title: 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 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.
authors.affiliation: Department of Radiation Medicine, Loma Linda University, Radiobiology Program CSP A1010, Loma Linda, CA 92354, USA. bbartnik@mednet.ucla.edu
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Bartnik
authors.forename: Igor
authors.initials: I
authors.lastname: Spigelman
authors.forename: André
authors.initials: A
authors.lastname: Obenaus
mesh_terms: D000818:Animals; D020520:Brain Infarction / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001931:Brain Mapping; D002452:Cell Count / Q000379:methods; D002540:Cerebral Cortex / Q000098:blood supply* / Q000473:pathology; D002614:Chelating Agents / Q000627:therapeutic use*; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods; D004195:Disease Models, Animal; D053331:Ectodysplasins; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006652:Histological Techniques / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D010586:Phagocytes / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D002614:Chelating Agents; D053331:Ectodysplasins; D005904:Glial Fibrillary Acidic Protein; D008565:Membrane Proteins; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid