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.

Electroencephalographic profile of Salvia amarissima Ortega and amarisolide A in the absence and presence of PTZ-induced seizures in mice.

Salvia amarissima Ortega is a plant used in traditional medicine to treat CNS's affections. Despite its depressant properties in anxiety and fibromyalgia, there is no scientific evidence about its capability to control seizure activity. This study aimed to investigate the effects of the S. amarissima aqueous extract (SAAE) and its metabolite amarisolide A (AMA) on the electrocorticographic (ECoG) activity. The ECoG profiles were previously and concurrently analyzed to the pentylenetetrazole (85 mg/kg, i.p.)-induced seizure behavior after thirty min of the administration of several doses of the SAAE (1, 10, 30, and 100 mg/kg, i.p.) and two doses of AMA (0.5 and 1 mg/kg, i.p.). A dosage of AMA (1 mg/kg,i.p.) was selected to explore a possible mechanism of action by using antagonists of inhibitory receptors such as GABAA (picrotoxin, 1 mg/kg, i.p.) or 5-HT1A of serotonin (WAY100635, 1 mg/kg, i.p.). Significant changes in the frequency bands and the spectral power were observed after the treatment alone. Additionally, SAAE and AMA produced significant and dose-dependent anticonvulsant effects by reducing the incidence and severity of seizures and increasing latency or survival. Both antagonists prevented the effects of AMA in the severity score of seizures and survival during the tonic-clonic seizures. In conclusion, our preclinical data support that S. amarissima possesses anticonvulsant properties, in part due to the presence of amarisolide A, mediated by different inhibitory mechanisms of action. Our scientific evidence suggests that this Salvia species and amarisolide A are potential neuroprotective alternatives to control seizures in epilepsy therapy.

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.

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.

Antinociceptive and antiedema effects produced in rats by Brassica oleracea var. italica sprouts involving sulforaphane.

Natural products are recognized as potential analgesics since many of them are part of modern medicine to relieve pain without serious adverse effects. The aim of this study was to investigate the antinociceptive and anti-inflammatory activities of an aqueous extract of Brassica oleracea var. italica sprouts (AEBS) and one of its main reported bioactive metabolites sulforaphane (SFN). Antinociceptive activity of the AEBS (30, 100, and 300 mg/kg, i.p. or 1000 and 2000 mg/kg, p.o.) and SFN (0.1 mg/kg, i.p.) was evaluated in the plantar test in rats to reinforce its analgesic-like activity at central level using the reference drug tramadol (TR, 50 mg/kg, i.p.). The anti-inflammatory-like response was determined in the carrageenan-induced oedema at the same dosages for comparison with ketorolac (KET, 20 mg/kg, i.p.) or indomethacin (INDO, 20 mg/kg, p.o.). A histological analysis of the swollen paw was included to complement the anti-inflammatory response. Additionally, acute toxicity observed in clinical analgesics as the most common adverse effects, such as sedation and/or gastric damage, was also explored. As a result, central and peripheral action of the AEBS was confirmed using enteral and parenteral administration, in which significant reduction of the nociceptive and inflammatory responses resembled the effects of TR, KET, or INDO, respectively, involving the presence of SFN. No adverse or toxic effects were observed in the presence of the AEBS or SFN. In conclusion, this study supports that Brassica oleracea var. italica sprouts are a potential source of antinociceptive natural products such as SFN for therapy of pain alone and associated to an inflammation condition.

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 evaluation of the anxiolytic-like effects of an aqueous extract of the Raphanus sativus L. sprouts in mice.

Raphanus sativus L. (Brassicaceae), commonly known as radish, is consumed worldwide as a vegetable. However, its benefits on mental health are unknown. The aim of this study was to evaluate its anxiolytic-like effects and safety using different experimental models. An aqueous extract of R. sativus sprouts (AERSS) was pharmacologically evaluated by intraperitoneal route (i.p.) at 10, 30, and 100 mg/kg and orally (p.o.) at 500 mg/kg on behavior by using open-field and plus-maze tests. In addition, its acute toxicity (LD50) was determined by the Lorke's method. Diazepam (1 mg/kg, i.p.) and buspirone (4 mg/kg, i.p.) were the reference drugs. A significant and anxiolytic-like dosage of AERSS (30 mg/kg, i.p.) resembling the effects of reference drugs was chosen to explore the involvement of GABAA/BDZs site (flumazenil, 5 mg/kg, i.p.) and serotonin 5-HT1A receptors (WAY100635, 1 mg/kg, i.p.) as a possible mechanism of action. A 500 mg/kg, p.o. dosage of AERSS produced an anxiolytic-like response equivalent to 100 mg/kg, i.p. No acute toxicity was observed since a LD50 > 2000 mg/kg, i.p. The phytochemical analysis allowed the identification and quantification of major presence of sulforaphene (2500 µM), sulforaphane (15 µM), iberin (0.75 µM), and indol-3-carbinol (0.75 µM), as major constituents. Both the GABAA/BDZs site and serotonin 5-HT1A receptors were involved in the anxiolytic-like activity of AERSS, depending on the pharmacological parameter or the experimental assay tested. Our results demonstrate that the anxiolytic activity of R. sativus sprouts involves GABAA/BDZs site and serotonin 5-HT1A receptors supporting its health benefits in the treatment of anxiety beyond the satisfaction of basic nutritional needs.

