Antidepressant- and anxiolytic-like activities and acute toxicity evaluation of the Psilocybe cubensis mushroom in experimental models in mice.

ETHNOPHARMACOLOGY RELEVANCE: Central nervous system (CNS) diseases can be diverse and usually present with comorbidity, as in the case of depression and anxiety. Despite alternatives like Psilocybe mushrooms for mental health there is no basic research to evidence their CNS benefits. AIM OF THE STUDY: To evaluate the anxiolytic- and antidepressant-like effects, as well as the acute toxicity of P. cubensis mushroom. MATERIAL AND METHODS: First, the acute toxicity (LD50) of P. cubensis (2000 mg/kg) was determined after the esophageal (p.o.) and intraperitoneal (i.p.) route of administration. The rota-rod test and electroencephalogram (EEG) were included to assess CNS toxicity in free moving mice. Anxiolytic (ambulatory or exploratory and rearing behaviors) and antidepressant behavioral responses were assayed in the open-field, plus-maze, and forced swimming test, respectively, after administration of 1000 mg/kg, p.o., of the whole P. cubensis mushroom or the polar aqueous (AQ) or methanolic (MeOH) extractions (1, 10, and/or 100 mg/kg, i.p.) in comparison to the reference drugs buspirone (4 mg/kg, i.p.), fluoxetine and/or imipramine (10 mg/kg, s.c. and i.p., respectively). A chemical analysis of the AQ and MeOH extractions was performed to detect psilocybin and/or psilocin by using UHPLC. RESULTS: Neurotoxic effects of P. cubensis mushroom administered at high doses were absent in mice assessed in the rota-rod test or for EEG activity. A LD50 > 2000 mg/kg was calculated by p.o. or i.p. administration. While significant and/or dose-response antidepressant-like effects were produced with the whole P. cubensis mushroom, p.o., and after parenteral administration of the AQ or MeOH extractions resembling the effects of the reference drugs. Behavioral responses were associated with an anxiolytic-like effect in the open-field as corroborated in the plus-maze tests. The presence of psilocybin and psilocin was mainly characterized in the AQ extraction. CONCLUSION: Our results provide preclinical evidence of the anxiolytic- and antidepressant-like effects of the P. cubensis mushroom without producing neurotoxicity after enteral or parenteral administration, where psilocybin and psilocin were identified mainly after AQ extraction. This study reinforces the benefits of the P. cubensis mushroom in mental health and therapy for anxiety and depression.

Antinociceptive effect of Mansoa alliacea polar extracts involves opioid receptors and nitric oxide in experimental nociception in mice.

To evaluate the antinociceptive effect and the possible mechanism of action of two polar extracts of Mansoa alliacea, a medicinal plant used in Perú, Brazil, and Mexico to treat rheumatic pain, we used the formalin and hot-plate tests in mice. We found that ethanolic (MA-EtOH) and aqueous (MA-AQ) extracts of M. alliacea induced antinociceptive effects in both nociceptive tests. The antinociceptive efficacy of the highest dosage (300 mg/kg) of both extracts were also compared by using intraperitoneal and oral administration in the formalin test. Results showed that intraperitoneal injection of the two extracts produced better antinociceptive effects than that obtained by their oral administration. The mechanism of action involved in their antinociceptive activity was determined in the formalin test. Results showed that the presence of A784168 (TRPV1 antagonist) did not alter the antinociceptive effect induced by any of the M. alliacea extracts, whereas naltrexone (opioid antagonist) partially prevented the antinociceptive effect only of MA-EtOH in both phases of the formalin test. Furthermore, the effects of the extracts were diminished by L-NAME (inhibitor of nitric oxide synthase), but not by ODQ (inhibitor of the soluble guanylyl cyclase) or glibenclamide (blocker of K+ATP channels) in the neurogenic phase. However, the effect of MA-AQ was diminished by all the inhibitors in the inflammatory phase. These results support the use of M. alliacea as a potential natural product with efficacy for pain relief depending on the form of preparation and the route of administration by involving opioid receptors and the production of nitric oxide.

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.

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.

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.

Role of ß-Caryophyllene in the Antinociceptive and Anti-Inflammatory Effects of Tagetes lucida Cav. Essential Oil.

Tagetes lucida Cav. (Asteraceae) is an ancient medicinal plant commonly used to alleviate pain. Nevertheless, scientific studies validating this property are lacking in the literature. Animal models of pain were used to evaluate the antinociceptive and anti-inflammatory activities of T. lucida essential oil (TLEO) and a bioactive metabolite. The chemical constitution and possible toxicity of the extract and the mechanism of action of ß-caryophyllene were also explored. Temporal course curves and dose-response graphics were generated using TLEO (0.1-10 mg/kg or 3.16-31.62 mg/kg) and ß-caryophyllene (3.16-10 mg/kg). Metamizole (80 mg/kg) and indomethacin (20 mg/kg) were used as reference drugs in the formalin assay and writhing test in rats and mice, respectively. The ß-caryophyllene mechanism of action was explored in the presence of naloxone (1 mg/kg), flumazenil (10 mg/kg), WAY100635 (0.16 mg/kg), or nitro-l-arginine methyl ester (L-NAME) (20 mg/kg) in the formalin test in rats. GC/MS analysis demonstrated the presence of geranyl acetate (49.89%), geraniol (7.92%), and ß-caryophyllene (6.27%). Significant and dose-dependent antinociceptive response was produced by TLEO and ß-caryophyllene without the presence of gastric damage. In conclusion, ß-caryophyllene was confirmed as a bioactive compound in the T. lucida analgesic properties by involving the participation of receptors like opioids, benzodiazepines, and Serotonin 1A receptor (5-HT1A), as well as nitric oxide.

The anxiolytic-like effect of rutin in rats involves GABAA receptors in the basolateral amygdala.

Rutin is a bioflavonoid found in medicinal plants used to reduce anxiety. Evidence is lacking of rutin's anxiolytic-like activity, putative mechanism(s) of action, and neural sites of effects. The basolateral amygdala (BLA) is the main brain region that regulates anxiety, through GABAA/benzodiazepine (BDZ) receptors, which are modulated by flavonoids. Therefore, the main aim of this study was to investigate whether the anxiolytic-like effect of rutin involves GABAA/BDZ receptors in the BLA. Rutin was administered systemically (30-1000 mg/kg, intraperitoneal) or microinjected into the BLA (16 nmol/4 µl, intracerebral), and its effects were assessed in the elevated plus-maze and open-field tests. Diazepam (1 mg/kg, intraperitoneal, or 7 nmol/4 µl, respectively) was used as a positive control. The mechanism of action was studied using flumazenil (BDZ antagonist, 5 mg/kg, intraperitoneal, or 7 nmol/4 µl, intracerebral) or picrotoxin (chloride channel GABAA antagonist, 0.3 nmol/4 µl, intracerebral). Rutin, administered systemically or intra-amygdala, induced anxiolytic-like responses, similar to those of diazepam. The effect of diazepam was completely blocked by flumazenil, which also partly antagonized the effects of systemic rutin. By contrast, flumazenil exerted no effect and picrotoxin had only a partial action when rutin was infused in the BLA. These results suggest that the anxiolytic-like effect of rutin in the BLA involves GABAergic neurotransmission that is not associated with BDZ receptors.