Antinociceptive effects of Raphanus sativus sprouts involve the opioid and 5-HT1A serotonin receptors, cAMP/cGMP pathways, and the central activity of sulforaphane.

Raphanus sativus L. cv. Sango, commonly known as red radish, is widely consumed around the world as a vegetable, but its benefit in pain relief is not sufficiently investigated. This study aimed to evaluate the antinociceptive effects of R. sativus and a possible mechanism of action. An aqueous extract of R. sativus sprouts (AERSS) was investigated by parenteral (10, 30, and 100 mg kg-1, i.p.) and enteral (500 mg kg-1, p.o.) administration in the neurogenic and inflammatory phases of the formalin test, where gastric damage was also evaluated as a possible adverse effect. Ketorolac (5 mg kg-1, i.p.) was used as the reference drug. Endogenous opioid and 5-HT1A serotonin receptors, as well as the cAMP/NO-cGMP pathways, were explored in the study of a possible mechanism of action by using their corresponding antagonists: naloxone, 1 mg kg-1, i.p., WAY100635, 1 mg kg-1, i.p., and enzymatic activators or inhibitors, respectively. Sulforaphane (SFN), a known bioactive metabolite, was analyzed using electroencephalography (EEG) to evidence its central involvement. A significant and dose-dependent antinociceptive activity was observed with the AERSS resembling the antinociceptive effect of the reference drug, with an equivalent significant response with a dose of 500 mg kg-1, p.o. without causing gastric damage. The participation of the endogenous opioid and 5-HT1A serotonin receptors at central and peripheral levels was also observed, with a differential participation of cAMP/NO-cGMP. SFN as one metabolite produced significant changes in the EEG analysis, reinforcing its effects on the CNS. Our preclinical evidence supports the benefits of consuming Raphanus sativus cv. Sango sprouts for pain relief.

Ethnobotanical, Phytochemical, and Pharmacological Properties of the Subfamily Nepetoideae (Lamiaceae) in Inflammatory Diseases.

Nepetoideae is the most diverse subfamily of Lamiaceae, and some species are well known for their culinary and medicinal uses. In recent years, there has been growing interest in the therapeutic properties of the species of this group regarding inflammatory illnesses. This study aims to collect information on traditional uses through ethnobotanical, pharmacological, and phytochemical information of the subfamily Nepetoideae related to inflammatory diseases. UNAM electronic resources were used to obtain the information. The analysis of the most relevant literature was compiled and organised in tables. From this, about 106 species of the subfamily are traditionally recognised to alleviate chronic pain associated with inflammation. Pharmacological studies have been carried out in vitro and in vivo on approximately 308 species belonging to the genera Salvia, Ocimum, Thymus, Mentha, Origanum, Lavandula, and Melissa. Phytochemical and pharmacological evaluations have been performed and mostly prepared as essential oil or high polarity extracts, whose secondary metabolites are mainly of a phenolic nature. Other interesting and explored metabolites are diterpenes from the abietane, clerodane, and kaurane type; however, they have only been described in some species of the genera Salvia and Isodon. This review reveals that the Nepetoideae subfamily is an important source for therapeutics of the inflammatory process.

Antidepressant-like effects of the Punica granatum and citalopram combination are associated with structural changes in dendritic spines of granule cells in the dentate gyrus of rats.