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.

Activation of Peripheral Cannabinoid Receptors Synergizes the Effect of Systemic Ibuprofen in a Pain Model in Rat.

Pharmacological synergism is a current strategy for the treatment of pain. However, few studies have been explored to provide evidence of the possible synergism between a non-steroidal anti-inflammatory drug (NSAID) and a cannabinoid agonist, in order to establish which combinations might be effective to manage pain. The aim of this study was to explore the synergism between ibuprofen (IBU) and the synthetic cannabinoid WIN 55,212-2 (WIN) to improve pain relief by analyzing the degree of participation of the CB1 and CB2 cannabinoid receptors in the possible antinociceptive synergism using an experimental model of pain in Wistar rats. First, the effective dose thirty (ED30) of IBU (10, 40, 80, and 160 mg/kg, subcutaneous) and WIN (3, 10, and 30 µg/p, intraplantar) were evaluated in the formalin test. Then, the constant ratio method was used to calculate the doses of IBU and WIN to be administered in combination (COMB) to determine the possible synergism using the isobolographic method. The participation of the CB1 and CB2 receptors was explored in the presence of the antagonists AM281 and AM630, respectively. The combination of these drugs produced a supra-additive response with an interaction index of 0.13. In addition, AM281 and AM630 antagonists reversed the synergistic effect in 45% and 76%, respectively, suggesting that both cannabinoid receptors are involved in this synergism, with peripheral receptors playing a relevant role. In conclusion, the combination of IBU + WIN synergism is mainly mediated by the participation of the CB2 receptor, which can be a good option for the better management of pain relief.

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.

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.

Tabernaemontana arborea and ibogaine induce paroxysmal EEG activity in freely moving mice: Involvement of serotonin 5-HT1A receptors.

Several Apocynaceae species, most notably Tabernanthe iboga, Voacanga africana and many Tabernaemontana species, produce ibogan-type alkaloids. Although a large amount of information exists about the Tabernaemontana genus, knowledge concerning chemistry and biological activity remains lacking for several species, especially related to their effects on the central nervous system (CNS). The aim of this study was to evaluate the effect of Tabernaemontana arborea Rose ex J.D.Sm. (T. arborea) hydroalcoholic extract (30, 56.2 and 100 mg/kg, i.p.) and two of its main alkaloids (ibogaine and voacangine, 30 mg/kg, i.p.) on electroencephalographic (EEG) activity alone and in the presence of the chemical convulsant agent pentylenetetrazole (PTZ, 85 mg/kg, i.p.) in mice. EEG spectral power analysis showed that T. arborea extract (56.2 and 100 mg/kg) and ibogaine (30 mg/kg, i.p.) promoted a significant increase in the relative power of the delta band and a significant reduction in alpha band values, denoting a CNS depressant effect. Voacangine (30 mg/kg, i.p.) provoked an EEG flattening pattern. The PTZ-induced seizures were not modified in the presence of T. arborea, ibogaine, or voacangine. However, sudden death was observed in mice treated with T. arborea extract at 100 mg/kg, i.p., combined with PTZ. Because T. arborea extract (100 mg/kg, i.p.) and ibogaine (30 mg/kg, i.p.), but not voacangine (30 mg/kg, i.p.), induced paroxysmal activity in the EEG, both were explored in the presence of a serotonin 5-HT1A receptor antagonist (WAY100635, 1 mg/kg, i.p.). The antagonist abolished the paroxysmal activity provoked by T. arborea (100 mg/kg, i.p.) but not that observed with ibogaine, corroborating the participation of serotonin neurotransmission in the T. arborea effects. In conclusion, high doses of the T. arborea extract induced abnormal EEG activity due in part to the presence of ibogaine and involving serotonin 5-HT1A receptor participation. Nevertheless, other possible constituents and mechanisms might participate in this complex excitatory activity that would be interesting to explore in future studies.

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.