A Novel apoE-Derived Therapeutic Reduces Vasospasm and Improves Outcome in a Murine Model of Subarachnoid Hemorrhage

Gao, Junling; Wang, Hai-Chen; Sheng, Huaxin; Lynch, John; Warner, David S.; Durham, Lori; Vitek, Michael P.; Laskowitz, Daniel T.

doi:10.1385/ncc:4:1:025

Cited by 79 publications

(73 citation statements)

References 31 publications

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“…The therapeutic efficacy of apoE-mimetics has been previously demonstrated in multiple animal models of a variety of neurological disorders, including TBI, MS, and subarachnoid hemorrhage (Lynch et al, 2005;Gao et al, 2006;Li et al, 2006). These beneficial effects are mostly associated with its neuroprotective activities.…”

Section: Discussionmentioning

confidence: 98%

An Apolipoprotein E-Mimetic Stimulates Axonal Regeneration and Remyelination after Peripheral Nerve Injury

Fowler²,

Neil³

et al. 2010

The Journal of Pharmacology and Experimental Therapeutics

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Elevated apolipoprotein E (apoE) synthesis within crushed sciatic nerves advocates that apoE could benefit axonal repair and reconstruction of axonal and myelin membranes. We created an apoE-mimetic peptide, COG112 (acetyl-RQIKIWFQNRRMK-WKKCLRVRLASHLRKLRKRLL-amide), and found that postinjury treatment with COG112 significantly improved recovery of motor and sensory function following sciatic nerve crush in C57BL/6 mice. Morphometric analysis of injured sciatic nerves revealed that COG112 promoted axonal regrowth after 2 weeks of treatment. More strikingly, the thickness of myelin sheaths was increased by COG112 treatment. Consistent with these histological findings, COG112 potently elevated growth associated protein 43 (GAP-43) and peripheral myelin protein zero (P0), which are markers of axon regeneration and remyelination, respectively. Electron microscopic examination further suggested that the apoE-mimetic COG112 may increase clearance of myelin debris. Schwann cell uptake of cholesterol-containing low-density lipoprotein particles was selectively enhanced by COG112 treatment in a Schwann cell line S16. Moreover, COG112 significantly promoted axon elongation in primary dorsal root ganglion cultures from rat pups. Considering that cholesterol and lipids are needed for reconstructing myelin sheaths and axon extension, these data support a hypothesis where supplementation with exogenous apoE-mimetics such as COG112 may be a promising strategy for restoring lost functional and structural elements following nerve injury.

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Section: Discussionmentioning

confidence: 98%

An Apolipoprotein E-Mimetic Stimulates Axonal Regeneration and Remyelination after Peripheral Nerve Injury

Fowler²,

Neil³

et al. 2010

The Journal of Pharmacology and Experimental Therapeutics

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“…L-37pA (DWLK-AFYDKVAEKLKEAF-P-DWLKAFYDKVAEKLKEAF) and D-37pA (i.e. D-amino acid version of 37pA) were synthesized by a solid-phase procedure as previously reported (10 In Vivo Exposures-Mice were injected intravenously (150 l in saline) with 20 mg/kg of L-4F or sc-4F peptide (control for L-4F), or with 1.2 mg/kg of COG1410 or 264 peptide (control for COG1410) 2 h prior to pulmonary exposures, similar to past reports (4,13). LPS exposure was by aerosol (300 g/ml, 20 min) and KC exposure by intratracheal delivery (0.25 or 0.5 g/60 l by oropharyngeal aspiration), both as previously described (15).…”

Section: Methodsmentioning

confidence: 97%

Apolipoproteins and Apolipoprotein Mimetic Peptides Modulate Phagocyte Trafficking through Chemotactic Activity

Madenspacher

Azzam

Gong

et al. 2012

Journal of Biological Chemistry

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Background:The anti-inflammatory properties of apolipoproteins are incompletely defined. Results: Apolipoprotein A-I and E mimetic peptides suppress CXCR2-dependent neutrophil migration in vivo. Mimetic L-37pA itself induces formyl peptide receptor-2-dependent chemotaxis. Conclusion: Apolipoprotein mimetics display complex structure-activity relationships to multiple chemotactic receptors. Significance: Apolipoproteins and their mimetics regulate leukocyte migration.

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“…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). …”

Section: Introductionmentioning

confidence: 99%

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

Kolls

Soderblom

et al. 2017

Ann Clin Transl Neurol

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ObjectiveAt present, the absence of a pharmacological neuroprotectant represents an important unmet clinical need in the treatment of ischemic and traumatic brain injury. Recent evidence suggests that administration of apolipoprotein E mimetic therapies represent a viable therapeutic strategy in this setting. We investigate the neuroprotective and anti‐inflammatory properties of the apolipoprotein E mimetic pentapeptide, CN‐105, in a microglial cell line and murine model of ischemic stroke.MethodsTen to 13‐week‐old male C57/BL6 mice underwent transient middle cerebral artery occlusion and were randomly selected to receive CN‐105 (0.1 mg/kg) in 100 μL volume or vehicle via tail vein injection at various time points. Survival, motor‐sensory functional outcomes using rotarod test and 4‐limb wire hanging test, infarct volume assessment using 2,3,5‐Triphenyltetrazolium chloride staining method, and microglial activation in the contralateral hippocampus using F4/80 immunostaining were assessed at various time points. In vitro assessment of tumor necrosis factor‐alpha secretion in a microglial cell line was performed, and phosphoproteomic analysis conducted to explore early mechanistic pathways of CN‐105 in ischemic stroke.ResultsMice receiving CN‐105 demonstrated improved survival, improved functional outcomes, reduced infarct volume, and reduced microglial activation. CN‐105 also suppressed inflammatory cytokines secretion in microglial cells in vitro. Phosphoproteomic signals suggest that CN‐105 reduces proinflammatory pathways and lower oxidative stress.Interpretation CN‐105 improves functional and histological outcomes in a murine model of ischemic stroke via modulation of neuroinflammatory pathways. Recent clinical trial of this compound has demonstrated favorable pharmacokinetic and safety profile, suggesting that CN‐105 represents an attractive candidate for clinical translation.

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A Novel apoE-Derived Therapeutic Reduces Vasospasm and Improves Outcome in a Murine Model of Subarachnoid Hemorrhage

Abstract: Consistent with the clinical literature, the apoE4 isoform is associated with an increased incidence of vasospasm and poor functional recovery after experimental SAH. An apoE-derived peptide represents a novel therapeutic approach for the treatment of SAH.

Cited by 79 publications

References 31 publications

An Apolipoprotein E-Mimetic Stimulates Axonal Regeneration and Remyelination after Peripheral Nerve Injury

An Apolipoprotein E-Mimetic Stimulates Axonal Regeneration and Remyelination after Peripheral Nerve Injury

Apolipoproteins and Apolipoprotein Mimetic Peptides Modulate Phagocyte Trafficking through Chemotactic Activity

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

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