Neonatal Models Of Stroke

These models generally require a permanent occlusion of one of the two major cerebral arteries in association with a transient occlusion of the other one to produce low cerebral blood flow, because of the presence of the Circle of Willis. In the Renolleau model (Renolleau et al., 1998) (see Figure 42.1B), anaesthetized rats were positioned on their backs, and a median incision was made in the neck to expose the left common carotid artery. Rats were then placed on the right side, and an oblique skin incision was made between the ear and the eye. After excision of the temporal muscle, the cranial bone was removed from the frontal suture to a level below the zygomatic arch. Then, the left middle cerebral artery (MCA), exposed just after its appearance over the rhinal fissure, was coagulated at the inferior level of the cerebral vein (see Figure 42.1B). After this procedure, a clip was placed to occlude the left common carotid artery. Rats were then placed in an incubator to avoid hypothermia. After 50 minutes, the clip was removed. Carotid blood flow restoration was verified with the aid of a microscope. Both neck and cranial skin incisions were then closed. During the surgical procedure, body temperature was maintained at 37 to 38°C. After recovery, pups were transferred to their mothers. Such an ischemic procedure leads to damage in the frontoparietal cortex, and in 20% of animals the head of the caudate putamen was also injured. The mean infarct volume is 58 ± 6 mm3 (24.3 ± 2.2% of ipsilateral hemisphere) at 48 hours of

Neonatal Stroke

Figure 42.2 Presence of a cortical infarct in a model of neonatal stroke in 7-day-old rat (P7), 24 hours after reperfusion. A: Reperfusion was detected in the MCA territory (MCA, open black arrow, with its different branches and anastomoses), after methylene blue injected in the jugular vein, except at the low level of the MCA (little black arrow). B: representative Cresyl violet-stained coronal section. Note the cortical ill-defined pale area. C-D: T2 and ADC IRM images (7 Tesla) on 1 mm slice thickness, respectively, demonstrated the presence of a cortical infarct.

Figure 42.2 Presence of a cortical infarct in a model of neonatal stroke in 7-day-old rat (P7), 24 hours after reperfusion. A: Reperfusion was detected in the MCA territory (MCA, open black arrow, with its different branches and anastomoses), after methylene blue injected in the jugular vein, except at the low level of the MCA (little black arrow). B: representative Cresyl violet-stained coronal section. Note the cortical ill-defined pale area. C-D: T2 and ADC IRM images (7 Tesla) on 1 mm slice thickness, respectively, demonstrated the presence of a cortical infarct.

reperfusion, with only 5 to 10% animals dying in the first few hours after the clip removal (Ducrocq et al, 2000; Joly et al., 2004). This model evolves in a cystic infarct three weeks post-ischemia (see Figure 42.2).

More recently several groups have adapted to the newborn the filament technique of transient middle cerebral artery occlusion (MCAo) that is preferentially used in adult animal models of stroke. This includes the P7 (Derugin et al., 1998) and the SHR P14 to P18 (35 g) Wistar rat (Ashwal et al., 1995). Duration of endovascular nylon filament (6-0, 0.07 mm) occlusion varied from approximately 90 to 180 min MCAo. The volume of infarct involving cortical and caudoputamenal regions observed in these rat pup models is similar to that in adult models (infarct volume was of 180 ± 29 mm3 corresponding to 49 ± 7% of the left hemisphere). However, reliably using such a model of reversible newborn MCAo without craniectomy is technically challenging, and the survival rate was very poor during the occlusion period or within the first hours of reperfusion.

In conclusion, the different models of cerebrovascular neonatal injury at one specific age (P7, for example) can be considered complementary since they analyze different types of cerebral insults (hypoxia-ischemia versus stroke), but no single model can ever replicate the human condition. All these models exhibited apoptotic features as demonstrated by electron microscopy (Pulera et al., 1998;

Renolleau et al., 1998; Puka-Sundvall et al., 2000), DNA cleavage in high molecular weight fragments and laddering (Ferrer et al., 1994b; Hill et al., 1995; Cheng et al., 1998; Charriaut-Marlangue et al., 1999) and TUNEL-positive nuclei (see Figure 42.3A, B).

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