A Comparison of Long-Term Functional Outcome After 2 Middle Cerebral Artery Occlusion Models in Rats

Abstract

Background and Purpose-Proven behavioral assessment strategies for testing potential therapeutic agents in rat stroke models are needed. Few studies include tasks that demand higher levels of sensorimotor and cognitive function. Because behavioral outcome and rate of recovery vary among ischemia models, there is a need to characterize and compare performance on specific tasks across models. Methods-To this end, sensorimotor and cognitive deficits were assessed during a 5-week period after either permanent proximal middle cerebral artery occlusion (pMCAO) or permanent distal middle cerebral artery occlusion combined with a 90-minute occlusion of both common carotid arteries (dMCAO/tCCAO) in Sprague-Dawley rats. The EBST, hindlimb and forelimb placing, and cylinder tests were given at regular intervals postinjury to assess sensorimotor function. Cognitive function was assessed with a multitrial water navigation task. Results-pMCAO, which caused both striatal and cortical damage, produced persistent sensorimotor and cognitive deficits. Limb placing responses and postural reflexes were impaired throughout the month of testing. A persistent bias for using the ipsilateral forelimb for wall movements in the cylinder test was observed as well as a bias for landing on the opposite forelimb. pMCAO rats were also impaired in the water navigation task. dMCAO/tCCAO, which caused only cortical damage, produced similar sensorimotor deficits, but these were greatly diminished by 2 weeks after injury.No impairment was found for water tank navigation. Correlations between forelimb placing (both models), water navigation performance (pMCAO model), and sensorimotor asymmetry (dMCAOtCCAO model) and infarct volume were observed. Conclusions-Based on the range of functions affected and stability of observed deficits, the pMCAO model appears to be preferable to the dMCAO/tCCAO model for use in assessing therapeutic agents for stroke.

Endovascular middle cerebral artery occlusion in rats as a model for studying vascular dementia

“…A more negative score indicates less responding to contralateral sensory stimulation (a) Neglect ratio ± SE, (b) average number of inappropriate responses ± SE. * P < 0.05 for individual comparison within 2-way ANOVA paradigm, rats with permanent MCA occlusion exhibited weaker improvement following repeated testing in a spatial memory test at 1 and 2 weeks after stroke when compared with shams (Roof et al 2001). This pattern is consistent with the presence of cognitive deficits that continue to worsen with time following an experimental stroke.…”

“…Sensorimotor performance has been quantified by assessing postural abnormalities, coordinated movements, balance, forelimb strength, locomotor activity, or sensory capabilities (DeVries et al 2001). Spontaneous partial or complete recovery of sensorimotor function has been frequently reported over time after ischemic stroke in this model (Markgraf et al 1994(Markgraf et al , 1997Yonemori et al 1999;DeVries et al 2001;Roof et al 2001;Karhunen et al 2003). Indeed, the validity of MCA occlusion as a model for human ischemic stroke has been criticized because of the transitory nature of the sensorimotor deficits (Cheng et al 2004).…”

“…Indeed, the validity of MCA occlusion as a model for human ischemic stroke has been criticized because of the transitory nature of the sensorimotor deficits (Cheng et al 2004). However, ensuring that the proximal MCA rather than the distal MCA is occluded appears to With a 3-0 monofilament suture inserted from left ECA and gradually advanced into the intracranial ICA, blood flow was blocked to the left MCA territory increase the likelihood of persistent sensorimotor dysfunction (Roof et al 2001). This is because distal MCA occlusion in rats is more commonly associated with cortical damage alone, whereas endovascular occlusion of the proximal MCA typically results in extensive brain damage in the cerebral cortex as well as the caudate-putamen (Roof et al 2001).…”

“…However, ensuring that the proximal MCA rather than the distal MCA is occluded appears to With a 3-0 monofilament suture inserted from left ECA and gradually advanced into the intracranial ICA, blood flow was blocked to the left MCA territory increase the likelihood of persistent sensorimotor dysfunction (Roof et al 2001). This is because distal MCA occlusion in rats is more commonly associated with cortical damage alone, whereas endovascular occlusion of the proximal MCA typically results in extensive brain damage in the cerebral cortex as well as the caudate-putamen (Roof et al 2001). Damage to the latter most likely contributes to persistent sensorimotor deficits after stroke (Reep et al 2004).…”

Improvements of the Stroke Model Guidelines Animal body weight and long-term functional concerns

“…Moreover, such long-term studies have been highly recommended during the Stroke Therapy Academic Industry Roundtable (Fisher et al 2007;Green 2002;1999;Wahlgren & Ahmed 2004). Indeed, as in clinical practice (Rothrock et al 1995), animals display a certain degree of spontaneous recovery within the short time after experimental cerebral ischemia (Hunter et al 1998;Roof et al 2001;Zausinger et al 2000;Zhang et al 2000). Although more demanding sensorimotor and cognitive tasks are powerful to reveal tiny deficits, long-term studies addressing such behaviors are unfortunately less abundant.…”