Interactions of sulindac and its metabolites with phospholipid membranes: An explanation for the peroxidation protective effect of the bioactive metabolite

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) treat inflammatory processes by inhibition of cycloxygenase (COX). However, their action against lipid peroxidation can be an alternative pathway to COX inhibition. Since inflammation and lipid peroxidation are cell-surface phenomena, the effects of NSAIDs on membrane models were investigated. Peroxidation was induced by peroxyl radical (ROO*) derived from AAPH and assessed in aqueous or lipid media using fluorescence probes with distinct lipophilic properties: fluorescein; HDAF and DPH-PA. The antioxidant effect of sulindac and its metabolites was tested and related with their membrane interactions. Drug-membrane interactions included the study of: drug location by fluorescence quenching; drug interaction with membrane surface by zeta-potential measurements; and membrane fluidity changes by steady-state anisotropy. Results revealed that the active NSAID (sulindac sulphide) penetrates into the lipid bilayer and protects the membrane against oxy-radicals. The inactive forms (sulindac and sulindac sulphone) present weaker interactions with the membrane and are better radical scavengers in aqueous media.

Antioxidant Activity of Vitamin E and Trolox: Understanding of the Factors that Govern Lipid Peroxidation Studies In Vitro

“…The fluorescent method used measures the rate of fluorescence intensity decay due to the susceptibility of the probe DPH-PA, which possesses a conjugated double-bond structure that reacts with free-radical species [17][18][19]21 . Therefore, the fluorescence decay indirectly reflects the rate of peroxidation.…”

“…The resultant suspension of multilamellar liposomes was then shaken while being sonicated for 30 s in an ultrasonic bath, which ensured complete recovery of the lipid from the flask walls. The suspension was further passed through two stacked polycarbonate filters (pore size 100 nm) using a extruder apparatus (Lipex Biomembranes, Vancouver, BC, Canada) to convert multilamellar vesicles to unilamellar vesicles (LUVs) following a previously described procedure [17][18][19] . During the preparation steps, the lipid and probe were shielded from light and oxygen as much as possible.…”

“…A reported procedure [17][18][19][20] was adapted to evaluate the antioxidant activity of vitamin E and Trolox. In summary, peroxyl radicals (ROO • ) were generated by thermodecom- position of the initiator (AAPH or AMVN), and lipid peroxidation was monitored in LUVs of EPC, labeled with the fluorescent probe DPH-PA, by measuring the decrease in fluorescence, which results from the oxidative degradation of the probe.…”

Novel γ-Secretase Enzyme Modulators Directly Target Presenilin Protein

“…However, despite the finding that its inactive analog sulindac sulfone did not compete, it could not be definitively answered whether sulindac sulfide targeted the same site as our GSM photoprobe. For example, the differential effects on labeling competition by these drugs could also have been due to their distinct radical scavenging (23) or membrane-partitioning properties (24).…”

Sulindac sulfide suppresses 5-lipoxygenase at clinically relevant concentrations

“…Hence, under these conditions, an interference of the drug with the downstream receptor signaling pathways or the release of AA cannot be excluded. Notably, strong radical scavenging activities against various reactive oxygen species have been reported for SSi [24,25], which may contribute to the drug's anti-inflammatory activity. Considering that the 5-LO enzyme activity in intact cells as well as in cell-free systems shows distinctive redox dependency [26,27], possible radical scavenging actions may therefore contribute to inhibition of 5-LO by SSi.…”