A Comprehensive Literature Review on Cardioprotective Effects of Bioactive Compounds Present in Fruits of Aristotelia chilensis Stuntz (Maqui).

Some fruits and vegetables, rich in bioactive compounds such as polyphenols, flavonoids, and anthocyanins, may inhibit platelet activation pathways and therefore reduce the risk of suffering from CVD when consumed regularly. Aristotelia chilensis Stuntz (Maqui) is a shrub or tree native to Chile with outstanding antioxidant activity, associated with its high content in anthocyanins, polyphenols, and flavonoids. Previous studies reveal different pharmacological properties for this berry, but its cardioprotective potential has been little studied. Despite having an abundant composition, and being rich in bioactive products with an antiplatelet role, there are few studies linking this berry with antiplatelet activity. This review summarizes and discusses relevant information on the cardioprotective potential of Maqui, based on its composition of bioactive compounds, mainly as a nutraceutical antiplatelet agent. Articles published between 2000 and 2022 in the following bibliographic databases were selected: PubMed, ScienceDirect, and Google Scholar. Our search revealed that Maqui is a promising cardiovascular target since extracts from this berry have direct effects on the reduction in cardiovascular risk factors (glucose index, obesity, diabetes, among others). Although studies on antiplatelet activity in this fruit are recent, its rich chemical composition clearly shows that the presence of chemical compounds (anthocyanins, flavonoids, phenolic acids, among others) with high antiplatelet potential can provide this berry with antiplatelet properties. These bioactive compounds have antiplatelet effects with multiple targets in the platelet, particularly, they have been related to the inhibition of thromboxane, thrombin, ADP, and GPVI receptors, or through the pathways by which these receptors stimulate platelet aggregation. Detailed studies are needed to clarify this gap in the literature, as well as to specifically evaluate the mechanism of action of Maqui extracts, due to the presence of phenolic compounds.

Antiplatelet activity and chemical analysis of leaf and fruit extracts from Aristotelia chilensis.

Aristotelia chilensis (Mol.) Stuntz, also known as maqui, is a plant native to Chile without chemical characterization and quantification of the bioactive compounds present in it. HPLC-UV and HPLC-MS/MS studies have shown the presence, at different concentrations, of phenolic and anthocyanin compounds in fruit and leave extracts of the domesticated maqui clones Luna Nueva, Morena, and Perla Negra. The extracts from leaves and unripe fruits of Luna Nueva and Morena clones significantly inhibit platelet aggregation induced by several agonists; the extracts inhibit platelet granule secretion by decreasing the exposure of P-selectin and CD63 at the platelet membrane. Reactive oxygen species formation in platelets is lower in the presence of maqui extracts. Statistical Pearson analysis supports the levels of phenolic and anthocyanin compounds being responsible for the antiaggregant maqui effects. This work is the first evidence of antiplatelet activity from Aristotelia chilensis giving added value to the use of leaves and unripe fruits from this species.

Regulation of arachidonic acid oxidation and metabolism by lipid electrophiles.

Arachidonic acid (AA) is a precursor of enzymatic and non-enzymatic oxidized products such as prostaglandins, thromboxanes, leukotrienes, lipoxins, and isoprostanes. These products may exert signaling or damaging roles during physiological and pathological conditions, some of them being markers of oxidative stress linked to inflammation. Recent data support the concept that cyclooxygenases (COX), lipoxygenases (LOX), and cytochrome P450 (CYP450) followed by cytosolic and microsomal dehydrogenases can convert AA to lipid-derived electrophiles (LDE). Lipid-derived electrophiles are fatty acid derivatives bearing an electron-withdrawing group that can react with nucleophiles at proteins, DNA, and small antioxidant molecules exerting potent signaling properties. This review aims to describe the formation, sources, and electrophilic anti-inflammatory actions of key mammalian LDE.

Structural considerations on lipoxygenase function, inhibition and crosstalk with nitric oxide pathways.

