It is very inexpensive, its physiological effects are relatively well understood, 13, 14 including vasodilation at high concentrations, and it is widely used in clinical practice and so regulatory approval would be easily gained. 11, 12 There are multiple pragmatic features in its favor as a potential neuroprotectant, as well as encouraging preclinical and clinical evidence. Magnesium is an endogenous, physiological anti-excitotoxic agent, acting by voltage-dependent inhibition of glutaminergic channels. 9 Further, in preterm fetal sheep, infusion of the non-competitive glutamatergic antagonist dizocilpine after HI was associated with very limited improvement in neuronal survival, in only one hippocampal region, and combined dizocilpine infusion with hypothermia did not augment hypothermic neuroprotection. 7 Consequently, excitotoxin antagonists failed to translate in adult clinical trials. 7 We now know that these excitatory channels are just one of many calcium channels that open during HI 8 and that the apparent benefit in small animal studies was confounded by drug-induced hypothermia. 5 There was great excitement when specific antagonists seemed to dramatically reduce cell death. 6 Exposure to excitotoxins can facilitate excessive entry of calcium into the cell and so activate delayed cell death pathways.
Early research on the mechanisms of delayed cell death after HI focused on the observation that excitatory amino acids (“excitotoxins”) such as glutamate accumulate in the extracellular space during HI and during intense seizures.
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