Rodent stroke induced by photochemical occlusion of proximal middle cerebral artery: Evolution monitored with MR imaging and histopathology
Introduction
Being pioneered by Watson et al. [1], photochemically induced thrombotic (PIT) stroke represents a general method that elicits various rodent models of focal cerebral ischemia. According to different approaches employed, the PIT stroke models can actually be classified into four types: type A, end-artery occlusion in the cortex, which is the classical type of the PIT model [2], [3], [4], [5], [6], [7]; type B, the “ring” model, which features certain “tissue at risk” or ischemic penumbra within the “ring” shape of photochemically induced cortical lesion [8], [9], [10], with both types A and B based on the occlusion of microvessels in the cortex; type C, middle cerebral artery (MCA) occlusion, which can be further divided into the proximal MCA occlusion (type C1) [11] and distal MCA occlusion (type C2) [12], [13], [14]; type D, common carotid artery occlusion, which causes multiple cerebral infarcts [15]. Since MCA territory is the most frequently insulted area for focal cerebral infarcts in clinic, type C PIT models most closely replicate the situations of stroke in humans [16]. Unlike other PIT models that are extensively reported in literature [1], [2], [3], [4], [5], [6], [8], [9], [10], [12], [13], [14], the proximal MCA occlusion or the type C1 PIT model has not been sufficiently characterized since its first introduction in 1993 [11].
Magnetic resonance imaging (MRI) proves to be pivotal in experimental stroke studies due to its in vivo, non-invasive and non-destructive features with excellent spatial and temporal resolution [6], [16], [17], [18]. Previous studies have shown that the PIT model of proximal MCA occlusion is advantageous over other models for its reproducible larger ischemic lesion and the possibility of reperfusion. Therefore, it appears ideal for studying “tissue at risk” or ischemic penumbra and for evaluating novel anti-stroke drugs particularly with MRI [19], [20], [21], [22]. Recently, a delayed perfusion phenomenon at MRI [23] and its relation to the collateral circulation, spontaneous reperfusion, and ischemic penumbra has been observed using this PIT model [24]. However, whether the pathological evolution of this stroke model differs from other models has not been systemically studied by in vivo MRI.
Therefore, the purpose of the present study was to further investigate the morphological changes of this particular PIT stroke model in rats using a clinical MRI scanner correlated with histopathology in a longitudinal manner.
Section snippets
Animal preparation
In compliance with the current institutional regulations for use and care of laboratory animals, 42 male Sprague–Dawley (SD) rats weighting 230–350 g were included in this study. Anesthesia was made with initial inhalation of 4% isoflurane for 3 min and maintained with 2% isoflurane in a mixture of 20% oxygen and 80% room air. Body temperature was kept at 37.5 ± 0.5 °C with a heating pad during the surgical operation. The left proximal MCA was occluded by a photothrombotic approach as detailed
Temporal evolution of cerebral ischemic volume on MR imaging
The ischemic lesion normally appeared first at the ventral part of the basal ganglia and then spread to the entire basal ganglia and ipsilateral cortex. At 1 h after MCA occlusion, the relative ischemic lesion volume depicted on T2WI was significantly smaller than that on DWI and ADC map. The lesion size gradually expanded and reached a maximum at day 1 on T2WI, DWI and ADC map similarly. The lesion remained almost unchanged up to day 3 followed by a significant decrease at day 9 on all MR
Comparisons with other photothrombosis stroke models
Despite similar basic principle and pathology, our PIT model with proximal MCA occlusion demonstrated a larger ischemic lesion covering both the cortex and striatum compared to other photothrombotic stroke models that affect only peripheral areas [4], [6], [7]. The main reason is that the proximal left MCA at the olfactory tract, rather than the end-artery [2], [3], [4], [5], [6], [7], [8], [9], [10] or distal MCA [12], [13], [14] chosen elsewhere, was thrombotically occluded with light
Summary
The evolution of the present photothrombotic stroke model in rats has been studied by MRI and histopathology, and compared with other photochemical stroke models. Better understanding of the serial changes on MRI and pathology in this stroke model may benefit research in cerebral ischemia and anti-stroke agents using MRI. Furthermore, the use of a commercial 1.5 T magnet could improve the interpretation of the results in this study and give them more relevance towards the clinical scenarios.
Acknowledgement
We thank Dr. Hilde Vandenhout for her help in manuscript editing.
References (40)
- et al.
Complementary use of T2-weighted and postcontrast T1- and T2*-weighted imaging to distinguish sites of reversible and irreversible brain damage in focal ischemic lesions in the rat brain
Magn Reson Imaging
(1995) - et al.
Dynamics of cerebral injury, perfusion, and blood–brain barrier changes after temporary and permanent middle cerebral artery occlusion in the rat
J Neurol Sci
(1999) - et al.
Changes in local cerebral blood flow in photochemically induced thrombotic occlusion model in rats
Eur J Pharmacol
(2000) - et al.
Neuroprotective effects depend on the model of focal ischemia following middle cerebral artery occlusion
Eur J Pharmacol
(1998) - et al.
Delayed perfusion phenomenon in a rat stroke model at 1.5 T MR: an imaging sign parallel to spontaneous reperfusion and ischemic penumbra?
Eur J Radiol
(2007) - et al.
Three openings of the blood–brain barrier produced by forebrain ischemia in the rat
Neurosci Lett
(1993) - et al.
Blood–brain barrier disruption in experimental focal ischemia: comparison between in vivo MRI and immunocytochemistry
Magn Reson Imaging
(1994) - et al.
Induction of reproducible brain infarction by photochemically initiated thrombosis
Ann Neurol
(1985) - et al.
Photochemically induced cerebral infarction. I. Early microvascular alterations
Acta Neuropathol (Berl)
(1987) - et al.
Photochemically induced cerebral infarction. II. Edema and blood–brain barrier disruption
Acta Neuropathol (Berl)
(1987)
Photochemically-induced cerebral infarction in the rat: comparison of NMR imaging and histologic changes
Acta Neurochir (Wien)
Evolution of photochemically induced focal cerebral ischemia in the rat. Magnetic resonance imaging and histology
Stroke
Histopathologic correlates of abnormal water diffusion in cerebral ischemia: diffusion-weighted MR imaging and light and electron microscopic study
Radiology
A photothrombotic ’ring’ model of rat stroke-in-evolution displaying putative penumbral inversion
Stroke
A photothrombotic ring stroke model in rats with remarkable morphological tissue recovery in the region at risk
Exp Brain Res
A photothrombotic ring stroke model in rats with sustained hypoperfusion followed by late spontaneous reperfusion in the region at risk
Exp Brain Res
Evaluation of the combination of a tissue-type plasminogen activator, SUN9216, and a thromboxane A2 receptor antagonist, vapiprost, in a rat middle cerebral artery thrombosis model
Stroke
Argon laser-induced arterial photothrombosis. Characterization and possible application to therapy of arteriovenous malformations
J Neurosurg
Comparative histopathologic consequences of photothrombotic occlusion of the distal middle cerebral artery in Sprague–Dawley and Wistar rats
Stroke
Simplified model of krypton laser-induced thrombotic distal middle cerebral artery occlusion in spontaneously hypertensive rats
Stroke
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