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Neurological Review
October 2006

Acidotoxicity Trumps Excitotoxicity in Ischemic Brain

Author Affiliations

Author Affiliation: Legacy Research, Robert S. Dow Neurobiology Laboratories, Portland, Ore.



Arch Neurol. 2006;63(10):1368-1371. doi:10.1001/archneur.63.10.1368

Plum entitled his 1982 Wartenberg Lecture “What Causes Infarction in Ischemic Brain?”1 This question remains incompletely answered 2 decades later, during which excitatory amino acids and calcium toxicity have been central research and therapeutic targets. Recently, attention has returned to a central neurochemical feature of ischemic brain injury, acidosis, which was focused on in Plum's lecture. Targeting this effector of injury as therapy for brain ischemia now may be closer at hand and may result in robust neuroprotection.

In the 1970s, Brown and Brierley2 described the prodromal morphologic features of ischemic cell change as that of microvacuolization in selectively vulnerable neurons (Figure 1). In 1984, Brian Meldrum and I,3 working at the Institute of Psychiatry in London, England, looked again at these vacuoles. We used ultrastructural studies of ischemic brain treated with the then new oxalate-pyroantimonate technique, with which calcium could be visualized as electron-dense deposits. Almost all of the microvacuoles were shown to be the result of mitochondrial dilation, and the dilated mitochondrial were further characterized by marked calcium loading (Figure 2). Thus, mitochondrial failure and intracellular calcium toxicity were demonstrated morphologically as central features of ischemic brain injury.3 This interesting result seemed similar to microvacuolization and mitochondrial calcium loading shown to occur with status epilepticus by Griffiths and Meldrum.4