Introduction: Natural products such as phytoestrogens-enriched foods or supplements have been considered as an alternative therapy to reduce depressive symptoms associated with menopause. It is known that the aqueous extract of Punica granatum (AE-PG) exerts antidepressant-like effects by activating ß-estrogen receptors and facilitates the antidepressant response of the clinical drug citalopram (CIT). However, the effects on neuroplasticity are unknown. Objectvie investigated the antidepressant-like response of combining AE-PG and CIT at sub-optimal doses, analyzing their effects on the formation and maturation of dendrite spines in granule cells as well as on the dendrite complexity. Methods: Ovariectomized Wistar rats (3-month-old) were randomly assigned to one of the following groups: A) control (saline solution as vehicle of CIT and AE-PG, B) AE-PG at a sub-threshold dose (vehicle of CIT plus AE-PG at 0.125 mg/kg), C) CIT at a sub-threshold dose (0.77 mg/kg plus vehicle of AE-PG), and D) a combination of CIT plus AE-PG (0.125 mg/kg and 0.77 mg/kg, respectively). All rats were treated intraperitoneally for 14 days. Antidepressant-like effects were evaluated using the force swimming test test (FST). The complexity of dendrites and the number and morphology of dendrite spines of neurons were assessed in the dentate gyrus after Golgi-Cox impregnation. The expressions of the mature brain-derived neurotrophic factor (mBDNF) in plasma and of mBDNF and synaptophysin in the hippocampus, as markers of synaptogenesis, were also determined. Results: Administration of CIT combined with AE-PG, but not alone, induced a significant antidepressant-like effect in the FST with an increase in the dendritic complexity and the number of dendritic spines in the dentate gyrus (DG) of the hippocampus, revealed by the thin and stubby categories of neurons at the granular cell layer. At the same time, an increase of mBDNF and synaptophysin expression was observed in the hippocampus of rats that received the combination of AE-PG and CIT.

A Proposal to Study the Safety and Efficacy of Psilocybe cubensis in Preclinical and Clinical Studies as a Therapeutic Alternative for Major Depressive Disorder.

The pharmacological treatment of depression consists of taking antidepressant drugs for prolonged periods; its modest therapeutic effect can often be associated with significant adverse effects, while its discontinuation can lead to relapses. Psilocybin is today a novel and breakthrough therapy for major depression. It is a natural alkaloid in Psilocybe mushrooms, which are endemic to Mexico. Research on a larger scale is lacking in various populations, including the Mexican people. This proposal contemplates the experimental design of a preclinical (toxicity and pharmacological evaluation of an extract in mice) and clinical study by including the chemical analysis of a species of Psilocybe cubensis mushroom to characterize its main constituents. The clinical study will consider the safety evaluation by exploring tolerated doses of Psilocybe cubensis by measuring pharmacokinetic parameters after oral administration in healthy adults and an open trial on a sample of patients with major depressive disorder to assess the safety and efficacy of fully characterized Psilocybe cubensis in a two-single doses treatment, (with assisted psychotherapy), compared with the traditional care model at the Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz in Mexico City. This report presents the design of a research project with preclinical and clinical experimental components.

Anxiolytic-like Effects and Quantitative EEG Profile of Palmitone Induces Responses Like Buspirone Rather Than Diazepam as Clinical Drugs.

Anxiety is a mental disorder with a growing worldwide incidence due to the SARS-CoV-2 virus pandemic. Pharmacological therapy includes drugs such as benzodiazepines (BDZs) or azapirones like buspirone (BUSP) or analogs, which unfortunately produce severe adverse effects or no immediate response, respectively. Medicinal plants or their bioactive metabolites are a shared global alternative to treat anxiety. Palmitone is one active compound isolated from Annona species due to its tranquilizing activity. However, its influence on neural activity and possible mechanism of action are unknown. In this study, an electroencephalographic (EEG) spectral power analysis was used to corroborate its depressant activity in comparison with the anxiolytic-like effects of reference drugs such as diazepam (DZP, 1 mg/kg) and BUSP (4 mg/kg) or 8-OH-DPAT (1 mg/kg), alone or in the presence of the GABAA (picrotoxin, PTX, 1 mg/kg) or serotonin 5-HT1A receptor antagonists (WAY100634, WAY, 1 mg/kg). The anxiolytic-like activity was assayed using the behavioral response of mice employing open-field, hole-board, and plus-maze tests. EEG activity was registered in both the frontal and parietal cortex, performing a 10 min baseline and 30 min recording after the treatments. As a result, anxiety-like behavior was significantly decreased in mice administered with palmitone, DZP, BUSP, or 8-OH-DPAT. The effect of palmitone was equivalent to that produced by 5-HT1A receptor agonists but 50% less effective than DZP. The presence of PTX and WAY prevented the anxiolytic-like response of DZP and 8-OH-DPAT, respectively. Whereas only the antagonist of the 5-HT1A receptor (WAY) inhibited the palmitone effects. Palmitone and BUSP exhibited similar changes in the relative power bands after the spectral power analysis. This response was different to the changes induced by DZP. In conclusion, brain electrical activity was associated with the anxiolytic-like effects of palmitone implying a serotoninergic rather than a GABAergic mechanism of action.

