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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1-12 |
| Number of pages | 12 |
| Journal | Translational Stroke Research |
| DOIs | |
| State | Accepted/In press - Apr 5 2017 |
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Keywords
- CpG ODN
- Ischemia
- Neuroprotection
- Nonhuman primate
- Preconditioning
- Stroke
ASJC Scopus subject areas
- Neuroscience(all)
- Clinical Neurology
- Cardiology and Cardiovascular Medicine
Cite this
Preclinical Development of a Prophylactic Neuroprotective Therapy for the Preventive Treatment of Anticipated Ischemia-Reperfusion Injury. / Bahjat, Frances; Alexander West, G.; Kohama, Steven; Glynn, Christine; Urbanski, Henryk; Hobbs, Theodore; Earl, Eric; Stevens, Susan L.; Stenzel-Poore, Mary.
In: Translational Stroke Research, 05.04.2017, p. 1-12.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Preclinical Development of a Prophylactic Neuroprotective Therapy for the Preventive Treatment of Anticipated Ischemia-Reperfusion Injury
AU - Bahjat, Frances
AU - Alexander West, G.
AU - Kohama, Steven
AU - Glynn, Christine
AU - Urbanski, Henryk
AU - Hobbs, Theodore
AU - Earl, Eric
AU - Stevens, Susan L.
AU - Stenzel-Poore, Mary
PY - 2017/4/5
Y1 - 2017/4/5
N2 - 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.
AB - 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.
KW - CpG ODN
KW - Ischemia
KW - Neuroprotection
KW - Nonhuman primate
KW - Preconditioning
KW - Stroke
UR - http://www.scopus.com/inward/record.url?scp=85017100478&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85017100478&partnerID=8YFLogxK
U2 - 10.1007/s12975-017-0532-8
DO - 10.1007/s12975-017-0532-8
M3 - Article
SP - 1
EP - 12
JO - Translational Stroke Research
JF - Translational Stroke Research
SN - 1868-4483
ER -