Evolution of ischemic damage and behavioural deficit over 6 months after MCAo in the rat: Selecting the optimal outcomes and statistical power for multi-centre preclinical trials.
Key disparities between the timing and methods of assessment in animal stroke studies and clinical trial may be part of the reason for the failure to translate promising findings. This study investigates the development of ischemic damage after thread occlusion MCAo in the rat, using histological and behavioural outcomes. Using the adhesive removal test we investigate the longevity of behavioural deficit after ischemic stroke in rats, and examine the practicality of using such measures as the primary outcome for future studies. Ischemic stroke was induced in 132 Spontaneously Hypertensive Rats which were assessed for behavioural and histological deficits at 1, 3, 7, 14, 21, 28 days, 12 and 24 weeks (n>11 per timepoint). The basic behavioural score confirmed induction of stroke, with deficits specific to stroke animals. Within 7 days, these deficits resolved in 50% of animals. The adhesive removal test revealed contralateral neglect for up to 6 months following stroke. Sample size calculations to facilitate the use of this test as the primary experimental outcome resulted in cohort sizes much larger than are the norm for experimental studies. Histological damage progressed from a necrotic infarct to a hypercellular area that cleared to leave a fluid filled cavity. Whilst absolute volume of damage changed over time, when corrected for changes in hemispheric volume, an equivalent area of damage was lost at all timepoints. Using behavioural measures at chronic timepoints presents significant challenges to the basic science community in terms of the large number of animals required and the practicalities associated with this. Multicentre preclinical randomised controlled trials as advocated by the MultiPART consortium may be the only practical way to deal with this issue.
Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, Austin Campus, Heidelberg, Australia.
Sarah S J
http://orcid.org/0000-0002-4754-6524
SS
Rewell
Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, Austin Campus, Heidelberg, Australia.
Leonid
L
Churilov
Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, Austin Campus, Heidelberg, Australia.
T Kate
TK
Sidon
Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, Austin Campus, Heidelberg, Australia.
Elena
E
Aleksoska
Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, Austin Campus, Heidelberg, Australia.
Susan F
SF
Cox
Department of Clinical Neurosciences, University of Edinburgh, Edinburgh, United Kingdom.
Malcolm R
MR
Macleod
Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, Austin Campus, Heidelberg, Australia.|University of Tasmania, School of Medicine, Faculty of Health, Hobart, Australia.
David W
DW
Howells
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology* / Q000503:physiopathology*; D003627:Data Interpretation, Statistical; D004195:Disease Models, Animal; D018450:Disease Progression; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000175:diagnosis / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D015337:Multicenter Studies as Topic / Q000379:methods / Q000706:statistics & numerical data; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000706:statistics & numerical data; D051381:Rats; D011918:Rats, Inbred SHR; D012107:Research Design; D020521:Stroke / Q000150:complications / Q000175:diagnosis / Q000473:pathology* / Q000503:physiopathology*