Pharmacological Interaction of Quercetin Derivatives of Tilia americana and Clinical Drugs in Experimental Fibromyalgia.

Fibromyalgia (FM) is a pain syndrome characterized by chronic widespread pain and CNS comorbidities. Tilia americana var. mexicana is a medicinal species used to treat anxiety, insomnia, and acute or chronic pain. However, its spectrum of analgesic efficacy for dysfunctional pain is unknown. To investigate a possible therapeutic alternative for FM-type pain, an aqueous Tilia extract (TE) and its flavonoid fraction (FF) containing rutin and isoquercitrin were evaluated alone and/or combined with clinical drugs (tramadol-TRA and pramipexol-PRA) using the reserpine-induced FM model in rats. Chromatographic analysis allowed the characterization of flavonoids, while a histological analysis confirmed their presence in the brain. TE (10-100 mg/kg, i.p.) and FF (10-300 mg/kg, i.p.) produced significant and dose-dependent antihyperalgesic and antiallodynic effects equivalent to TRA (3-10 mg/kg, i.p.) or PRA (0.01-1 mg/kg, s.c.). Nevertheless, the combination of FF + TRA or FF + PRA resulted in an antagonistic interaction by possible competitive action on the serotonin transporter or µ-opioid and D2 receptors, respectively, according to the in silico analysis. Flavonoids were identified in cerebral regions because of their self-epifluorescence. In conclusion, Tilia possesses potential properties to relieve FM-type pain. However, the consumption of this plant or flavonoids such as quercetin derivatives in combination with analgesic drugs might reduce their individual benefits.

Protective Effect of Tilia americana var. mexicana Against Kainic Acid-induced Damage in Brain, Liver, and Kidney: Behavioral and Biochemical Changes.

Tiliaamericana var. mexicana (Tilia) possesses anticonvulsant, antioxidant, neuroprotective, and hepatoprotective activities. The spectrum of anticonvulsant activity in status epilepticus models has not been sufficiently explored. We evaluated the effects of ethyl acetate (EAc), and methanol (ME) extracts on kainic acid (KA)-induced seizures by measuring rats'behavior (severity and latency) and lipoperoxidation in different brain areas (cerebellum, brain hemispheres, cortex, and medulla), kidneys, and liver. Male Wistar rats were administered KA (10 mg/kg, i.p.) after three days of pretreatment with Tilia extract (100 mg/kg). The EAc and ME Tilia extracts significantly decreased the severity of phase 1 and phase 2 seizures, respectively. The ME Tilia extract increased the latency to seizure (27 ± 2 min) compared to the control (13 ± 2 min). The ME and EAc Tilia extracts significantly prevented the increased lipid peroxidation caused by KA-induced seizures in the cerebellum, brain hemispheres, cortex, medulla, liver, and kidneys. The vehicle olive oil (OO) also showed anticonvulsant effects, decreasing the severity of seizures to phase 3 and lipoperoxidation levels in the cerebellum, brain hemispheres, cortex, medulla, liver, and kidneys. The anticonvulsant activity of Tilia is mediated by antioxidant effects in central and systemic areas that involve synergistic interactions among the chemical constituents of these extracts (glucosides of quercetin and kaempferol), while vehicle OO showed the same effects, probably due to its constituent oleuropein.

Anxiety-like Behavior and GABAAR/BDZ Binding Site Response to Progesterone Withdrawal in a Stress-Vulnerable Strain, the Wistar Kyoto Rats.

