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 life-long complications. We postulate that a 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 D19293 5 as a prophylactic treatment for patients at risk of cerebral ischemic injury.

CpG preconditioning reduces accumulation of lysophosphatidylcholine in ischemic brain tissue after middle cerebral artery occlusion

“…The fact that TLRs are known to be involved in ischemia indicates their stimulation prior to ischemic stroke can provide neuroprotection [10]. In particular, systemic administration of CpG has been shown to provide neuroprotection against subsequent ischemic brain injury [10][11][12]. Although the exact mechanisms that follow pharmacological preconditioning are not fully understood, encouraging findings of mediated damage have been reported after prophylactic treatments [11].…”

Ischemic preconditioning induces cortical microglial proliferation and a transcriptomic program of robust cell cycle activation

“…Genomic approaches to IPC have demonstrated a striking array of gene expression changes in mouse cortex following a preconditioning stimulus (Stenzel-Poore et al, 2004). Identifying key molecular and cellular mediators for IPC has important translational implications for progress in development of effective therapeutics for human stroke patients (Anrather & Iadecola, 2016;Bahjat et al, 2017;McDonough & Weinstein, 2016).…”

Chick Embryo: A Preclinical Model for Understanding Ischemia-Reperfusion Mechanism

“…Although many notable drug development achievements have been made in the last two decades in ischemic research, a key challenge in drug candidate screening is the lack of a suitable screening model, which can translate preclinical drug candidates into clinical success ( Andreadou et al, 2008 ; Bahjat et al, 2017 ). In this study, we critically evaluated the role anti-oxidative, anti-ischemic, and anti-inflammatory drugs after 6 h of I/R.…”