A novel therapeutic derived from apolipoprotein E reduces brain inflammation and improves outcome after closed head injury

Lynch, John; Wang, Haichen; Mace, Brian; Leinenweber, Stephen; Warner, David S.; Bennett, Ellen; Vitek, Michael P.; McKenna, Suzanne; Laskowitz, Daniel T.

doi:10.1016/j.expneurol.2004.11.014

Cited by 121 publications

(103 citation statements)

References 26 publications

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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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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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“…COG133, a peptide based on apoE amino acid residues 133-149, has been reported to demonstrate neuroprotective, antioxidant, anti-excitotoxic, and antiinflammatory properties in vitro and in vivo (Aono et al, 2003;Laskowitz et al, 2001;Lynch et al, 2003Lynch et al, ,2005McAdoo et al, 2005;Misra et al, 2001). Subsequently, COG1410 was developed, composed of apoE residues 138-149, with aminoisobutyric acid (Aib) substitutions at positions 140 and 145 (Laskowitz et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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

Jiang

Brody

2012

Journal of Neurotrauma

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Traumatic axonal injury (TAI) accounts for at least 35% of the morbidity and mortality in traumatic brain injury (TBI) patients without space-occupying lesions. It is also believed to be a key determinant of adverse outcomes such as cognitive dysfunction across the spectrum of TBI severity. Previous studies have shown that COG1410, a synthetic peptide derived from the apolipoprotein E (apoE) receptor binding region, has anti-inflammatory effects after experimental TBI, with improvements in cognitive recovery. However, the effects of COG1410 on axonal injury following TBI are not known. The current study evaluated the effects of 1 mg/kg daily COG1410 versus saline administered intravenously starting 30 min after controlled cortical impact (CCI) injury on pericontusional TAI in young, wild-type C57BL6/J male mice. We found that COG1410 did not affect the number of amyloid precursor protein (APP)-immunoreactive axonal varicosities in the pericontusional corpus callosum and external capsule at 24 h, but reduced APP-immunoreactive varicosities by 31% at 3 days ( p = 0.0023), and 36% at 7 days ( p = 0.0009). COG1410 significantly reduced the number of Iba1-positive cells with activated microglial morphology at all three time points by 21-30%. There was no effect of COG1410 on pericontusional white matter volume or silver staining at any time point. This indicates a possible effect of COG1410 on delayed but not immediate TAI. Future studies are needed to investigate the underlying mechanisms, therapeutic time window, and physiological implications of this effect.

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“…A recently developed technique uses a calibrated, stereotactically guided, pneumatic impact to the closed skull. 10,[55][56][57] Indeed, more clinically relevant injuries are produced, along with the resultant short-term neurologic and longerterm cognitive deficits. 58 Statins have demonstrated benefit in a variety of animal TBI models.…”

Section: Preclinical Models Of Acute Brain Injurymentioning

confidence: 99%

Statins in Traumatic Brain Injury

Wible

Laskowitz

2010

Neurotherapeutics

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Summary: Traumatic brain injury (TBI) is a common cause of long-term neurological morbidity, with devastating personal and societal consequences. At present, no pharmacological intervention clearly improves outcomes, and therefore a compelling unmet clinical need remains. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or "statins," offer a potential novel therapeutic strategy for TBI. Statins are well tolerated, easy to administer, and have a long clinical track record in critically ill patients. Their side effects are well defined and easily monitored. Preclinical studies have shown significant benefit of statins in models of TBI and related disease processes, including cerebral ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage. In fact, multiple mechanisms have been defined by which statins may exert benefit after acute brain injury. Statins are currently positioned to be translated into clinical trials in acute brain injury and have the potential to improve outcomes after TBI.

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A novel therapeutic derived from apolipoprotein E reduces brain inflammation and improves outcome after closed head injury

Cited by 121 publications

References 26 publications

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

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

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

Statins in Traumatic Brain Injury

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