Stress susceptibility could play a role in developing premenstrual anxiety due to abnormalities in the hypothalamus-pituitary-adrenal (HPA) axis and impairments in the GABAA receptors' benzodiazepine (BDZ) site. Hence, we studied the stress-vulnerable Wistar Kyoto rat strain (WKY) to evaluate progesterone withdrawal (PW) effects on anxiety, HPA axis response, and to explore indicators of GABAA functionality in the BDZ site. For five days, ovariectomized WKY rats were administered 2.0 mg/kg of progesterone. Twenty-four hours after the last administration, rats were tested in the anxiety-like burying behavior test (BBT) or elevated plus maze test (EPM), and corticosterone was determined. [3H]Flunitrazepam binding autoradiography served as the BDZ binding site index of the GABAA receptor in amygdala nuclei and hippocampus's dentate gyrus (DG). Finally, different doses of diazepam in PW-WKY rats were tested in the BBT. PW induced anxiety-like behaviors in both BBT and EPM compared with No-PW rats. PW increased corticosterone, but was blunted when combined with PW and BBT. PW increased [3H]Flunitrazepam binding in the DG and central amygdala compared with No-PW rats. Diazepam at a low dose induced an anxiogenic-like response in PW rats, suggesting a paradoxical response to benzodiazepines. Overall, PW induced anxiety-like behavior, a blunted HPA axis response, and higher GABAAR/BZD binding site sensitivity in a stress-vulnerable rat strain. These findings demonstrate the role of stress-susceptibility in GABAAR functionality in a preclinical approximation of PMDD.

Antinociceptive and gastroprotective activities of Bocconia arborea S. Watson and its bioactive metabolite dihydrosanguinarine in murine models.

ETHNOPHARMACOLOGICAL RELEVANCE: Bocconia arborea S. Watson (Papaveraceae) is known as "palo llora sangre" and is used in Mexican traditional medicine for the treatment of infections, it is also used as anxiolytic, analgesic, and antidiabetic, among others. AIM OF THE STUDY: to evaluate the antinociceptive and gastroprotective activities of extracts from B. arborea and dihydrosanguinarine (DHS) in murine models. MATERIALS AND METHODS: Organic extracts [hexane (HEX), dichloromethane (DCM) and methanol (MeOH)] were obtained by maceration. DHS was isolated and purified from HEX and DCM by precipitation and chromatographic column, respectively. Organic extracts and DHS were evaluated to determine their antinociceptive effect using formalin test in murine model. Also, the ambulatory effect of the HEX and DHS was determined in Open field test. The possible mechanism of action of DHS was explored in the presence of naltrexone (NTX, 1 mg/kg, i.p.), and picrotoxin (PTX, 1 mg/kg, i.p.). Gastric damage as possible adverse effect or gastroprotection were also investigated. Whereas DHS acute toxicological study was done, and 100 mg/kg of DHS was examined by electroencephalographic (EEG) analysis to discard neurotoxic effects. RESULTS: The B. arborea extracts significantly showed effects in both neurogenic and inflammatory phases of the formalin test, where the HEX extract reached the major antinociceptive effect. A significant and dose-response (10, 30, and 100 mg/kg) antinociceptive activity was observed with the HEX (ED50 = 69 mg/kg) and DHS (ED50 = 85 mg/kg) resembling the effect of the reference analgesic drug tramadol (30 mg/kg). The significant effect of DHS was inhibited in the presence of NTX and PTX. Neither the extracts or DHS produced sedative effects or gastric damage per se at antinociceptive doses. The EEG analysis demonstrated central depressant activity but not sedative or neurotoxic effects at the highest antinociceptive dosage tested, and LD50 is higher than 2000 mg/kg. CONCLUSIONS: HEX, DCM, and MeOH extracts showed significant antinociceptive activity, and DHS was identified as one of bioactive compounds without producing sedative, neurotoxic or gastric damage effects, as possible adverse effects reported for analgesic drugs. A role of opioid and GABAA neurotransmission appears to be involved as mechanisms of action of DHS, suggesting its potential for pain therapy and reinforcing the traditional use of B. arborea.

Pomegranate and Its Components, Punicalagin and Ellagic Acid, Promote Antidepressant, Antioxidant, and Free Radical-Scavenging Activity in Ovariectomized Rats.

