Neurological sequelae and long-term behavioural assessment of rats with transient middle cerebral artery occlusion
Introduction
Animal models have provided useful insights into the pathophysiology of stroke and played an influential role in the development of treatment strategies (Ginsberg, 1996). Middle cerebral artery occlusion (MCAo), the most commonly used model for cerebral ischaemic stroke in rats, represents the most prevalent (60%) form of stroke in humans (American Heart Association, 1998). However, recent reviews (Hunter et al., 1995, Hunter et al., 1998, Ginsberg, 1996, Grotta, 1996, Hossman, 1997, Corbett and Nurse, 1998, de Keyser et al., 1999, Muir and Grosset, 1999, STAIR, 1999) of the failure of pharmacological agents to improve stroke outcomes in clinical trials have pinpointed the problems in translating experimental animal studies to clinical applications for humans. One of the problems of these pre-clinical studies is the lack of long-term functional assessment. Long-term studies are important to determine if the effects of the treatments have significance for functional outcome and ideally a battery of tests should evaluate a variety of functional parameters relevant to the damage.
Functional impairment after stroke in rats can be divided into transient neurological deficits and long-term motor and cognitive dysfunctions. Evaluation of short- and long-term deficits provide complementary information. A variety of subjective neurological scoring systems are used at present to assess rats with MCAo damage for short periods of time and as outcome measures of treatment (Bederson et al., 1986, Capdeville et al., 1986, Menzies et al., 1992, Wahl et al., 1992, Garcia et al., 1995, Rogers et al., 1997, de Courten Myers et al., 1998, Hunter et al., 2000). However, animals typically show spontaneous recovery on these scales and therefore their predictive value for long-term outcomes is questionable. Neurological scores can, nevertheless, perform two functions, namely a global assessment of general post-surgical impairment and induction of stroke-specific dysfunction. Both of these can be used to assign animals to groups and to discriminate between general surgical and ischaemic trauma. A sham-operated group undergoing the same procedures as the MCAo group without the occlusion is also a prerequisite to disentangle the effects of the surgery per se and the damage caused by the occlusion.
Long-term testing of motor and cognitive deficits may indicate whether a treatment is likely to improve functional outcome. However, one of the major problems of behavioural testing after stroke is that animals (and humans alike) show spontaneous recovery on some tests. Several studies (Markgraf et al., 1992, Grabowski et al., 1993, Borlongan and Sanberg, 1995, Okada et al., 1995, Yonemori et al., 1996, Rogers et al., 1997, Sakai et al., 1996, Smith et al., 1997, Stroemer et al., 1998, Ward et al., 1999, Hunter et al., 2000) previously used a variety of tests to assess permanent or transient MCAo damage at various time points (mostly<1 month). To evaluate the effects of treatment on functional outcome, a battery of tests charting impairment resistant to spontaneous recovery will be necessary to determine possible beneficial or detrimental effects. A battery of tests evaluating impairments of several functions is necessary since MCAo damages various anatomical and functional regions of the brain (striatum, somatosensory and motor cortices) which can be affected differentially by the treatments.
Post-operative procedures are presented here to maximize long-term survival, the neurological scoring procedures that allow one to determine which animals will be included or excluded in the treatment groups, and the battery of tests used to assess long-term functional deficits after MCAo.
Section snippets
Materials and methods
All procedures were in accordance with the requirements of the United Kingdom Animals (Scientific Procedures) Act of 1986 and the ethical review process of the Institute of Psychiatry, University of London.
Duration of post-operative care
The duration of post-operative care in single housing was determined chiefly by rate of weight recovery. Control animals recovered faster than rats with occlusion of the middle cerebral artery. On average control animals spent significantly (t=4.368, P<0.001, df=78) fewer days to recover from surgery (7 days on average) compared to MCAo animals (10 days on average).
Food intake and defecation
Although food intake and defecation were estimated by rating rather than measuring, they provided useful insights into the
Discussion
The failure of recent clinical trials for stroke treatments have led to criticisms of the validity and usefulness of animal models for pre-clinical studies. Some of the suggestions for improving pre-clinical experiments include longer survival times and functional assessment (STAIR, 1999). A method for long-term functional assessment of rats with transient MCAo consists of two phases, firstly a good post-operative recovery regime is necessary to ensure long-term survival with neurological
Acknowledgements
MM was supported by scholarships from NATO and the Ministère de l'Education Nationale du Luxembourg. This study was sponsored by ReNeuron Ltd.
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