title: Preclinical Development of a Prophylactic Neuroprotective Therapy for the Preventive Treatment of Anticipated Ischemia-Reperfusion Injury.
abstract: Ischemia-reperfusion brain injury can be iatrogenically induced secondary to life-saving procedures. Prophylactic treatment of these patients offers a promising prevention for lifelong complications. We postulate that a cytosine-guanine (CpG) oligodeoxynucleotide (ODN) can provide robust antecedent protection against cerebral ischemic injury with minimal release of pro-inflammatory cytokines, making it an ideal candidate for further clinical development. Mouse and nonhuman primate (NHP) models of cerebral ischemic injury were used to test whether an A-type CpG ODN, which induces minimal systemic inflammatory cytokine responses, can provide prophylactic protection. Extent of injury in the mouse was measured by histological staining of live tissue. In the NHP, injury was assessed 2 and 7 days post-occlusion from T2-weighted magnetic resonance images and neurological and motor deficits were cataloged daily. Plasma cytokine levels were measured using species-specific Luminex assays. Prophylactic administration of an A-type CpG ODN provided robust protection against cerebral ischemic injury in the mouse with minimal systemic inflammation. Rhesus macaques treated with D192935, a mixture of human optimized A-type CpG ODNs, had smaller infarcts and demonstrated significantly less neurological and motor deficits following ischemic injury. Our findings demonstrate the translational potential of D192935 as a prophylactic treatment for patients at risk of cerebral ischemic injury.
authors.affiliation: Department of Molecular Microbiology and Immunology, L220, Oregon Health and Science University, 3181 Sam Jackson Park Road, Portland, Oregon, 97239, USA.
authors.forename: Frances Rena
authors.initials: FR
authors.lastname: Bahjat
authors.affiliation: Houston Methodist Neurosurgery, Houston, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Alexander West
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Kohama
authors.affiliation: Department of Molecular Microbiology and Immunology, L220, Oregon Health and Science University, 3181 Sam Jackson Park Road, Portland, Oregon, 97239, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Glynn
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, USA.
authors.forename: Henryk F
authors.initials: HF
authors.lastname: Urbanski
authors.affiliation: Division of Animal Resources, Oregon National Primate Research Center, Beaverton, OR, USA.
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Hobbs
authors.affiliation: Advanced Imaging Research Center, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Earl
authors.affiliation: Department of Molecular Microbiology and Immunology, L220, Oregon Health and Science University, 3181 Sam Jackson Park Road, Portland, Oregon, 97239, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Stevens
authors.affiliation: Department of Molecular Microbiology and Immunology, L220, Oregon Health and Science University, 3181 Sam Jackson Park Road, Portland, Oregon, 97239, USA. poorem@ohsu.edu.
authors.forename: Mary P
authors.initials: MP
authors.lastname: Stenzel-Poore
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D020520:Brain Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000209:etiology; D002545:Brain Ischemia / Q000517:prevention & control*; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009460:Neurologic Examination; D018696:Neuroprotective Agents / Q000737:chemistry / Q000627:therapeutic use*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000627:therapeutic use*; D010805:Physical Conditioning, Animal / Q000502:physiology; D015427:Reperfusion Injury / Q000150:complications / Q000517:prevention & control*; D013997:Time Factors
chemical_list: D016207:Cytokines; D018696:Neuroprotective Agents; D009838:Oligodeoxyribonucleotides
keywords: CpG ODN; Ischemia; Neuroprotection; Nonhuman primate; Preconditioning; Stroke