Previous reports described the antidepressant-like action of the aqueous extract of pomegranate (Punica granatum: AEPG). Thus we evaluated the effect of AEPG and the main compounds found in the extract, punicalagin (PNCG) and ellagic acid (EA), on forced swimming test and the redox environment (reactive oxygen species [ROS] production, lipoperoxidation [LPX], and cellular function) in the brain of rats treated with 3 weeks post ovariectomy exposed ex vivo to pro-oxidants. Also, we selected PNCG and EA to study their antidepressant-like effects (0.001, 0.01, 0.1, 1.0, and 10 mg/kg) in the forced swimming test and their scavenging capacities in chemical combinatorial assays (expressed as IC50 values). We observed a 2-fold increase in the formation of ROS and LPX in the brain after exposure to FeSO4. However, these effects were significantly attenuated when rats were treated with AEPG, PNCG, and EA (1 mg/kg and 0.010 mg/kg for 14 days). AEPG and EA significantly increased the cellular function values of brains that had been affected by the effect of FeSO4 and with ONOO-. PNCG and EA significantly reduced immobility behavior at the lower doses used in this study. The capacity of scavenging compounds to eliminate radicals was for hydroxyl radical (⋅OH), superoxide anion (O2⋅⁣-), and peroxynitrite (ONOO-) as follows: AEPG > punicalagin > ellagic acid. In conclusion, the AEPG and their active compounds PNCG and EA promote antidepressant-like actions and antioxidant activity as they attenuate oxidative damage and prevent cellular dysfunction in ovariectomized rat brains.

A Review on the Ethnopharmacology and Phytochemistry of the Neotropical Sages (Salvia Subgenus Calosphace; Lamiaceae) Emphasizing Mexican Species.

Salvia is the most diverse genus within the mint family (Lamiaceae), many of its species are well-known due to their medicinal and culinary uses. Most of the ethnopharmacological and phytochemical studies on Salvia are centred on species from the European and Asian clades. However, studies about the most diverse clade, the Neotropical sages (Salvia subgenus Calosphace; 587 spp.), are relatively scarce. This review aims to compile the information on the traditional medicinal uses, pharmacological and phytochemistry properties of the Neotropical sages. To do so, we carried out a comprehensive review of the articles available in different online databases published from the past to 2022 (i.e., PubMed, Scopus, and Web of Science, among others) and summarized the information in tables. To uncover phylogenetic patterns in the distribution of four different groups of metabolites (mono-, sesqui-, di-, and triterpenes), we generated presence-absence matrices and plotted the tip states over a dated phylogeny of Salvia. We found several studies involving Mexican species of Salvia, but only a few about taxa from other diversity centres. The main traditional uses of the Mexican species of Calosphace are medicinal and ceremonial. In traditional medicine 56 species are used to treat diseases from 17 categories according to the WHO, plus cultural-bound syndromes. Pharmacological studies reveal a wide range of biological properties (e.g., antinociceptive, anti-inflammatory, anxiolytic, cytotoxic, and antidiabetic, etc.) found in extracts and isolated compounds of 38 Neotropical sages. From extracts of these species, at least 109 compounds have been isolated, identified and evaluated pharmacologically; 73 of these compounds are clerodanes, 21 abietanes, six flavonoids, five sesquiterpenoids, and four triterpenoids. The most characteristic metabolites found in the Neotropical sages are the diterpenes, particularly clerodanes (e.g., Amarisolide A, Tilifodiolide), that are found almost exclusively in this group. The Neotropical sages are a promising resource in the production of herbal medication, but studies that corroborate the properties that have been attributed to them in traditional medicine are scarce. Research of these metabolites guided by the phylogenies is recommended, since closely related species tend to share the presence of similar compounds and thus similar medicinal properties.

Antihyperalgesic and Antiallodynic Effects of Amarisolide A and Salvia amarissima Ortega in Experimental Fibromyalgia-Type Pain.

Salvia amarissima Ortega is an endemic species of Mexico used in folk medicine to alleviate pain and as a nervous tranquilizer. The S. amarissima extract and one of its abundant metabolites, identified and isolated through chromatographic techniques, were investigated to obtain scientific evidence of its potential effects to relieve nociplastic pain such as fibromyalgia. Then, the extract and amarisolide A (3-300 mg/kg, i.p.) were pharmacologically evaluated in reserpine-induced fibromyalgia-type chronic pain and in depressive-like behavior (as a common comorbidity) by using the forced swimming test in rats. The 5-HT1A serotonin receptor (selective antagonist WAY100635, 1 mg/kg, i.p.) was explored after the prediction of a chemical interaction using in silico analysis to look for a possible mechanism of action of amarisolide A. Both the extract and amarisolide A produced significant and dose-dependent antihyperalgesic and antiallodynic effects in rats, as well as significant antidepressive behavior without sedative effects when the antinociceptive dosages were used. The 5-HT1A serotonin receptor participation was predicted by the in silico descriptors and was corroborated in the presence of WAY100635. In conclusion, S. amarissima possesses antihyperalgesic, antiallodynic, and anti-depressive activities, partially due to the presence of amarisolide A, which involves the 5-HT1A serotonin receptor. This pharmacological evidence suggests that S. amarissima and amarisolide A are both potential alternatives to relieve pain-like fibromyalgia.

