Long-term behavioral assessment of function in an experimental model for ischemic stroke.
Middle cerebral artery occlusion (MCAO) in rats is a well-studied experimental model for ischemic stroke leading to brain infarction and functional deficits. Many preclinical studies have focused on a small time window after the ischemic episode to evaluate functional outcome for screening therapeutic candidates. Short evaluation periods following injury have led to significant setbacks due to lack of information on the delayed effects of treatments, as well as short-lived and reversible neuroprotection, so called false-positive results. In this report, we evaluated long-term functional deficit for 90 days after MCAO in two rat strains with two durations of ischemic insult, in order to identify the best experimental paradigm to assess injury and subsequent recovery. Behavioral outcomes were measured pre-MCAO followed by weekly assessment post-stroke. Behavioral tests included the 18-point composite neurological score, 28-point neuroscore, rearing test, vibrissae-evoked forelimb placing test, foot fault test and the CatWalk. Brain lesions were assessed to correlate injury to behavior outcomes at the end of study. Our results indicate that infarction volume in Sprague-Dawley rats was dependent on occlusion duration. In contrast, the infarction volume in Wistar rats did not correlate with the duration of ischemic episode. Functional outcomes were not dependent on occlusion time in either strain; however, measurable deficits were detectable long-term in limb asymmetry, 18- and 28-point neuroscores, forelimb placing, paw swing speed, and gait coordination. In conclusion, these behavioral assays, in combination with an extended long-term assessment period, can be used for evaluating therapeutic candidates in preclinical models of ischemic stroke.
Behavioral and Functional Neuroscience Laboratory, Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford University School of Medicine, United States.
Angelo
A
Encarnacion
Nobutaka
N
Horie
Hadar
H
Keren-Gill
Tonya M
TM
Bliss
Gary K
GK
Steinberg
Mehrdad
M
Shamloo
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D002545:Brain Ischemia / Q000175:diagnosis* / Q000473:pathology / Q000503:physiopathology*; D004185:Disability Evaluation; D004195:Disease Models, Animal; D008297:Male; D009460:Neurologic Examination / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D020127:Recovery of Function / Q000502:physiology; D020521:Stroke / Q000175:diagnosis* / Q000473:pathology / Q000503:physiopathology*
J Neurosci Methods. 2009 Oct 30;184(1):95-103
19660497
Neuropharmacology. 2000 Mar 3;39(5):777-87
10699444
Stroke. 1986 May-Jun;17(3):472-6
3715945
Pediatr Res. 2005 Aug;58(2):297-301
16055937
Circulation. 2010 Feb 23;121(7):e46-e215
20019324
Brain Res. 1995 Mar 27;675(1-2):20-6
7796130
J Neurol. 2004 Apr;251(4):388-97
15083282
Stroke. 2009 Mar;40(3 Suppl):S136-8
19064784
Stroke. 2007 Feb;38(2 Suppl):840-5
17261749
Stroke. 2005 Sep;36(9):2000-5
16040589
Restor Neurol Neurosci. 2004;22(2):73-9
15272142
J Transl Med. 2009 Nov 17;7:97
19919699
Neuropathol Appl Neurobiol. 1998 Dec;24(6):487-97
9888159
Exp Brain Res. 1992;89(1):67-78
1601103
J Cereb Blood Flow Metab. 2008 Dec;28(12):1936-50
18628778
Stroke. 1995 Apr;26(4):627-34; discussion 635
7709410
Science. 1940 Nov 29;92(2396):515-6
17753921
Lab Anim. 2006 Jan;40(1):1-8
16460584
J Neurosci. 1995 Jul;15(7 Pt 2):5372-8
7623159
Brain Res. 2008 Sep 22;1231:103-12
18675262
Stroke. 1993 Jul;24(7):1072-5; discussion 1075-6
8322382
Hypertension. 1992 Jan;19(1):40-6
1730437
Neuropathol Appl Neurobiol. 2000 Jun;26(3):232-42
10886681
Brain Res. 2007 Jan 26;1130(1):181-7
17173875
J Cereb Blood Flow Metab. 2010 Apr;30(4):729-33
20068574
Exp Neurol. 2005 Oct;195(2):524-39
16051217
Brain Res. 1986 Nov 5;397(1):27-36
3801863
Exp Neurol. 2005 Feb;191(2):310-7
15649486
Brain Res. 1995 Dec 8;702(1-2):145-52
8846069
J Neurol Sci. 2000 Mar 15;174(2):141-6
10727700