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.

Identification of some bioactive metabolites and inhibitory receptors in the antinociceptive activity of Tagetes lucida Cav.

Tagetes lucida Cav. is an ancient medicinal plant used to treat different ailments involving neurological diseases and pain. However, scientific studies to validate their medicinal properties as analgesic have not been described. The aim of this study was to evaluate the T. lucida antinociceptive response using pain models. Bioactive compounds and a possible mechanism of action were also explored. Dose-response effects of an ethanol crude extract were investigated in the writhing and formalin tests in mice and rats, respectively. The extract was fractionated to isolate active fractions and bioactive compounds (quercetagetin 7­O­ß­d­glucoside and 6,7­dimethoxycoumarin) using the formalin test. The antinociceptive effects were compared to the reference drugs (tramadol 10 mg/kg, diclofenac 50 mg/kg, and/or ketorolac 1 mg/kg, i.p.). The ethanol extract was explored in the presence of naloxone (3 mg/kg, i.p. a non-selective opioid receptor antagonist) and WAY100635 (0.5 mg/kg, s.c., a selective 5-HT1A receptor antagonist) to screen their participation as possible inhibitory mechanisms involved in the antinociceptive response of T. lucida. The ethanol crude extract, fractions, and pure compounds caused a significant antinociceptive response resembling the effect of the reference drugs. Both opioid and 5-HT1A receptors participated in the analgesic -like activity of the extract, which did not produce gastric damage. On the contrary, the gastric damage produced as an adverse effect of the analgesic ketorolac was prevented when combined with the extract. In conclusion, these preliminary data provide evidence and give support to the properties attributed to T. lucida in the traditional medicine to alleviate pain.

Effects of Moringa oleifera leaf powder on metabolic syndrome induced in male Wistar rats: a preliminary study.

Objective To evaluate the preventive effects of Moringa oleifera on metabolic syndrome (MS) in male Wistar rats. Methods MS was induced by feeding rats a high-fat diet and drinking water containing 10% fructose for 6 weeks. In the preventive group, M. oleifera was orally administered for 3 weeks prior to the induction of MS, while in the treatment group, M. oleifera was administered for 3 weeks after the onset of MS. The treatment groups were compared with a control group of untreated rats with induced MS. Fasting glucose, oral glucose tolerance, insulin tolerance, total cholesterol, triglycerides, abdominal circumference, and systolic and diastolic blood pressure were measured before and after MS induction and/or M. oleifera treatment. Results After the induction of MS, the control group had higher fasting glucose levels than the preventive group. No significant differences were observed in insulin tolerance, oral glucose tolerance, cholesterol, triglycerides, abdominal circumference, or systolic or diastolic blood pressure. Compared with untreated controls, rats in the treatment group had significantly improved glucose tolerance, triglycerides, and abdominal circumference. Conclusions M. oleifera treatment attenuates MS in Wistar rats.

Peripheral involvement of the nitric oxide-cGMP pathway in the indomethacin-induced antinociception in rat.

The role of nitric oxide (NO) in the antinociceptive effect of indomethacin was assessed in the pain-induced functional impairment model in the rat (PIFIR model), a model of inflammatory and chronic pain similar to that observed in clinical gout. Oral administration of indomethacin (5.6 mg/kg), a nonselective cyclooxygenase inhibitor, significantly decreased the nociceptive response elicited by uric acid injected into the knee joint of the right hind limb (2.0+/-3.0 and 149.7+/-18.0 area units [au], in the absence and the presence of indomethacin, respectively). This effect of indomethacin was reduced in nearly 50% by local pretreatment with the nonselective inhibitor of NO synthase, N G-L-nitro-arginine methyl ester (L-NAME) (72.9+/-10.7 vs. 149.7+/-18.0 au, P<0.05). On the other hand, local administration of L-arginine (a NO synthase substrate) or sodium nitroprusside (a non-enzymatic NO donor) each increased in almost 40% the antinociceptive effect of indomethacin (230.9+/-12.6 and 226.6+/-9.7 vs. 149.7+/-18.0 au, P<0.05), whereas D-arginine (the inactive isomer of arginine) had no effect on the indomethacin antinociceptive response (208.0+/-34.9 vs. 149.7+/-18.0 au). These results suggest that, the antinociceptive effect of indomethacin involves, at least in part, the NO-cyclic GMP pathway at peripheral level.

Evidence for a central mechanism of action of S-(+)-ketoprofen.

