A new primate model of focal stroke: endothelin-1-induced middle cerebral artery occlusion and reperfusion in the common marmoset.
The purpose of the present set of studies was to develop a new primate model of focal ischemia with reperfusion for long-term functional assessment in the common marmoset. Initially, the cerebral vascular anatomy of the marmoset was interrogated by Araldite-cast and ink-perfusion methods to determine the feasibility of an intravascular surgical approach. The methods showed that the internal carotid artery was highly tortuous in its passage, precluding the development of an extracranial method of inducing temporary middle cerebral artery occlusion in the marmoset. A pilot dose-response study investigated an intracranial approach of topically applying endothelin-1 (ET-1) to the M2 portion of the middle cerebral artery in a small sample of marmosets for up to 6 hours (n = 2 or 3 per group). Dose-dependent reductions in middle cerebral artery vessel caliber followed by gradual reperfusion were inversely related to increases in corrected lesion volume after ET-1 treatment, relative to vehicle control application. Finally, the functional consequences of ET-1-induced lesions to the M2 vascular territory were assessed up to 24 hours after surgery using the optimal dose established in the pilot study (2.5 nmol/25 microL). ET-1-treated marmosets (n = 4) showed marked contralateral motor deficits in grip strength and retrieval of food rewards and contralateral sensory/motor neglect towards tactile stimulation, relative to their ipsilateral side and vehicle-treated marmosets (n = 4). Strong correlations were shown between contralateral impairments and histopathologic parameters, which revealed unilateral putamen and cortical damage to the middle cerebral artery territory. No deficits were shown on general mobility, and self-care was promptly resumed in ET-1 marmosets after surgery. These results show that this novel model of ischemia with reperfusion in the marmoset has the potential to assess long-term function and to gauge the efficacy of novel therapeutic strategies targeted for clinical stroke.
Virley
David
D
Neurology and GI CEDD, GlaxoSmithKline Pharmaceuticals, Harlow, Essex, United Kingdom. David_J_Virley@gsk.com
Hadingham
Sarah J
SJ
Roberts
Jenny C
JC
Farnfield
Belinda
B
Elliott
Heather
H
Whelan
Greg
G
Golder
Jackie
J
David
Chris
C
Parsons
Andrew A
AA
Hunter
A Jackie
AJ
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000473:pathology; D002144:Callithrix; D003216:Conditioning, Operant / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology*; D004853:Epoxy Resins; D005260:Female; D005552:Forelimb / Q000502:physiology; D018737:Hand Strength / Q000502:physiology; D006614:Hindlimb / Q000502:physiology; D020244:Infarction, Middle Cerebral Artery / Q000139:chemically induced* / Q000473:pathology* / Q000523:psychology; D008297:Male; D010477:Perfusion; D010796:Phthalic Anhydrides; D010812:Physical Stimulation; D010865:Pilot Projects; D012018:Reflex / Q000502:physiology; D015427:Reperfusion Injury / Q000473:pathology* / Q000523:psychology; D012201:Reward; D020521:Stroke / Q000503:physiopathology* / Q000523:psychology; D014828:Vocalization, Animal / Q000502:physiology
D019332:Endothelin-1; D004853:Epoxy Resins; D010796:Phthalic Anhydrides; C005752:araldite