Abstract
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-RQIKIWFQNRRMKWKKCLRVRLASHLRKLRKRLL-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.
Footnotes
This work is supported in part by the National Institutes of Health National Institute of Neurological Diseases and Stroke [Grants NS052920, NS061392, NS058239]; the National Institutes of Health National Cancer Institute [Grant CA141819]; and the National Institutes of Health National Institute of Aging [Grant AG020473].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.167882.
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ABBREVIATIONS:
- Antp
- antennapedia
- apoE
- apolipoprotein E
- DRG
- dorsal root ganglion
- GAP-43
- growth-associated protein 43
- LDL
- low-density lipoprotein
- LPS
- lipopolysaccharide
- LRP
- low-density lipoprotein receptor-related protein
- MS
- multiple sclerosis
- NGF
- nerve growth factor
- NO
- nitric oxide
- P0
- peripheral myelin protein zero
- PTD
- protein transduction domain
- SFI
- sciatic functional index
- TNF-α
- tumor necrosis factor-α
- TBI
- traumatic brain injury
- Fmoc
- 9-fluorenylmethoxycarbonyl
- PCR
- polymerase chain reaction
- ANOVA
- analysis of variance
- FBS
- fetal bovine serum
- PBS
- phosphate-buffered saline
- DMEM
- Dulbecco's modified Eagle's medium
- DiI
- 3,3′-dioctadecylindocarbocyanine
- IT
- immediate treatment
- DT
- delayed treatment
- COG112
- (acetyl-RQIKIWFQNRRMKWKKCLRVRLASHLRKLRKRLL-amide)
- COG133
- acetyl-LRVRLASHLRKLRKRLL-amide
- COG112-DT
- delayed treatment with COG112
- COG112-IT
- immediate treatment with COG112.
- Received March 4, 2010.
- Accepted April 19, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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