PMID- 28972155 OWN - NLM STAT- MEDLINE DCOM- 20171219 LR - 20220331 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 292 IP - 45 DP - 2017 Nov 10 TI - Defining a mechanistic link between pigment epithelium-derived factor, docosahexaenoic acid, and corneal nerve regeneration. PG - 18486-18499 LID - 10.1074/jbc.M117.801472 [doi] AB - The cornea is densely innervated to sustain the integrity of the ocular surface. Corneal nerve damage produced by aging, diabetes, refractive surgeries, and viral or bacterial infections impairs tear production, the blinking reflex, and epithelial wound healing, resulting in loss of transparency and vision. A combination of the known neuroprotective molecule, pigment epithelium-derived factor (PEDF) plus docosahexaenoic acid (DHA), has been shown to stimulate corneal nerve regeneration, but the mechanisms involved are unclear. Here, we sought to define the molecular events of this effect in an in vivo mouse injury model. We first confirmed that PEDF + DHA increased nerve regeneration in the mouse cornea. Treatment with PEDF activates the phospholipase A(2) activity of the PEDF-receptor (PEDF-R) leading to the release of DHA; this free DHA led to enhanced docosanoid synthesis and induction of bdnf, ngf, and the axon growth promoter semaphorin 7a (sema7a), and as a consequence, their products appeared in the mouse tears. Surprisingly, corneal injury and treatment with PEDF + DHA induced transcription of neuropeptide y (npy), small proline-rich protein 1a (sprr1a), and vasoactive intestinal peptide (vip) in the trigeminal ganglia (TG). The PEDF-R inhibitor, atglistatin, blocked all of these changes in the cornea and TG. In conclusion, we uncovered here an active cornea-TG axis, driven by PEDF-R activation, that fosters axon outgrowth in the cornea. CI - (c) 2017 by The American Society for Biochemistry and Molecular Biology, Inc. FAU - Pham, Thang Luong AU - Pham TL AD - From the Department of Ophthalmology and Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, Louisiana 70112-2223. FAU - He, Jiucheng AU - He J AD - From the Department of Ophthalmology and Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, Louisiana 70112-2223. FAU - Kakazu, Azucena H AU - Kakazu AH AD - From the Department of Ophthalmology and Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, Louisiana 70112-2223. FAU - Jun, Bokkyoo AU - Jun B AD - From the Department of Ophthalmology and Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, Louisiana 70112-2223. FAU - Bazan, Nicolas G AU - Bazan NG AD - From the Department of Ophthalmology and Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, Louisiana 70112-2223. FAU - Bazan, Haydee E P AU - Bazan HEP AD - From the Department of Ophthalmology and Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, Louisiana 70112-2223 hbazan1@lsuhsc.edu. LA - eng GR - P30 GM103340/GM/NIGMS NIH HHS/United States GR - R01 EY019465/EY/NEI NIH HHS/United States PT - Comparative Study PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20170926 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Enzyme Inhibitors) RN - 0 (Eye Proteins) RN - 0 (Nerve Growth Factors) RN - 0 (Nerve Tissue Proteins) RN - 0 (Neuroprotective Agents) RN - 0 (Phenylurea Compounds) RN - 0 (Receptors, Neuropeptide) RN - 0 (Serpins) RN - 0 (atglistatin) RN - 0 (pigment epithelium-derived factor) RN - 0 (pigment epithelium-derived factor receptor) RN - 25167-62-8 (Docosahexaenoic Acids) SB - IM MH - Administration, Ophthalmic MH - Animals MH - Cornea/drug effects/*innervation/pathology/physiology MH - Docosahexaenoic Acids/administration & dosage/metabolism/*therapeutic use MH - Drug Therapy, Combination MH - Enzyme Inhibitors/administration & dosage/pharmacology MH - Eye Proteins/administration & dosage/agonists/antagonists & inhibitors/genetics/metabolism/pharmacology/*therapeutic use MH - Gene Expression Regulation/drug effects MH - Injections, Intraperitoneal MH - Male MH - Mice, Inbred C57BL MH - *Models, Neurological MH - Nerve Growth Factors/administration & dosage/pharmacology/*therapeutic use MH - Nerve Regeneration/*drug effects MH - Nerve Tissue Proteins/agonists/antagonists & inhibitors/genetics/metabolism MH - Neuroprotective Agents/administration & dosage/metabolism/pharmacology/therapeutic use MH - Organ Culture Techniques MH - Phenylurea Compounds/administration & dosage/pharmacology MH - Receptors, Neuropeptide/*agonists/antagonists & inhibitors/metabolism MH - Serpins/administration & dosage/pharmacology/*therapeutic use MH - Trigeminal Ganglion/drug effects/pathology/physiology MH - Trigeminal Nerve/*drug effects/pathology/physiology MH - Trigeminal Nerve Injuries/drug therapy PMC - PMC5682960 OTO - NOTNLM OT - DHA OT - NGF OT - PEDF OT - Sema7A OT - adipose triglyceride lipase OT - brain-derived neurotrophic factor (BDNF) OT - cornea OT - lipid signaling OT - neuropeptides OT - phospholipase A COIS- The authors declare that they have no conflicts of interest with the contents of this article EDAT- 2017/10/04 06:00 MHDA- 2017/12/20 06:00 PMCR- 2017/09/26 CRDT- 2017/10/04 06:00 PHST- 2017/06/09 00:00 [received] PHST- 2017/09/22 00:00 [revised] PHST- 2017/10/04 06:00 [pubmed] PHST- 2017/12/20 06:00 [medline] PHST- 2017/10/04 06:00 [entrez] PHST- 2017/09/26 00:00 [pmc-release] AID - S0021-9258(20)32968-9 [pii] AID - M117.801472 [pii] AID - 10.1074/jbc.M117.801472 [doi] PST - ppublish SO - J Biol Chem. 2017 Nov 10;292(45):18486-18499. doi: 10.1074/jbc.M117.801472. Epub 2017 Sep 26.