Abstract
BackgroundFor successful translation to clinical stroke studies, the Stroke Therapy Academic Industry Round Table criteria have been proposed. Two important criteria are testing of therapeutic interventions in conscious animals and the presence of a co-morbidity factor. We chose to work with hypertensive rats since hypertension is an important modifiable risk factor for stroke and influences the clinical outcome. We aimed to compare the susceptibility to ischemia in hypertensive rats with those in normotensive controls in a rat model for induction of ischemic stroke in conscious animals.MethodsThe vasoconstrictor endothelin-1 was stereotactically applied in the vicinity of the middle cerebral artery of control Wistar Kyoto rats (WKYRs) and Spontaneously Hypertensive rats (SHRs) to induce a transient decrease in striatal blood flow, which was measured by the Laser Doppler technique. Infarct size was assessed histologically by Cresyl Violet staining. Sensory-motor functions were measured at several time points using the Neurological Deficit Score. Activation of microglia and astrocytes in the striatum and cortex was investigated by immunohistochemistry using antibodies against CD68/Iba-1 and glial fibrillary acidic protein.Results and conclusionsThe SHRs showed significantly larger infarct volumes and more pronounced sensory-motor deficits, compared to the WKYRs at 24 h after the insult. However, both differences disappeared between 24 and 72 h. In SHRs, microglia were less susceptible to activation by lipopolysaccharide and there was a reduced microglial activation after induction of ischemic stroke. These quantitative and qualitative differences may be relevant for studying the efficacy of new treatments for stroke in accordance to the Stroke Therapy Academic Industry Round Table criteria.
Highlights
For successful translation to clinical stroke studies, the Stroke Therapy Academic Industry Round Table criteria have been proposed
Additional genetic factors exacerbating the effects of experimental stroke cannot be excluded in Spontaneously Hypertensive rats (SHRs), we preferred to use this strain to study the effects of hypertension on experimental ischemic stroke, because increased susceptibility to a reduction in blood flow has been shown to be related to the development of hypertension in this strain
Induction of ischemic stroke in conscious Wistar Kyoto rats (WKYRs) and SHRs We first performed a dose-range finding study in order to induce an infarct situated in the striatum and cortex of conscious WKYRs
Summary
For successful translation to clinical stroke studies, the Stroke Therapy Academic Industry Round Table criteria have been proposed. Many clinical trials with neuroprotective drugs in patients with acute ischemic stroke have yielded disappointing results [1,2] This failure may be due to the use of inadequate animal models. To facilitate translation to the clinic, the Stroke Therapy Academic Industry Round table (STAIR) has developed criteria for more clinically relevant research in animal models of ischemic stroke. An important requirement is testing of stroke-prone spontaneously hypertensive rat (SPSHR), which develops spontaneous strokes. This model exhibits increased sensitivity to experimental stroke which may, in addition to genetically determined hypertension, be due to additional genetic factors [8]. An increased infarct size in SHRs compared to normotensive controls was observed in early and late stage hypertensive rats, but not in pre-hypertensive rats [9]
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