Potential of wild olive (acebuche) oil as an ocular protective factor in vascular retinopathies associated with arterial hypertension

Abstract

Arterial hypertension (AH) contributes to the excessive production of reactive oxygen species (ROS) that promote hypertensive-mediated organ damage (HMOD) via different mechanisms, including inflammatory and profibrotic processes. The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system has been postulated as the main source of superoxide anion (O2·-) contributing to nitric oxide (NO) synthase (NOS) uncoupling and vascular damage in the hypertensive context. Because the eye is highly vascularized, it is not surprising that AH is a risk factor for several vision-threatening eye conditions. The retina is one of the organs most affected by AH, a condition that favours the development/progression of vascular retinopathies, including hypertensive retinopathy (AH), diabetic retinopathy (DR), or age-related macular degeneration (AMD). Other ocular tissues, such as the cornea, might also be affected by AH. The effective prevention of retinal microvascular and neurodegenerative damage that occur in the hypertensive background requires rigorous control of blood pressure. To achieve this challenging goal, antihypertensive drug therapies can be reinforced with the implementation of physical activity and healthy dietary habits. In this sense, unlike the well-known benefits of extra virgin olive oil (EVOO) within the so-called Mediterranean diet, the potential therapeutic effects of the wild olive tree (also known in Spain as acebuche, ACE) have remained largely unknown. Therefore, the aim of this doctoral thesis is to evaluate the potential benefit of ACE oil as an oculoprotective agent in eye diseases associated with arterial hypertension. After unveiling some mechanisms of HMOD, at the level of the retina and cornea, secondary to sustained exposure to Nω-nitro-L-arginine methyl ester (L-NAME), our experimental approach focused on the study of the antihypertensive, antioxidant, anti-inflammatory, and anti-fibrotic effects of an ACE oil-enriched diet in a rodent model (C57B/6J mice) of AH induced by a 6-week treatment with L-NAME. The effects of another EVOO-based diet were also studied in parallel to investigate possible differential effects between the two oils. Finally, a novel ocular pharmaceutical formulation based on ACE oil nanoemulsions was tested in vivo in hypertensive mice. Our results showed clear signs of HMOD in our animal model at the level of the retina and cornea, including retinal dysfunction, reduced retinal blood flow, increased intraocular pressure, and overexpression of NADPH oxidase and other oxidative/inflammatory/fibrotic factors. The observed alterations were alleviated in L-NAME-treated animals subjected to dietary intake of ACE oil or EVOO, especially in the former. Overall, anti-hypertensive systemic and local ocular effects, along with antioxidant, anti-inflammatory and anti-fibrotic properties, were achieved by ACE oil and EVOO administration through modulation of the NADPH oxidase system, NO metabolism, and several inflammation- and fibrosis-related transcription factors. Interestingly, the administration of ACE oil-containing nanoemulsions (NEs) by either topical instillation or intravitreal injection also proved to be an efficient pharmaceutical formulation to ameliorate HMOD in the retina and cornea of L-NAME-treated mice. Taken together, the results presented in this doctoral thesis demonstrate a beneficial effect of ACE oil against hypertensive ocular damage, which might be helpful for the prevention/treatment of retinopathies associated with arterial hypertension, such as HR, AMD, and DR, among others. Based on our observations, not only would ACE oil be effective from a prevention perspective but also as a therapeutic option using different approaches (e.g., ACE oil-enriched diets, and/or ACE oil-encompassing NEs administered as an ophthalmic formulation). All these possibilities warrant further studies and open new research opportunities focused on the health effects of ACE oil.