cog1410 and Infarction--Middle-Cerebral-Artery

Growing clinical evidence implicates isoform-specific effects of apolipoprotein E (apoE) in reducing neuroinflammation and mediating adaptive responses following ischemic and traumatic brain injury. However, the intact apoE holoprotein does not cross the blood-brain barrier and thus has limited therapeutic potential. We have created a small peptide, COG1410 (acetyl-AS-Aib-LRKL-Aib-KRLL-amide), derived from the apoE receptor-binding region. COG1410 retains the anti-inflammatory and neuroprotective biological properties of the intact holoprotein and penetrates the blood-brain barrier. In the current study, we utilized a murine model of transient focal cerebral ischemia and reperfusion to demonstrate that intravenous (IV) administration of COG1410 reduces infarct volume and radiographic progression of infarct, and improves functional outcome as assessed by rotarod when delivered up to 4h after ischemia onset.

Topics: Analysis of Variance; Animals; Apolipoproteins E; Brain Edema; Brain Infarction; Chromatography, Liquid; Disease Models, Animal; Encephalitis; Functional Laterality; Gene Expression Regulation; Infarction, Middle Cerebral Artery; Magnetic Resonance Imaging; Male; Mass Spectrometry; Mice; Mice, Inbred C57BL; Movement Disorders; Recovery of Function; RNA, Messenger; Time Factors; Tumor Necrosis Factor-alpha

Apolipoprotein E (apoE) is the primary apolipoprotein synthesized in the brain in response to injury with known neuroprotective effects exerted through antioxidant, antiinflammatory, antiexcitotoxic, and neurotrophic mechanisms. We have previously demonstrated that COG1410, an apoE mimetic peptide, exerts neuroprotective and antiinflammatory effects in a murine model of traumatic brain injury (TBI). As in TBI, ischemia-reperfusion injury is a component of acute stroke, which displays a pharmacogenetic association with the APOE4 gene. Using an intraluminal middle cerebral occlusion (MCAO) model in rats, we found that a single intravenous injection of COG1410 at 120 min post-MCAO significantly improved vestibulomotor function, decreased poststroke locomotor asymmetry, and decreased infarct volume of the ipsilateral hemisphere. These results support further exploration of a novel apoE-mimetic peptide, COG1410, as a therapeutic treatment for stroke.

Topics: Animals; Apolipoproteins E; Brain; Disease Models, Animal; Infarction, Middle Cerebral Artery; Ketamine; Male; Motor Activity; Postural Balance; Rats; Rats, Sprague-Dawley