Skip to main content
SpringerLink
Log in

Changes in Retinal N-Acylethanolamines and their Oxylipin Derivatives During the Development of Visual Impairment in a Mouse Model for Glaucoma

  • Original Article
  • Published:
Lipids

Abstract

Neurons are especially susceptible to oxidative damage, which is increasingly implicated in neurodegenerative disease. Certain N-acylethanolamines (NAEs) have been shown to protect neurons from oxidative stress. Since glaucoma may be considered a neurodegenerative disorder and the survival of retinal neurons could also be influenced by N-acylethanolamines, our goal was to quantify changes in certain N-acylethanolamine species and their oxylipin derivatives in the retina of a mouse model for glaucoma. We also sought to identify relationships between these and parameters of glaucoma disease development, specifically intraocular pressure, visual acuity, and contrast sensitivity. Five N-acylethanolamine species and three NAE oxylipin derivatives were quantified in retina from young and aged DBA/2Crl mice. N-Acylethanolamines and NAE-oxylipins in retinal extracts were quantified against deuterated standards by isotope dilution gas chromatography–mass spectrometry. Levels (nmol/g dry weight) of N-arachidonoylethanolamine (anandamide; NAE 20:4) were significantly (p = 0.008) decreased in aged (2.875 ± 0.6702) compared to young animals (5.175 ± 0.971). Conversely, the anandamide oxylipin, 15(S)-HETE ethanolamide (15(S)-HETE EA), was significantly (p = 0.042) increased in aged (0.063 ± 0.009) compared to young animals (0.039 ± 0.011). Enzymatic depletion of the anandamide pool by 15-lipoxygenase and consequent accumulation of 15(S)-HETE ethanolamine may contribute to decreased visual function in glaucomatous mice. Since N-acylethanolamines effectively attenuate glaucoma pathogenesis and associated visual impairment, our data provides additional rationale and novel targets for glaucoma therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

9NAE-HOD:

(9S,12Z,10E)-9-Hydroxy-10,12 octadecadienoylethanolamine

13NAE-HOD:

(13S,9Z,11E)-13-Hydroxy-9,11-octadecadienoylethanolamine

15(S)-HETE EA:

15(S)-Hydroxy-N-(2-hydroxyethyl)-5Z,8Z,11Z,13E-eicosatetraenamide

BSTFA:

N,O-Bis(trimethylsilyl) trifluoroacetamide

CS:

Contrast sensitivity

GC/MS:

Gas chromatography–mass spectrometry

IOP:

Intraocular pressure

LC-APCI-MS:

Liquid chromatography–atmospheric pressure chemical ionization–mass spectrometry

LCPUFA:

Long chain polyunsaturated fatty acids

NAE:

N-Acylethanolamine

NAE 16:0:

N-Palmitoylethanolamine, N-(2-hydroxyethyl)-hexadecanamide

NAE 18:0:

N-Stearoylethanolamine, N-(octadecanoyl)-ethanolamine

NAE 18:1:

N-Oleoylethanolamine, N-(9Z-octadecenoyl)-ethanolamine

NAE 18:2:

N-Linoleoylethanolamine, N-(2-hydroxyethyl)-9Z,12Z-octadecadienamide

NAE 20:4:

Anandamide, N-arachidonoylethanolamine, N-(2-hydroxyethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide

RP-HPLC:

Reverse phase-high performance liquid chromatography

TMS:

Trimethylsilyl

VA:

Visual acuity

References

  1. Terland O, Flatmark T, Tangeras A, Gronberg M (1997) Dopamine oxidation generates an oxidative stress mediated by dopamine semiquinone and unrelated to reactive oxygen species. J Mol Cell Cardiol 29(6):1731–1738

    Article  CAS  PubMed  Google Scholar 

  2. Floyd RA, Towner RA, He T, Hensley K, Maples KR (2011) Translational research involving oxidative stress and diseases of aging. Free Radic Biol Med 51(5):931–941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Andersen JK (2004) Oxidative stress in neurodegeneration: cause or consequence? Nat Med 10(Suppl):S18–S25

    Article  PubMed  Google Scholar 

  4. Ohia SE, Opere CA, Leday AM (2005) Pharmacological consequences of oxidative stress in ocular tissues. Mutat Res 579(1–2):22–36

    Article  CAS  PubMed  Google Scholar 

  5. Foster PJ, Buhrmann R, Quigley HA, Johnson GJ (2002) The definition and classification of glaucoma in prevalence surveys. Br J Ophthalmol 86(2):238–242

    Article  PubMed  PubMed Central  Google Scholar 

  6. Sacca SC, Izzotti A, Rossi P, Traverso C (2007) Glaucomatous outflow pathway and oxidative stress. Exp Eye Res 84(3):389–399

