COG1410, a novel apolipoprotein‐E mimetic, improves functional and morphological recovery in a rat model of focal brain ischemia

Abstract

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.

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

“…However, these peptides were limited by their relatively larger size, resulting in lower CNS penetration and higher cost of production. CN‐105, our current apoE‐mimetic pentapeptide, retains the beneficial neuroprotective effect in ischemic stroke observed in other apoE‐mimetic peptides31, 32 and possesses increased CNS penetration and potency 35…”

“…To overcome this limitation, smaller apoE‐mimetic peptides, derived from the helical receptor binding region of apoE, have been developed that retain the functional effects of the holoprotein on receptor binding29 in reducing inflammation17 and neuronal excitotoxicity 30. Moreover, these apoE‐mimetic compounds have demonstrated long‐term functional and histological improvements in preclinical models of ischemic stroke31, 32 and numerous other acute CNS injuries33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 (Table 1). …”

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

“…This duplicates the anti-inflammatory action of complete apoE . Examples include traumatic brain injury (Lynch et al, 2005;Laskowitz et al, 2007;Hoane et al, 2009;Kaufman et al, 2010), stroke (Tukhovskaya et al, 2009), and AD (Vitek et al, 2012). Cramer et al (2012) describe removal of A␤ plaque and correction of functional deficits in a strain of mice prone to AD-like changes after oral administration of bexarotene, an anti-tumor drug in clinical use.…”

Administration of COG1410 Reduces Axonal Amyloid Precursor Protein Immunoreactivity and Microglial Activation after Controlled Cortical Impact in Mice

“…COG1410 reportedly retains most of the properties of COG133, and expands the therapeutic window to 120 min post-experimental TBI. The effects of COG1410 have been assessed based on vestibulomotor function, microglial activation, neuronal cell death in the hippocampus, and neurodegenerative pathology (Hoane et al, 2009;James et al, 2009;Laskowitz et al, 2010;Tukhovskaya et al, 2009).…”