Lipoxygenases (LOX) are non-heme iron-containing enzymes that catalyze regio- and stereo-selective dioxygenation of polyunsaturated fatty acids (PUFA). Mammalian LOXs participate in the eicosanoid cascade during the inflammatory response, using preferentially arachidonic acid (AA) as substrate, for the synthesis of leukotrienes (LT) and other oxidized-lipid intermediaries. This review focus on lipoxygenases (LOX) structural and kinetic implications on both catalysis selectivity, as well as the basic and clinical implications of inhibition and interactions with nitric oxide (•NO) and nitroalkenes pathways. During inflammation •NO levels are increasingly favoring the formation of reactive nitrogen species (RNS). •NO may act itself as an inhibitor of LOX-mediated lipid oxidation by reacting with lipid peroxyl radicals. Besides, •NO may act as an O2 competitor in the LOX active site, thus displaying a protective role on lipid-peroxidation. Moreover, RNS such as nitrogen dioxide (•NO2) may react with lipid-derived species formed during LOX reaction, yielding nitroalkenes (NO2FA). NO2FA represents electrophilic compounds that could exert anti-inflammatory actions through the interaction with critical LOX nucleophilic amino acids. We will discuss how nitro-oxidative conditions may limit the availability of common LOX substrates, favoring alternative routes of PUFA metabolization to anti-inflammatory or pro-resolutive pathways.

"Shooting pain" in lumbar radiculopathy and trigeminal neuralgia, and ideas concerning its neural substrates.

Patients with radicular low back pain (radicular LBP, sciatica) frequently describe their pain as "shooting" or "radiating." The dictionary meaning of these words implies rapid movement, and indeed, many sufferers report feeling pain moving rapidly from the lower back or buttock into the leg. But, others do not. Moreover, the sensation of movement is paradoxical; it is neither predicted nor accounted for by current ideas about the pathophysiology of radicular LBP. We have used a structured questionnaire to evaluate the sensory qualities associated with "shooting" and "radiating" in 155 patients, 98 with radicular LBP and 57 with trigeminal neuralgia, a second chronic pain condition in which shooting/radiating are experienced. Results indicated a spectrum of different sensations in different people. Although many sciatica patients reported rapid downward movement of their pain, even more reported downward expansion of the area of pain, some reported upward movement, and for some, there was no spatial dynamic at all. The velocity of movement or expansion was also variable. By cross-referencing sensations experienced in the sciatica and trigeminal neuralgia cohorts with known signal processing modes in the somatosensory system, we propose testable hypotheses concerning the pathophysiology of the various vectorial sensations reported, their direction and velocity, and the structures in which they are generated. Systematic evaluation of qualitative features of "shooting" and "radiating" pain at the time of diagnosis can shed light on the pain mechanism in the individual patient and perhaps contribute to a better therapeutic outcomes.

Combining nuclear magnetic resonance with molecular dynamics simulations to address sumatriptan interaction with model membranes.

The goal of this work is to obtain a complete map on the interactions between sumatriptan, an amphiphilic ionizable anti-migraine drug, with lipid bilayers. To this end, we combined two physico-chemical techniques - nuclear magnetic resonance and molecular dynamics simulations - to obtain a detailed picture at different pH values. Both approaches were used considering the strength and constraints of each one. NMR experiments were performed at pH 7.4 where at least 95% of the drug molecules are in their protonated state. From NMR, sumatriptan shows partition on the interfacial region of model membranes (near the head groups and intercalating between adjacent lipids), inducing changes in chemical environment and affecting lipid dynamics of liposomes, in a dose dependent manner. Due to the experimental instability of lipid bilayers at high pH, we took advantage of the molecular dynamics power to emulate different pH values, to simulate sumatriptan in bilayers including at fully uncharged state. Simulations show that the neutral species have preferential orientation within the bilayer interface while the distribution of protonated drugs is independent on the initial conditions. In summary, several properties depicted the interfacial partition of the anti-migraine drug at the water-lipid interface at different conditions. Both techniques were found complementary to shed light on the structural and dynamics of sumatriptan-lipid bilayer interactions.

Free radical-dependent inhibition of prostaglandin endoperoxide H Synthase-2 by nitro-arachidonic acid.

Prostaglandin endoperoxide H synthase (PGHS) is a heme-enzyme responsible for the conversion of arachidonic acid (AA) to prostaglandin H2 (PGH2). PGHS have both oxygenase (COX) and peroxidase (POX) activities and is present in two isoforms (PGHS-1 and -2) expressed in different tissues and cell conditions. It has been reported that PGHS activity is inhibited by the nitrated form of AA, nitro-arachidonic acid (NO2AA), which in turn could be synthesized by PGHS under nitro-oxidative conditions. Specifically, NO2AA inhibits COX in PGHS-1 as well as POX in both PGHS-1 and -2, in a dose and time-dependent manner. NO2AA inhibition involves lowering the binding stability and displacing the heme group from the active site. However, the complete mechanism remains to be understood. This review describes the interactions of PGHS with NO2AA, focusing on mechanisms of inhibition and nitration. In addition, using a novel approach combining EPR-spin trapping and mass spectrometry, we described possible intermediates formed during PGHS-2 catalysis and inhibition. This literature revision as well as the results presented here strongly suggest a free radical-dependent inhibitory mechanism of PGHS-2 by NO2AA. This is of relevance towards understanding the underlying mechanism of inhibition of PGHS by NO2AA and its anti-inflammatory potential.

