title: Proof of concept: pharmacological preconditioning with a Toll-like receptor agonist protects against cerebrovascular injury in a primate model of stroke.
abstract: Cerebral ischemic injury is a significant portion of the burden of disease in developed countries; rates of mortality are high and the costs associated with morbidity are enormous. Recent therapeutic approaches have aimed at mitigating the extent of damage and/or promoting repair once injury has occurred. Often, patients at high risk of ischemic injury can be identified in advance and targeted for antecedent neuroprotective therapy. Agents that stimulate the innate pattern recognition receptor, Toll-like receptor 9, have been shown to induce tolerance (precondition) to ischemic brain injury in a mouse model of stroke. Here, we demonstrate for the first time that pharmacological preconditioning against cerebrovascular ischemic injury is also possible in a nonhuman primate model of stroke in the rhesus macaque. The model of stroke used is a minimally invasive transient vascular occlusion, resulting in brain damage that is primarily localized to the cortex and as such, represents a model with substantial clinical relevance. Finally, K-type (also referred to as B-type) cytosine-guanine-rich DNA oligonucleotides, the class of agents employed in this study, are currently in use in human clinical trials, underscoring the feasibility of this treatment in patients at risk of cerebral ischemia.
authors.affiliation: Department of Molecular Microbiology and Immunology, Oregon Health and Science University, 3181 Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Frances Rena
authors.initials: FR
authors.lastname: Bahjat
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Williams-Karnesky
authors.forename: Steven G
authors.initials: SG
authors.lastname: Kohama
authors.forename: G Alexander
authors.initials: GA
authors.lastname: West
authors.forename: Kristian P
authors.initials: KP
authors.lastname: Doyle
authors.forename: Maxwell D
authors.initials: MD
authors.lastname: Spector
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Hobbs
authors.forename: Mary P
authors.initials: MP
authors.lastname: Stenzel-Poore
mesh_terms: D000818:Animals; D004247:DNA / Q000627:therapeutic use; D004195:Disease Models, Animal; D019194:Ischemic Preconditioning / Q000379:methods*; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use*; D020127:Recovery of Function / Q000187:drug effects; D020521:Stroke / Q000473:pathology / Q000517:prevention & control*; D051193:Toll-Like Receptors / Q000819:agonists*
chemical_list: C423449:CpG ODN 1826; D009838:Oligodeoxyribonucleotides; D051193:Toll-Like Receptors; D004247:DNA