Novel Hydroxytyrosol-Donepezil Hybrids as Potential Antioxidant and Neuroprotective Agents

Abstract

It is well-accepted that the endogenous antioxidant protection system progressively decays in elderly people, and that the oxidative stress contributes to different neurodegenerative disorders such as Alzheimer’s Diseases (AD). The lower incidence of AD in countries which feature the Mediterranean Diet was associated to the high consumption of extra virgin olive oil and its polyphenolic fraction, in particular hydroxytyrosol. The protective role of these bio-phenols against oxidative stress, suggested that we combine their antioxidant/free radical scavenging activity with donepezil, an active ingredient which has just been approved for the treatment of AD. Different synthetic strategies were tested to conjugate the two different synthons in good yields. Additionally, a nitro-hydroxytyrosol derivative was synthesized to extend the application to other neurodegeneration inflammatory models. Then, their bioactivity was measured in different chemical and biological tests on a human neuroblastoma cell line (SHSY-5Y). Remarkable results on cell viability and the regulation of the redox state of cells were obtained. All hybrids showed negligible cell death under 1 μM and are stable and non toxic. Reactive oxygen species (ROS) measurements showed that the nitro-hybrid was the more effective one at reducing the ROS amount to physiological values. Then, in light of the bio-metal hypothesis of diverse neurodegenerative disorders, we tested these new compounds on the chelation properties of redox-active metals. The nitro-hybrid was able to chelate all of the tested metal cations, suggesting that we propose it as potential lead compound for a new class of neuroprotective antioxidant agents.

Potential Properties of Natural Nutraceuticals and Antioxidants in Eye Protection

“…However, there are some limits related to the ideal administration of this mixture: first of all, not all the components are hydrophobic, and could, therefore, easily cross the biological membranes. In order to address and solve this problem, one could imagine the formation of a single liquid form, hydrophobic, through appropriate chemical reactions [243][244][245][246] and administered as eye drops [247,248]. With this method of formulation two important limits could be avoided: the degrading action in the gastrointestinal system and the bioavailability of the compounds following digestion [249][250][251].…”

Potential Properties of Natural Nutraceuticals and Antioxidants in Age-Related Eye Disorders

“…The protective effects of exogenous antioxidants, taken through diet, are added to those generated by endogenous antioxidants, as described. The integration of exogenous antioxidants could take place with the administration of vitamins A, C and E and Coenzyme Q10 [ 304 , 305 , 306 ]. In this review, the protective roles of some exogenous antioxidants (vitamin A, vitamin C, Coenzyme Q10, lutein, quercetin, PUFAs and curcumin), against the main eye pathologies, in which oxidative damage is directly involved, have been investigated.…”

Role of Hydroxytyrosol and Oleuropein in the Prevention of Aging and Related Disorders: Focus on Neurodegeneration, Skeletal Muscle Dysfunction and Gut Microbiota

“…Several HTyr derivatives were tested for their neuroprotective action. A report showed that a nitro-HTyr was able to reduce ROS in an SH-SY5Y neuroblastoma cell line treated with H 2 O 2 (100 μM, 30 min–3 h) and also was able to chelate several metal cations [ 259 ]. In another report, a series of alkyl nitrohydroxytyrosyl ether derivatives were synthesized from free HTyr and tested for their antioxidant effect in comparison with nitro-HTyr and free HTyr, using different assays, such as oxygen radical scavenging capacity (ORAC).…”