    Article  CAS  PubMed  Google Scholar 

  7. Almasieh M, Wilson AM, Morquette B, Cueva Vargas JL, Di Polo A (2012) The molecular basis of retinal ganglion cell death in glaucoma. Prog Retin Eye Res 31(2):152–181

    Article  CAS  PubMed  Google Scholar 

  8. Tezel G (2011) The immune response in glaucoma: a perspective on the roles of oxidative stress. Exp Eye Res 93(2):178–186

    Article  CAS  PubMed  Google Scholar 

  9. Aslan M, Dogan S, Kucuksayan E (2013) Oxidative stress and potential applications of free radical scavengers in glaucoma. Redox Rep 18(2):76–87

    Article  CAS  PubMed  Google Scholar 

  10. Schmid HH (2000) Pathways and mechanisms of N-acylethanolamine biosynthesis: can anandamide be generated selectively? Chem Phys Lipids 108(1–2):71–87

    Article  CAS  PubMed  Google Scholar 

  11. Di Marzo V (1998) ‘Endocannabinoids’ and other fatty acid derivatives with cannabimimetic properties: biochemistry and possible physiopathological relevance. Biochim Biophys Acta 1392(2–3):153–175

    Article  PubMed  Google Scholar 

  12. Di Marzo V, De Petrocellis L (2010) Endocannabinoids as regulators of transient receptor potential (TRP) channels: a further opportunity to develop new endocannabinoid-based therapeutic drugs. Curr Med Chem 17(14):1430–1449

    Article  PubMed  Google Scholar 

  13. Sinor AD, Irvin SM, Greenberg DA (2000) Endocannabinoids protect cerebral cortical neurons from in vitro ischemia in rats. Neurosci Lett 278(3):157–160

    Article  CAS  PubMed  Google Scholar 

  14. Duncan RS, Xin H, Goad DL, Chapman KD, Koulen P (2011) Protection of neurons in the retinal ganglion cell layer against excitotoxicity by the N-acylethanolamine, N-linoleoylethanolamine. Clin Ophthalmol 5:543–548

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Garg P, Duncan RS, Kaja S, Zabaneh A, Chapman KD, Koulen P (2011) Lauroylethanolamide and linoleoylethanolamide improve functional outcome in a rodent model for stroke. Neurosci Lett 492(3):134–138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Duncan RS, Chapman KD, Koulen P (2009) The neuroprotective properties of palmitoylethanolamine against oxidative stress in a neuronal cell line. Mol Neurodegener 4:50

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kilaru A, Tamura P, Garg P, et al (2011) Changes in N-acylethanolamine pathway related metabolites in a rat model of cerebral ischemia/reperfusion. J Glycom Lipidom 1(1):101

    Article  Google Scholar 

  18. Kilaru A, Isaac G, Tamura P et al (2010) Lipid profiling reveals tissue-specific differences for ethanolamide lipids in mice lacking fatty acid amide hydrolase. Lipids 45(9):863–875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Grillo SL, Keereetaweep J, Grillo MA et al (2013) N-Palmitoylethanolamine depot injection increased its tissue levels and those of other acylethanolamide lipids. Drug Des Dev Ther 7:747–752

    CAS  Google Scholar 

  20. Faure L, Nagarajan S, Hwang H et al (2014) Synthesis of phenoxyacyl-ethanolamides and their effects on fatty acid amide hydrolase activity. J Biol Chem 289(13):9340–9351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Faure L, Cavazos R, Khan BR et al (2015) Effects of synthetic alkamides on Arabidopsis fatty acid amide hydrolase activity and plant development. Phytochemistry 110:58–71

    Article  CAS  PubMed  Google Scholar 

  22. Rouzer CA, Marnett LJ (2011) Endocannabinoid oxygenation by cyclooxygenases, lipoxygenases, and cytochromes P450: cross-talk between the eicosanoid and endocannabinoid signaling pathways. Chem Rev 111(10):5899–5921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Urquhart P, Nicolaou A, Woodward DF (2015) Endocannabinoids and their oxygenation by cyclo-oxygenases, lipoxygenases and other oxygenases. Biochim Biophys Acta 1851(4):366–376

    Article  CAS  PubMed  Google Scholar 

  24. McKinnon SJ, Schlamp CL, Nickells RW (2009) Mouse models of retinal ganglion cell death and glaucoma. Exp Eye Res 88(4):816–824

    Article  CAS  PubMed  Google Scholar 

  25. Burroughs SL, Kaja S, Koulen P (2011) Quantification of deficits in spatial visual function of mouse models for glaucoma. Invest Ophthalmol Vis Sci 52(6):3654–3659

    Article  PubMed  PubMed Central  Google Scholar 

  26. Venables BJ, Waggoner CA, Chapman KD (2005) N-Acylethanolamines in seeds of selected legumes. Phytochemistry 66(16):1913–1918