Lamiaceae in Mexican Species, a Great but Scarcely Explored Source of Secondary Metabolites with Potential Pharmacological Effects in Pain Relief.

The search for molecules that contribute to the relief of pain is a field of research in constant development. Lamiaceae is one of the most recognized families world-wide for its use in traditional medicine to treat diseases that include pain and inflammation. Mexico can be considered one of the most important centers of diversification, and due to the high endemism of this family, it is crucial for the in situ conservation of this family. Information about the most common genera and species found in this country and their uses in folk medicine are scarcely reported in the literature. After an extensive inspection in bibliographic databases, mainly Sciencedirect, Pubmed and Springer, almost 1200 articles describing aspects of Lamiaceae were found; however, 217 articles were selected because they recognize the Mexican genera and species with antinociceptive and/or anti-inflammatory potential to relieve pain, such as Salvia and Agastache. The bioactive constituents of these genera were mainly terpenes (volatile and non-volatile) and phenolic compounds such as flavonoids (glycosides and aglycone). The aim of this review is to analyze important aspects of Mexican genera of Lamiaceae, scarcely explored as a potential source of secondary metabolites responsible for the analgesic and anti-inflammatory properties of these species. In addition, we point out the possible mechanisms of action involved and the modulatory pathways investigated in different experimental models. As a result of this review, it is important to mention that scarce information has been reported regarding species of this family from Mexican genera. In fact, despite Calosphace being one of the largest subgenera of Salvia in the world, found mainly in Mexico, it has been barely investigated regarding its potential biological activities and recognized bioactive constituents. The scientific evidence regarding the different bioactive constituents found in species of Lamiaceae demonstrates that several species require further investigation in preclinical studies, and of course also in controlled clinical trials evaluating the efficacy and safety of these natural products to support their therapeutic potential in pain relief and/or inflammation, among other health conditions. Since Mexico is one of the most important centers of diversification, and due to the high endemism of species of this family, it is crucial their rescue, in situ conservation, and investigation of their health benefits.

Synergistic Herb-Herb Interaction of the Antinociceptive and Anti-Inflammatory Effects of Syzygium aromaticum and Rosmarinus officinalis Combination.

The use of alternative medicine to treat pain has been increased, and the combination of several medicinal plants for its relief is a common practice in traditional medicine. The present study is aimed at determining whether a combination of Syzygium aromaticum (S. aromaticum) and Rosmarinus officinalis L. (R. officinalis) potentiates their antinociceptive and anti-inflammatory effects. These effects were explored using the formalin and carrageenan assays in rats, respectively. Animals received local pretreatment with S. aromaticum oil or R. officinalis ethanolic extract (0.1-100 µg/paw) alone or combined in a 1 : 1 rate. Concentration-response curves were built to compare pharmacological responses after an individual administration of S. aromaticum, R. officinalis, or their combination. The pharmacological interaction was investigated by an isobolographic study using the EC50 of each component in a fixed 1 : 1 ratio. S. aromaticum and R. officinalis administered alone showed significant and concentration-dependent antinociceptive and anti-inflammatory effects, but R. officinalis was more potent than S. aromaticum in both the antinociceptive and anti-inflammatory effects (EC50 = 7.96 ± 0.6 µg/paw vs. EC50 = 41.6 ± 1.7 µg/paw; EC50 = 1.97 ± 0.3 µg/paw vs. EC50 = 26.9 ± 2.5 µg/paw, respectively). The isobolographic analysis of the combination of these species in a 1 : 1 ratio showed a synergistic interaction between S. aromaticum and R. officinalis since Z mix (experimental value) was lower than Z add (theoretical value) for both the antinociceptive effect (Z mix = 0.45 ± 0.1 < Z add = 24.8 ± 1.3) and the anti-inflammatory effect (Z mix = 5.2 ± 0.6 < Z add = 14.4 ± 2.2), suggesting a potentiation for both pharmacological effects. These results prove evidence of the efficacy of mixture herb-herb used in folk medicine for pain therapy. It also emphasizes the requirement of pharmacological studies to explore the efficacy and safety of herb interactions.

