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Gauging recovery after hemorrhagic stroke in rats: implications for cytoprotection studies

Gauging recovery after hemorrhagic stroke in rats: implications for cytoprotection studies,Crystal L MacLellan,Angela M Auriat,Steven C McGie,Reginia

Gauging recovery after hemorrhagic stroke in rats: implications for cytoprotection studies   (Citations: 28)
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Successful clinical translation of prospective cytoprotectants will likely occur only with treatments that improve functional recovery in preclinical (rodent) studies. Despite this assumption, many rely solely on histopathologic end points or the use of one or two simple behavioral tests. Presently, we used a battery of tests to gauge recovery after a unilateral intracerebral hemorrhagic stroke (ICH) targeting the striatum. In total, 60 rats (N = 15 per group) were stereotaxically infused with 0 (SHAM), 0.06 (MILD lesion), 0.12 (MODERATE lesion), or 0.18 U (SEVERE lesion) of bacterial collagenase. This created a range of injury akin to moderate (from SEVERE to MODERATE or MODERATE to MILD lesion size B30% reduction) and substantial cytoprotection (SEVERE to MILD lesion size—51% reduction). Post-ICH functional testing occurred over 30 days. Tests included the horizontal ladder and elevated beam tests, swimming, limb-use asymmetry (cylinder) test, a Neurologic Deficit Scale, an adhesive tape removal test of sensory neglect, and the staircase and single pellet tests of skilled reaching. Most tests detected significant impairments (versus SHAM), but only a few (e.g., staircase) frequently distinguished among ICH groups and none consistently differentiated among all ICH groups. However, by using a battery of tests we could behaviorally distinguish groups. Thus, preclinical testing would benefit from using a battery of behavioral tests as anything less may miss treatment effects. Such testing must be based on factors including the type of lesion, the
Conference: JSAI Workshops , 2006
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    • ...

      The behavioral method most commonly used after striatal ICH in rats (...

    Crystal L MacLellanet al. A critical appraisal of experimental intracerebral hemorrhage research

    • ...We used the collagenase model of ICH because it results in consistent hemorrhaging and functional impairment (MacLellan et al., 2006)...
    • ...Collagenase infusion caused significant striatal injury with some ventriculomegaly at a 46 day survival as illustrated in other publications (MacLellan et al., 2006)...
    • ...Impairments in skilled reaching often follow stroke in humans (Jorgensen et al., 1995b) as also occurs in rodent stroke models (Kleim et al., 2007), including ICH (MacLellan et al., 2006; Peeling et al., 2001a)...
    • ...Previous work has established that this test, which measures forelimb reaching ability, is sensitive to motor system injury (Montoya et al., 1991), including striatal ICH (MacLellan et al., 2006)...
    • ...This test is persistently sensitive to motor system damage, including ICH (Auriat et al., 2006; MacLellan et al., 2006)...
    • ...both. Independent forelimb use was expressed as % contralateral use=(contralateral contacts/contralateral contacts+ ipsilateral contacts)×100 (Auriat et al., 2006; MacLellan et al., 2006)...
    • ...The cylinder test measures spontaneous forelimb usage, which is persistently altered by damage to the motor system (Schallert, 2006) including ICH (MacLellan et al., 2006)...
    • ...We have found that this model of ICH, developed by Rosenberg et al., results in consistenthemorrhaging withinthestriatum(MacLellan etal., 2006; Rosenberg et al., 1990)...
    • ...The volume of each hemisphere was calculated as: (average area of complete coronal section of the hemisphere −area of damage −area of ventricle)×interval between sections×number of sections (MacLellan et al., 2006)...

    Angela M. Auriatet al. Delayed rehabilitation lessens brain injury and improves recovery afte...

    • ...Autologous blood (Bullock et al, 1984; MacLellan et al, 2006b, c) (100mL taken from the tail within 60 secs of infusion) or bacterial collagenase (MacLellan et al, 2006a; Rosenberg et al, 1990) (0.2 U in 1.0mL sterile saline) was infused into the striatum over 10 mins...
    • ...Behavior was assessed the day before ICH and from 1 day to 1 month after ICH using a Neurological Deficit Scale that included tests of spontaneous circling, contralateral forelimb flexion, hindlimb retraction, beam walking ability, and bilateral forepaw grasp (MacLellan et al, 2006a)...
    • ...Recovery from the initial functional impairment was considerably more gradual and incomplete in the collagenase model (MacLellan et al, 2006a, b, c) despite similar impairment at the outset...

    Crystal L MacLellanet al. Intracerebral hemorrhage models in rat: comparing collagenase to blood...

    • ...Finally, neurological recovery was evaluated by several simple tests (e.g., balance) that combined formed a neurological defi cit scale (NDS) score (MacLellan et al., 2006a,b)...
    • ...A score of 0 represented no deficit whereas 11 represented maximum impairment (MacLellan et al., 2006a,b)...
    • ...Finally, systemic and brain-selective cooling reduces edema after intracerebral hemorrhage in rats (Fingas et al., 2007; MacLellan et al., 2006a,b), but in these studies this effect did not detectably improve functional or histological outcome...
    • ...A possible explanation for the lack of a significant treatment effect is that the severe injury caused by pMCAO resulted in bilateral impairments, which would reduce asymmetry scores, as occurs transiently after large striatal hemorrhagic lesions (MacLellan et al., 2006a,b)...
    • ...However, a recent striatal hemorrhage studyalso found this test does not always distinguish among variations in lesion size (MacLellan et al., 2006a,b)...

    Darren L. Clarket al. Comparison of 12, 24 and 48 h of systemic hypothermia on outcome after...

    • ...2006c) (100 μL taken from the tail within 60 secs of infusion) or bacterial collagenase (...

    Crystal L MacLellanet al. Intracerebral hemorrhage models in rat: comparing collagenase to blood...

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