    Article  CAS  PubMed  Google Scholar 

  27. Kilaru A, Herrfurth C, Keereetaweep J et al (2011) Lipoxygenase-mediated oxidation of polyunsaturated N-acylethanolamines in Arabidopsis. J Biol Chem 286(17):15205–15214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Keereetaweep J, Blancaflor EB, Hornung E et al (2013) Ethanolamide oxylipins of linolenic acid can negatively regulate Arabidopsis seedling development. Plant Cell 25(10):3824–3840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Straiker A, Stella N, Piomelli D et al (1999) Cannabinoid CB1 receptors and ligands in vertebrate retina: localization and function of an endogenous signaling system. Proc Natl Acad Sci USA 96(25):14565–14570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hungund BL, Basavarajappa BS (2004) Role of endocannabinoids and cannabinoid CB1 receptors in alcohol-related behaviors. Ann N Y Acad Sci 1025:515–527

    Article  CAS  PubMed  Google Scholar 

  31. Chen J, Matias I, Dinh T et al (2005) Finding of endocannabinoids in human eye tissues: implications for glaucoma. Biochem Biophys Res Commun 330(4):1062–1067

    Article  CAS  PubMed  Google Scholar 

  32. Scholz M, Buder T, Seeber S et al (2008) Dependency of intraocular pressure elevation and glaucomatous changes in DBA/2J and DBA/2J-Rj mice. Invest Ophthalmol Vis Sci 49(2):613–621

    Article  PubMed  Google Scholar 

  33. Harazny J, Scholz M, Buder T et al (2009) Electrophysiological deficits in the retina of the DBA/2J mouse. Doc Ophthalmol 119(3):181–197

    Article  PubMed  Google Scholar 

  34. Conrad DJ (1999) The arachidonate 12/15 lipoxygenases. A review of tissue expression and biologic function. Clin Rev Allergy Immunol 17(1–2):71–89

    Article  CAS  PubMed  Google Scholar 

  35. Calandria JM, Marcheselli VL, Mukherjee PK et al (2009) Selective survival rescue in 15-lipoxygenase-1-deficient retinal pigment epithelial cells by the novel docosahexaenoic acid-derived mediator, neuroprotectin D1. J Biol Chem 284(26):17877–17882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Martini AC, Forner S, Bento AF, Rae GA (2014) Neuroprotective effects of lipoxin A4 in central nervous system pathologies. Biomed Res Int 2014:316204. doi:10.1155/2014/316204

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The present study was supported in part by grants from the National Eye Institute (EY022774), the National Institute on Aging (AG010485, AG022550 and AG027956), the National Center for Research Resources and National Institute of General Medical Sciences (RR027093) of the National Institutes of Health (PK). The content of the present study is the sole responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Lipid analysis was supported by a grant from the US Department of Energy, Office of Science, Basic Energy Sciences program (DE-FG02-05ER15647; KDC). K.D.C. is grateful to the US National Science Foundation for providing individual research and development leave to assist in the supervision of this research and the preparation of this manuscript by agreement under the Intergovernmental Personnel Act. Additional partial support was provided by the Felix and Carmen Sabates Missouri Endowed Chair in Vision Research, a Challenge Grant from Research to Prevent Blindness and the Vision Research Foundation of Kansas City (PK) and is gratefully acknowledged. The authors thank Margaret, Richard and Sara Koulen for their generous support and encouragement.

Author information

Author notes

  1. Jantana Keereetaweep

    Present address: Biology Department, Brookhaven National Laboratory, 50 Bell Avenue, Upton, NY, 11973-5000, USA

Authors and Affiliations

  1. Department of Ophthalmology, Vision Research Center, School of Medicine, University of Missouri–Kansas City, Kansas City, MO, 64108, USA

    Christa L. Montgomery, Heather M. Johnson, Stephanie L. Grillo & Peter Koulen

  2. Department of Biological Sciences, Center for Plant Lipid Research, University of North Texas, Denton, TX, USA

    Jantana Keereetaweep, Kent D. Chapman & Peter Koulen

  3. Department of Basic Medical Science, School of Medicine, University of Missouri–Kansas City, Kansas City, MO, USA

    Peter Koulen

Authors
  1. Christa L. Montgomery
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jantana Keereetaweep
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heather M. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stephanie L. Grillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kent D. Chapman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peter Koulen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter Koulen.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 838 kb)

Supplementary material 2 (DOCX 14 kb)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Montgomery, C.L., Keereetaweep, J., Johnson, H.M. et al. Changes in Retinal N-Acylethanolamines and their Oxylipin Derivatives During the Development of Visual Impairment in a Mouse Model for Glaucoma. Lipids 51, 857–866 (2016). https://doi.org/10.1007/s11745-016-4161-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11745-016-4161-x

Keywords

Search

Navigation