Capsaicin Fluidifies the Membrane and Localizes Itself near the Lipid–Water Interface

Capsaicin is the chemical responsible for making some peppers spicy hot, but additionally it is used as a pharmaceutical to alleviate different pain conditions. Capsaicin binds to the vanilloid receptor TRPV1, which plays a role in coordinating chemical and physical painful stimuli. A number of reports have also shown that capsaicin inserts in membranes and its capacity to modify them may be part of its molecular mode of action, affecting the activity of other membrane proteins. We have used differential scanning calorimetry, X-ray diffraction, ³¹P NMR, and ²H NMR spectroscopy to show that capsaicin increases the fluidity and disorder of 1,2-palmitoyl-<i>sn</i>-glycero-3-phosphocholine membrane models. By using ¹H NOESY MAS NMR based on proton–proton cross-peaks between capsaicin and 1-palmitoyl-2-oleoyl-<i>sn</i>-glycero-3-phosphocholine resonances, we determined the location profile of this molecule in a fluid membrane concluding that it occupies the upper part of the phospholipid monolayer, between the lipid–water interface and the double bond of the acyl chain in position <i>sn</i>-2. This location explains the disorganization of the membrane of both the lipid–water interface and the hydrophobic palisade

Insights into the Impact of a Membrane-Anchoring Moiety on the Biological Activities of Bivalent Compounds As Potential Neuroprotectants for Alzheimer’s Disease

Bivalent compounds anchoring in different manners to the membrane were designed and biologically characterized to understand the contribution of the anchor moiety to their biological activity as neuroprotectants for Alzheimer’s disease. Our results established that the anchor moiety is essential, and we identified a preference for diosgenin, as evidenced by <b>17MD</b>. Studies in primary neurons and mouse brain mitochondria also identified <b>17MD</b> as exhibiting activity on neuritic outgrowth and the state 3 oxidative rate of glutamate while preserving the coupling capacity of the mitochondria. Significantly, our studies demonstrated that the integrated bivalent structure is essential to the observed biological activities. Further studies employing bivalent compounds as probes in a model membrane also revealed the influence of the anchor moiety on how they interact with the membrane. Collectively, our results suggest diosgenin to be an optimal anchor moiety, providing bivalent compounds with promising pharmacology that have potential applications for Alzheimer’s disease