Synergistic Interaction in the Analgesic-Like Effects of Maqui Berry and Citrus Is Antagonized by Sweeteners.

Although physiologically pain has a protective function, in many diseases, it is one of the most prominent symptoms. Today, new trends are focused on finding more natural alternatives to conventional treatments to alleviate it. Thereby, the purpose of this investigation was to obtain preclinical data of the antinociceptive properties of a lyophilized obtained from a newly designed maqui-citrus beverage alone and added with different sweeteners. To achieve this objective, maqui berry and citrus pharmacological activity were studied separately, as well as the interaction of both ingredients. In addition, due to the controversy generated regarding the intake of sugars, related to different metabolic diseases, the influence of different sweeteners (stevia, sucralose, or sucrose) was studied to determine their possible influence on the bioactive compounds of this product. For the attainment of our goals, a pharmacological evaluation, using the 1% formalin test, a nociceptive pain model in mice, was performed by using a sub-efficacious dosage of Maqui (25 mg/kg, i.p.) alone and combined with citrus, and then compared with the effects obtained in the presence of the different sweeteners. As a result, the antinociceptive response of the maqui was synergized in the presence of citrus in the neurogenic and inflammatory phases of the formalin test. However, this response was partially or totally reduced in the presence of the sweeteners. Our study gives preclinical evidence that a combination of maqui and citrus might exert beneficial actions to relieve pain, whereas the presence of sweeteners could reduce or avoid it.

Bertholletia excelsa Seeds Reduce Anxiety-Like Behavior, Lipids, and Overweight in Mice.

Overweight, obesity, and psychiatric disorders are serious health problems. To evidence the anxiolytic-like effects and lipid reduction in mice receiving a high-calorie diet and Bertholletia excelsa seeds in a nonpolar extract (SBHX, 30 and 300 mg/kg), animals were assessed in open-field, hole-board, and elevated plus-maze tests. SBHX (3 and 10 mg/kg) potentiated the pentobarbital-induced hypnosis. Chronic administration of SBHX for 40 days was given to mice fed with a hypercaloric diet to determine the relationship between water and food intake vs. changes in body weight. Testes, epididymal white adipose tissue (eWAT), and liver were dissected to analyze fat content, triglycerides, cholesterol, and histological effects after administering the hypercaloric diet and SBHX. Fatty acids, such as palmitoleic acid (0.14%), palmitic acid (21.42%), linoleic acid (11.02%), oleic acid (59.97%), and stearic acid (7.44%), were identified as constituents of SBHX, producing significant anxiolytic-like effects and preventing body-weight gain in mice receiving the hypercaloric diet without altering their water or food consumption. There was also a lipid-lowering effect on the testicular tissue and eWAT and a reduction of adipocyte area in eWAT. Our data evidence beneficial properties of B. excelsa seeds influencing global health concerns such as obesity and anxiety.

Antinociceptive effects of maqui-berry (Aristotelia chilensis (Mol.) Stuntz).

Maqui-berry is characterised by presenting a high concentration of (poly)phenols, accounting anthocyanins (cyanidin and delphinidin) for over 85% of the total. These coloured flavonoids have demonstrated potential neurological activity, but the evidence of their antinociceptive properties is scarce. In order to cover this gap, different doses (suitable for human administration) of a maqui-berry powder (1.6% anthocyanin), using enteral and parenteral routes of administration, were compared at central and peripheral levels using a nociceptive pain model (formalin test) in mice. Gastric damage analysis as possible adverse effects of analgesic and anti-inflammatory drugs was also explored. Dose-antinociceptive response was confirmed using both routes of administration and in both neurogenic and inflammatory phases of the formalin test, without gastric damage. In conclusion, these preliminary data provide evidence of pharmacological properties of maqui-berry to alleviate nociceptive pain.

