Relevance of Experimental Ischemia in Cats for Stroke Management: A Comparative Reevaluation

Abstract

Repeat studies in animal models of acute focal ischemia can be compared to incidental studies in the course of ischemic stroke in order to shed light on the development of changes causing ischemic infarcts or recovery of critically perfused tissue. Positron emission tomography (PET) studies of regional cerebral blood flow, cerebral metabolic rate for oxygen, oxygen extraction fraction (OEF), cerebral metabolic rate of glucose and flumazenil (FMZ) binding in the cat middle cerebral artery occlusion (MCAO) model and in patients with acute ischemic hemispheric stroke were reviewed. After permanent MCAO, the development of ‘misery-perfused’ penumbral tissue and its centrifugal conversion into necrosis could be demonstrated, resembling focal pathophysiological changes in patients with ischemic attacks. In the experimental model and in vascular insults in humans, a chance of recovery existed if collateral perfusion developed spontaneously within the first hours. In transient MCAO, reperfusion was only effective in preventing infarction when it was initiated as long as misery perfusion persisted; in these cases tissue was salvaged and large infarcts did not develop. In the other instances when oxygen metabolism broke down, and an increased OEF was no longer seen, reperfusion even at levels above preocclusion had no effect, and large space-occupying infarcts developed. These experimental findings are comparable to the variable outcome after thrombolytic therapy; if reperfusion is achieved within the therapeutic window of tissue viability, large infarcts are prevented and complete or partial recovery can be achieved. In the experimental model of focal ischemia and in human stroke, FMZ can be utilized as a marker of neuronal integrity. If FMZ binding in the cortex is decreased below 4 times the mean value of white matter in the acute stage, permanent infarcts were observed on late CT/MRI; this irreversible damage could not be prevented by thrombolytic therapy. These results demonstrated that PET studies in suitable ischemia models in cats can help to explain various courses and diverging outcomes of acute ischemic stroke. Comparable findings from experimental ischemia and human stroke may affect the selection of appropriate therapeutic strategies.

Low-Dose Lithium Stabilizes Human Endothelial Barrier by Decreasing MLC Phosphorylation and Universally Augments Cholinergic Vasorelaxation Capacity in a Direct Manner

“…We investigated thoracic and middle cerebral arteries. Relaxation of cerebral vessels during and after an ischemia/reperfusion leads to collateral cerebral blood flow, and thus characterizes an intrinsic strategy of the cerebral vasculature to protect neuroglial structures but also vasculature including endothelium against ischemic injury (Heiss et al, 2001), likewise reported for the heart (Koerselman et al, 2003; Meier et al, 2013). Indeed, cerebral collateral status and sufficiently enlarged calibers of collateral arteries have recently been identified as most relevant for final infarct volume, vasogenic edema formation (with subsequent midline shift), and hence patient outcome (Volny et al, 2016; van den Wijngaard et al, 2016; van der Hoeven et al, 2016).…”

A Surgical Model of Permanent and Transient Middle Cerebral Artery Stroke in the Sheep

“…Rabbits have an arterial anatomy that permits endovascular autologous clot occlusion of various intracranial arteries including the MCA [22] and the basilar artery [23], however their brains are lissencephalic like the rat and not generally representative of the human gyrencephalic brain. Cats are of a similar size to rabbits and have a gyrencephalic brain, however their vascular anatomy precludes an endovascular approach to occlusion and the surgical approach is transorbital [24]. Both rabbits and cats are considerably smaller than sheep or pigs, and although weight itself does not predict phylogenetic order, larger brains allow for easier surgical manipulation and limit the requirement of higher resolution imaging.…”

Comparison of PET and DW / PW-MRI in Acute Ischemic Stroke

“…This tissue, termed the penumbra, 1 is perfused at a level within the thresholds of functional impairment and morphological integrity and has the capacity to recover if perfusion is improved. The extent of this tissue compartment is dependent on residual flow and duration of flow disturbance: It can be clearly demonstrated in animal experiments with permanent and transient occlusion of cerebral vessels 11 that the volume of functionally impaired but morphologically intact tissue is large and involves even the centre of the vascular territory with impaired blood supply immediately after the onset of the perfusional disturbance, and it becomes progressively smaller with time elapsed since the vascular attack. 5 This concept as developed in animal experiments defines the penumbra as a dynamic process depending on residual perfusion and duration, with conversion into irreversible neuronal damage over time, progressing from the centre of dense ischemia to the surrounding tissue with less severe but still critically hypoperfused adjacent areas.…”