Cell-permeant calcium buffer induced neuroprotection after cortical devascularization

• Published in: Experimental neurology 2005-04, Vol.192 (2), p.357-364
• Main Authors: Bartnik, Brenda L., Spigelman, Igor, Obenaus, André
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Brain Infarction - metabolism; Brain Infarction - pathology; Brain Injuries - drug therapy; Brain Injuries - metabolism; Brain Injuries - pathology; Brain Injuries - physiopathology; Brain Mapping; Cell Count - methods; Cell permeant calcium buffer; Cerebral Cortex - blood supply; Cerebral Cortex - pathology; Chelating Agents - therapeutic use; Development. Senescence. Regeneration. Transplantation; Diffusion Magnetic Resonance Imaging - methods; Diffusion weighted MRI; Disease Models, Animal; Drug toxicity and drugs side effects treatment; Ectodysplasins; Egtazic Acid - analogs & derivatives; Egtazic Acid - therapeutic use; Fundamental and applied biological sciences. Psychology; Glial Fibrillary Acidic Protein - metabolism; Histological Techniques - methods; Immunohistochemistry - methods; Ischemia; Male; Medical sciences; Membrane Proteins - metabolism; Phagocytes - metabolism; Pharmacology. Drug treatments; Rat; Rats; Rats, Wistar; Space life sciences; Time Factors; Toxicity: nervous system and muscle; Vertebrates: nervous system and sense organs
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2004.11.009

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 Ca 2+ 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.