Anticonvulsant activity of Valeriana edulis roots and valepotriates on the pentylenetetrazole-induced seizures in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: For many centuries, Mexican Valerian (Valeriana edulis ssp. procera) has been an important plant in folk medicine. It has been considered useful to control epilepsy; however, electroencephalographic evidence of its anticonvulsant activity is missing in literature. AIM OF THE STUDY: In the present study, in situ electroencephalographic (EEG) analysis was performed along with administration of a crude ethanol extract of V. edulis and its valepotriate fraction on the pentylenetetrazole (PTZ)-induced convulsive behavior in rats. MATERIALS AND METHODS: Experiments were performed using male Wistar rats with nail-shaped electrodes implanted in the frontal and parietal cortices for EEG recording. All animals received a single dose of PTZ (35 mg/kg, i.p.) to test the anticonvulsant activity of V. edulis crude extract and valepotriate fraction (100 mg/kg, i.p.) 15 and/or 30 min after administration. EEG recordings were obtained from the cortices and were evaluated to assess ictal behavior over 60-75 min. Chromatographic analysis of the valepotriate fraction and in silico predictions of pharmacodynamic properties were also explored. The latency, frequency and duration of seizures evaluated using EEG recordings from the frontal and parietal cortices of rats showed significant changes demonstrating the inhibition of paroxystic activity. RESULTS: The spectral analysis confirmed the reduction of excitatory activity induced by V. edulis extract, which was improved in the presence of the valepotriate fraction as compared to that induced by ethosuximide (a reference anticonvulsant drug). The presence of valepotriates such as: isodihydrovaltrate (18.99%), homovaltrate (13.51%), 10-acetoxy-valtrathydrin (4%) and valtrate (1.34%) was identified by chromatographic analysis. Whereas, not only GABAA receptor participation but also the cannabinoid CB2 receptor was found to be likely involved in the anticonvulsant mechanism of action after in silico prediction. CONCLUSIONS: Our data support the anticonvulsant properties attributed to this plant in folk medicine, due to the presence of valepotriates.

Study of Antispasmodic and Antidiarrheal Activities of Tagetes lucida (Mexican Tarragon) in Experimental Models and Its Mechanism of Action.

Tagetes lucida has been used in traditional medicine as a remedy to alleviate several gastrointestinal disorders that provoke stomachaches, abdominal cramps, and diarrhea. However, there is not enough scientific evidence that supports these effects. Therefore, the purpose of this study was to evaluate antispasmodic and antidiarrheal activities of aqueous extract of T. lucida (AqExt-TL) as well as its mechanism of action in experimental models. Antispasmodic activity and the mechanism of action of AqExt-TL were assessed on segments of the guinea pig ileum precontracted with KCl, acetylcholine (ACh), or electrical field stimulation (EFS). Furthermore, the antispasmodic effect of two coumarins (umbelliferone and herniarin) previously identified in this species was evaluated. Antidiarrheal activity of AqExt-TL was determined using the charcoal meal test in mice. AqExt-TL showed antispasmodic activity in segments of the guinea pig ileum precontracted with KCl (83.7 ± 1.9%) and ACh (77.2 ± 5.3%) at the maximal concentration; however, practically, it did not alter the contractions induced by EFS (10.1 ± 2.2%). Antispasmodic activity of AqExt-TL was not significantly altered by hexamethonium (a ganglionic blocker) or L-NAME (an inhibitor of nitric oxide synthase). However, this extract decreased the maximal contractile response to calcium (82.7 ± 8.5%), serotonin (68.1 ± 8.5%), and histamine (63.9 ± 5.9%) in their concentration-response curves. Umbelliferone and herniarin also induced an antispasmodic effect on tissues precontracted with KCl. In addition, low doses of AqExt-TL reduced to 50% the distance traveled by charcoal meal in the gastrointestinal transit model in mice as loperamide, an antidiarrheal agent, did. These results provided evidence of the antispasmodic and antidiarrheal activity of T. lucida, which supports its use in the folk medicine in relieving symptoms in some gastrointestinal disorders. In the antispasmodic effect, the blockade of histaminergic and serotoninergic pathway as well as the calcium channels seems to be involved. Finally, umbelliferone and herniarin could be partially responsible for the antispasmodic activity induced by T. lucida.