoskeletons are broken down by calcium- activated proteases, and calcium-dependent microtubule disassembly. Thus, impaired movement devastates the mitochondrial capacity to generate ATP.

Themes: It is widely accepted that Calcium is one of the triggers/mediators of ischemic cell death, yet the mechanism remains to be elucidated. During ischemia, the lack of oxygen and glucose inhibit the cells capacity to both extrude calcium and sequester it in intracellular stores. All this evidence does support the idea of a Calcium Overload chain reaction leading to cell death.

An Exception via Zinc? Studies done at Johns Hopkins University have shown that Zinc ions can enter excitable cells in a voltage-dependent manner. Not only were the Zinc ions shown to enter through L-type CALCIUM channels, but that they mediated voltage dependent gene expression.

Time for more Studies: Demonstrating a clear link between ischemia/reperfusion and the accumulation of intracellular Zinc may pave the road to understanding the likely role Zinc plays as a second messenger in mediating cell death post ischemia. Conclusions: Further investigation is crucial to a true understanding of the phenomenon.