A sumatriptan coarse-grained model to explore different environments: interplay with experimental techniques.

In this work, we developed a coarse-grained model of sumatriptan suitable for extensive molecular dynamics simulations. First, we confirmed the interfacial distribution of this drug in bilayers through cryogenic transmission electron microscopy and small-angle X-ray scattering techniques, as was predicted by our previous atomistic simulations. Based on these simulations, we developed a coarse-grained model for sumatriptan able to reproduce its overall molecular behavior, captured by atomistic simulations and experiments. We then tested the sumatriptan model in a micellar environment along with experimental characterization of sumatriptan-loaded micelles. The simulation results showed good agreement with photon correlation spectroscopy and electrophoretic mobility experiments performed in this work. The particle size of the obtained micelles was comparable with the simulated ones; meanwhile, zeta-potential results suggest adsorption of the drug on the micellar surface. This model is a step forward in the search for a suitable drug-delivery system for sumatriptan.

Naratriptan aggregation in lipid bilayers: perspectives from molecular dynamics simulations.

In order to understand the interaction between naratriptan and a fully hydrated bilayer of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidyl-choline (POPC), we carried out molecular dynamics simulations. The simulations were performed considering neutral and protonated ionization states, starting from different initial conditions. At physiological pH, the protonated state of naratriptan is predominant. It is expected that neutral compounds could have larger membrane partition than charged compounds. However, for the specific case of triptans, it is difficult to study neutral species in membranes experimentally, making computer simulations an interesting tool. When the naratriptan molecules were originally placed in water, they partitioned between the bilayer/water interface and water phase, as has been described for similar compounds. From this condition, the drugs displayed low access to the hydrophobic environment, with no significant effects on bilayer organization. The molecules anchored in the interface, due mainly to the barrier function of the polar and oriented lipid heads. On the other hand, when placed inside the bilayer, both neutral and protonated naratriptan showed self-aggregation in the lipid tail environment. In particular, the protonated species exhibited a pore-like structure, dragging water through this environment. Graphical Abstract Different behaviour of Naratriptan and Sumatriptan, when the drugs were originally placed in the lipid core.

Triptan partition in model membranes.

In this work, we report a molecular dynamics simulations study of protonated triptans, sumatriptan and naratriptan, in a fully hydrated bilayer of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidyl-choline (POPC). The simulations were carried out at two concentrations for each drug. Our results show partition between the lipid head-water interphase and water phase for both triptans, with increasing access to the water phase with increasing concentrations. The triptans were stabilized at the interphase through different specific interactions with the POPC bilayer such as hydrogen bonds, salt bridges, and cation-π. Besides, sumatriptan and naratriptan protonated molecules have no access to the hydrophobic region of the bilayer at the studied conditions. Similar results were found for both drugs, however protonated naratriptan shows slightly higher affinity for the water phase. This behavior was attributed to the bulky lateral amino group in its structure under the studied conditions (drugs were originally placed at the water phase). This work represents a first insight to the comprehensive understanding of triptan partition in model membranes.

Concentration effects of sumatriptan on the properties of model membranes by molecular dynamics simulations.

In this work, we report a molecular dynamics simulations study of protonated sumatriptan (pSMT) in a fully hydrated bilayer of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidyl-choline at the fluid lamellar phase. The simulations were carried out at three different drug/lipid stoichiometries, 1:75, 1:10 and 1:3, under NPT conditions. Our results show partition of pSMT between the lipid head-water interphase and water phase. The main interactions that stabilized the systems were hydrogen bonds, salt bridges and cation-π. Besides, pSMT molecules have no access to the hydrophobic region of the bilayer at the studied concentrations. From an atomistic point of view, this work could contribute to the discussion of drug-membrane interactions regarding the limitation of sumatriptan to cross the blood-brain barrier.

Trigeminal neuralgia during sleep.

Pain paroxysms in trigeminal neuralgia (TN) are sudden and extremely intense. Nonetheless, many clinicians who treat TN report that patients are rarely if ever awakened at night by pain attacks. If true, this observation is important as it implies the presence of a powerful sleep protective mechanism. We queried TN patients and their habitual sleep partners about painful awakenings and discovered that such awakenings are in fact quite common. As during the day, pain paroxysms during sleep are typically induced by natural stimuli at TN trigger points. Brief attacks sometimes occur without frankly awakening the patient, but they appear nonetheless to be painful.