Cell-permeant calcium buffer induced neuroprotection after cortical devascularization

Abstract

An excitotoxic cascade resulting in a significant intracellular calcium load is thought to be a primary mechanism leading to neuronal death after ischemia. One way to protect neurons from injury is through the use of cell-permeant calcium buffers. These molecules have been reported to be neuroprotective via their ability to increase the cell's overall Ca2+ buffering load as well as by attenuating neurotransmitter release. However, their efficacy when given after injury has yet to be determined. We used diffusion-weighted magnetic resonance imaging (DWI), histological, and immunohistochemical methods to determine the neuroprotective efficacy of 2-aminophenol-N, N, O-triacetic acid acetoxymethyl ester (APTRA-AM) after focal cerebral ischemia. Injured animals were given two injections of APTRA-AM at 1 and 12 h after injury. Animals were imaged prior to injury and then at 12, 24, 48 h and 3 and 7 days after injury. After 7 days the animals were euthanized for correlative cresyl violet histology and immunohistochemistry. Injury resulted in a decrease in the apparent diffusion coefficient (ADC) of the injured area within the first 12 h of injury, which returned to normal by 7 days. In contrast, animals injected with APTRA-AM showed no significant change in the ADC at any time point studied. Tissue analysis showed that APTRA-AM significantly reduced the infarct size by 85% and extent of inflammatory cell infiltration by 94%. The results clearly demonstrate significant neuroprotection by APTRA-AM when given after injury. © 2004 Elsevier Inc. All rights reserved.