Evolution of Brain Infarction after Transient Focal Cerebral Ischemia in Mice

Abstract

The evolution of brain infarction after transient focal cerebral ischemia was studied in mice using multiparametric imaging techniques. One-hour focal cerebral ischemia was induced by occluding the middle cerebral artery using the intraluminal filament technique. Cerebral protein synthesis (CPS) and the regional tissue content of adenosine triphosphate (ATP) were measured after recirculation times from 0 hours to 3 days. The observed changes were correlated with the expression of the mRNAs of hsp-70, c-fos, and junB, as well as the distribution of DNA double-strand breaks, visualized by TUNEL. At the end of 1 hour of ischemia, protein synthesis was suppressed in a larger tissue volume than ATP in accordance with the biochemical differentiation between core and penumbra. Hsp70 mRNA was selectively expressed in the cortical penumbra, whereas c-fos and junB mRNAs were increased both in the lateral part of the penumbra and in the ipsilateral cingulate cortex with normal metabolism. During reperfusion after withdrawal of the intraluminal filament, suppression of CPS persisted except in the most peripheral parts of the middle cerebral artery territory, in which it recovered between 6 hours and 3 days. ATP, in contrast, returned to normal levels within 1 hour but secondarily deteriorated from 3 hours on until, between 1 and 3 days, the ATP-depleted area merged with that of suppressed protein synthesis leading to delayed brain infarction. Hsp70 mRNA, but not c-fos and junB, was strongly expressed during reperfusion, peaking at 3 hours after reperfusion. TUNEL-positive cells were detected from 3 hours on, mainly in areas with secondary ATP depletion. These results stress the importance of an early recovery of CPS for the prevention of ischemic injury and suggest that TUNEL is an unspecific response of delayed brain infarction.

Mice overexpressing human caspase 3 appear phenotypically normal but exhibit increased apoptosis and larger lesion volumes in response to transient focal cerebral ischaemia

“…Brief occlusion of the MCA in C57BL/6J mice has been reported to produce an ischaemic lesion that is restricted to the striatum while more prolonged ischaemia results in damage to both striatum and overlying cortex, although there is evidence that the precise threshold for induction of cortical damage may differ from one laboratory to another. [61][62][63] In the present study, human caspase 3 overexpressing mice exhibited larger and more consistent lesions at each of the three time points investigated. Moreover, in the 45 min occlusion group, where damage was restricted to the striatum of WT littermates, the transgenic mice exhibited consistent damage to both cortex and striatum.…”

Transforming Growth Factor-α Attenuates N-Methyl-D-aspartic Acid Toxicity in Cortical Cultures by Preventing Protein Synthesis Inhibition through an Erk1/2-dependent Mechanism

“…Transient Exposure to NMDA Causes Persistent Inhibition of Protein Synthesis and eIF4E Dephosphorylation-We then addressed suppression of translation, another important aspect involved in neuronal death (6,8,10). We found a persistent inhibition of amino acid incorporation into proteins following transient exposure to NMDA, which was prevented by TGF-␣.…”

“…Indeed, glutamate receptor overactivation results in an increase in intracellular calcium and extensive neuronal death by excitotoxicity (9). Likewise, persistent blockade of protein synthesis is associated with brain damage (10), and neuronal survival after focal ischemia may depend on the recovery of protein synthesis (11). Intracellular Ca 2ϩ overload by activation of glutamate receptors (12) or disturbances of endoplasmic reticulum Ca 2ϩ homeostasis decrease protein synthesis (13)(14)(15)(16).…”

Transient Cooling during Early Reperfusion Attenuates Delayed Edema and Infarct Progression in the Spontaneously Hypertensive Rat. Distribution and Time Course of Regional Brain Temperature Change in a Model of Postischemic Hypothermic Protection

“…The 90 mins insults employed in the present studies are below the temporal threshold for maximal infarction in this model (Kaplan et al, 1991;Ren et al, 2004), and it is not surprising that infarct evolution would occur more slowly after shorter insults. Secondary energy failure continues to progress between 1-and 3-days recirculation after 1 h focal ischemia in the mouse (Hata et al, 2000). Furthermore, brief hyperthermia initiated 24 h after 1 h focal ischemia increases infarct volume in a Sprague-Dawley model (Kim et al, 1996), and this capacity for delayed exacerbation of injury suggests persistent ongoing pathology.…”