Omega-3 fatty acids promote neuroprotection, decreased apoptosis and reduced glial cell activation in the retina of a mouse model of OPA1-related autosomal dominant optic atrophy

Maria Kalogerou; Sotiris Ioannou; Panagiotis Kolovos; Ekatherine Prokopiou; Louiza Potamiti; Kyriacos Kyriacou; Michail Panagiotidis; Maria Ioannou; Eleni Fella; Elena Panayiotou Worth; Tassos Georgiou

doi:10.1016/j.exer.2021.108901

Omega-3 fatty acids promote neuroprotection, decreased apoptosis and reduced glial cell activation in the retina of a mouse model of OPA1-related autosomal dominant optic atrophy

Exp Eye Res. 2022 Feb:215:108901. doi: 10.1016/j.exer.2021.108901. Epub 2021 Dec 20.

Authors

Affiliations

¹ Ophthalmos Research and Educational Institute, Egkomi, 2417, Nicosia, Cyprus; Center of Excellence in Biobanking and Biomedical Research, School of Medicine, University of Cyprus, Aglantzia, 2029, Nicosia, Cyprus. Electronic address: kalogerou.maria@ucy.ac.cy.
² Transgenic Mouse Facility, The Cyprus Institute of Neurology and Genetics, Agios Dometios, 2371, Nicosia, Cyprus. Electronic address: sotiris.ioann@gmail.com.
³ Ophthalmos Research and Educational Institute, Egkomi, 2417, Nicosia, Cyprus. Electronic address: pankoaua@hotmail.com.
⁴ Ophthalmos Research and Educational Institute, Egkomi, 2417, Nicosia, Cyprus. Electronic address: prokopiou.k@unic.ac.cy.
⁵ Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Agios Dometios, 2371, Nicosia, Cyprus. Electronic address: louizap@cing.ac.cy.
⁶ Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Agios Dometios, 2371, Nicosia, Cyprus; The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Agios Dometios, 2371, Nicosia, Cyprus. Electronic address: kyriacos@cing.ac.cy.
⁷ Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Agios Dometios, 2371, Nicosia, Cyprus. Electronic address: mihalisp@cing.ac.cy.
⁸ Department of Neuropathology, The Cyprus Institute of Neurology and Genetics, Agios Dometios, 2371, Nicosia, Cyprus. Electronic address: mariai@cing.ac.cy.
⁹ Department of Neuropathology, The Cyprus Institute of Neurology and Genetics, Agios Dometios, 2371, Nicosia, Cyprus. Electronic address: elenife@cing.ac.cy.
¹⁰ Department of Neuropathology, The Cyprus Institute of Neurology and Genetics, Agios Dometios, 2371, Nicosia, Cyprus. Electronic address: panagiot@cing.ac.cy.
¹¹ Ophthalmos Research and Educational Institute, Egkomi, 2417, Nicosia, Cyprus. Electronic address: tassosgeorgiou@hotmail.com.

PMID: 34933001
DOI: 10.1016/j.exer.2021.108901

Abstract

The purpose of this study was to evaluate the neuroprotective effects of omega-3 polyunsaturated fatty acid (ω3-PUFA) supplementation in a mouse model of OPA1-associated autosomal dominant optic atrophy (ADOA). The blood level of arachidonic acid (AA) and eicosapentaenoic acid (EPA) served to adjust the treatment dosage (AA/EPA = 1.0-1.5). Eight-month-old mice were allocated to four groups (n = 20/group): the ω3-PUFA-treated Opa1^enu/+, untreated Opa1^enu/+, ω3-PUFA-treated wild-type and untreated wild-type groups. Treated mice received the ω3-PUFAs, EPA and docosahexaenoic acid (DHA; 5:1 ratio) by daily gavage for 4 months based on the measured AA/EPA ratio. Blood, retina and optic nerve (ON) fatty acid levels were determined by gas chromatography, and the retina and ON were histologically examined. Western blotting and/or immunohistochemistry was performed to analyse retinal mediators involved in Opa1-mutation-mediated apoptosis, inflammation and oxidative stress. Increased EPA and reduced AA levels were primarily observed predominantly in the blood and retinal tissues, and a similarly high EPA level tended to be observed in the ONs of ω3-PUFA-treated mice. Retinal ganglion cell and ON axonal densities were higher in both mouse strains upon ω3-PUFA treatment than in the corresponding untreated groups. Caspase-3 expression analysis showed fewer apoptotic retinal cells in both groups of treated mice. Decreases in inflammatory microglia and astrocytes activation and proapoptotic Bcl-2-associated X protein (Bax) expression were noted in the treated groups, with no difference in the antioxidant superoxide dismutase-2 expression. ω3-PUFA supplementation had neuroprotective effects on the retinas of Opa1^enu/+ and wild-type mice via blockade of microglia and astrocytes activation and suppression of Bax and caspase-3. Our findings indicated that inhibition of oxidative stress may not be involved in ω3-PUFA-mediated neuroprotection. These novel findings support the use of ω3-PUFAs as a beneficial therapy in the occurrence of ADOA, posing the basis for future clinical trials to confirm these observations.

Keywords: Autosomal dominant optic atrophy; Neuroprotection; OPA1; Omega-3 polyunsaturated fatty acid.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Arachidonic Acid / metabolism
Caspase 3 / metabolism
Disease Models, Animal
Docosahexaenoic Acids / pharmacology
Eicosapentaenoic Acid / pharmacology
Fatty Acids, Omega-3* / pharmacology
GTP Phosphohydrolases / metabolism
Mice
Neuroglia* / metabolism
Neuroglia* / pathology
Neuroprotection
Neuroprotective Agents* / pharmacology
Optic Atrophy, Autosomal Dominant* / drug therapy
Optic Atrophy, Autosomal Dominant* / genetics
Optic Atrophy, Autosomal Dominant* / metabolism
Optic Atrophy, Autosomal Dominant* / pathology
Retina / metabolism
bcl-2-Associated X Protein / metabolism

Substances

Fatty Acids, Omega-3
Neuroprotective Agents
bcl-2-Associated X Protein
Docosahexaenoic Acids
Arachidonic Acid
Eicosapentaenoic Acid
Caspase 3
GTP Phosphohydrolases
Opa1 protein, mouse