It has been observed that some non-steroidal anti-inflammatory drugs (NSAIDs) may act through several mechanisms, in addition to central inhibition of prostaglandin synthesis. These other mechanisms include the L-arginine-nitric oxide (L-arginine-NO) pathway, as well as endogenous opiate and serotonergic mechanisms. Some of these mechanisms can explain the efficacy of NSAIDs in chronic pain conditions such as rheumatoid arthritis. The present study was designed to elucidate the involvement of the above pathways/mechanisms in the antinociceptive effect of S-(+)-ketoprofen at supraspinal and spinal levels. S-(+)-ketoprofen induced dose-dependent antinociception in the pain-induced functional impairment model in the rat. The antinociceptive effect of S-(+)-ketoprofen was not altered by i.t. or intracerebroventricula (i.c.v.) pre-treatment with L-arginine (29.6 microg/site) and L-nitro-arginine-monomethylester (L-NAME) (21.1 microg/site) and neither was the effect of S-(+)-ketoprofen modified by the opiate antagonist, naloxone (1 mg/kg, s.c.). In marked contrast, both i.c.v. administration of the 5-hydroxytryptamine (5-HT)(1)/5-HT(2)/5-HT(7) receptor antagonist, methiothepin (1.5 microg/site), and i.t. administration of the 5-HT(3)/5-HT(4) receptor antagonist, tropisetron (0.9 microg/site), significantly inhibited the S-(+)-ketoprofen-induced antinociceptive effect. These data suggest that the antinociceptive response to S-(+)-ketoprofen involves serotoninergic mechanisms via both supraspinal 5-HT(1)/5-HT(2)/5-HT(7) receptors and 5-HT(3) receptors located at spinal level. A role of the L-arginine-NO and opiate systems in S-(+)-ketoprofen-induced antinociception in the pain-induced functional impairment model in the rat model seems unlikely.

Análisis del efecto de la sal en el desarrollo de obesidad / Analysis of the effect of salt intake on the development of obesity

Introducción: el transporte de la glucosa y de muchos aminoácidos en el intestino es realizado por el cotransportador SGLT1 únicamente si esta unido al ion sodio. La sal aporta un ion sodio por cada molécula que se consume y en los humanos su ingesta comúnmente es de diez veces más de la cantidad necesaria y generalmente se acompaña de dietas ricas en carbohidratos. Este trabajo se planteo pensando en que una estrategia simple para reducir de peso sería el disminuir la cantidad de sal en los alimentos. Objetivo: estudiar el efecto que tiene la sal en la dinámica de la absorción de glucosa y el efecto de una dieta rica en carbohidratos y sal en el desarrollo de obesidad en ratas Wistar. Métodos: para corroborar la hipótesis se evaluó el efecto de la sal en la dinámica de la absorción de la glucosa en el intestino realizando curvas de tolerancia a la glucosa con sal y sin sal. También se analizó si una dieta rica en carbohidratos y sal favorece el desarrollo de obesidad en ratas Wistar. Resultados: los experimentos mostraron que la ingesta de sal no influye en la dinámica de la absorción intestinal de la glucosa, ni en el desarrollo de obesidad en la rata Wistar. Conclusión: el sodio que de manera natural recircula desde el citoplasma de los enterocitos hacia la luz del intestino mantiene saturado al cotransportador de la glucosa SGLT1 y garantiza en todo momento el transporte de la glucosa que se ingiere en la dieta.

Introduction: Intestinal transport of glucose and many amino acids is performed by the SGLT1 cotransporter only when the latter is bound to the sodium ion. Salt contributes a sodium ion per molecule ingested. Human salt intake is often tenfold the required amount, and is generally accompanied by a carbohydrate-rich diet. The present study is based on the assumption that reducing the amount of salt in foods is a simple weight-loss strategy. Objective: Study the effect of salt on glucose absorption dynamics and the effect of a diet rich in carbohydrates and salt on the development of obesity in Wistar rats. Methods: To corroborate the hypothesis, an evaluation was conducted of the effect of salt on intestinal glucose absorption, based on glucose tolerance curves with and without salt. An analysis was also made of whether a diet rich in carbohydrates and salt leads to the development of obesity in Wistar rats. Results: Experiments showed that salt intake does not influence intestinal glucose absorption or the development of obesity in Wistar rats. Conclusion: Sodium naturally recirculating from the cytoplasm of enterocytes to the intestinal lumen keeps the SGLT1 glucose cotransporter saturated and at all times ensures the transport of the glucose ingested in the diet.

[Synergism of caffeine on antinociceptive effects of metamizole]. / Sinergismo de la cafeína sobre los efectos antinociceptivos del metamizol.

BACKGROUND: Combinations of analgesic drugs have been used as an option for treating pain because some types of pain are difficult to relieve with conventional analgesics. This group of drugs has been combined with analgesics or drugs without analgesic effect and is called adjuvant. One such drug is caffeine. METHODS: We undertook the present study to analyze if caffeine is able to potentiate the antinociceptive effect of metamizole in the formalin model. RESULTS: Metamizole produced a dose-dependent antinociceptive effect with ED(50) = 329.61 mg/kg in the formalin model. Caffeine at the following doses (3.16, 10.0, 17.8 and 31.6 mg/kg) also showed antinociceptive effect. When a subeffective dose of metamizole (100 mg/kg) was combined with caffeine (3.16, 10.0, 17.8 or 31.6 mg/kg), higher antinociceptive effects were produced than the corresponding effects produced by metamizole alone. One combination presented potentiation effect; the other combination showed antinociceptive effect that was not different from the effects of metamizole alone. Two combinations showed an effect lower than the corresponding effect produced by metamizole alone. CONCLUSIONS: Adjuvant caffeine is able to change the effect of metamizole in the inflammatory pain model, in which caffeine also presents an antinociceptive effect.

Análisis del efecto de la sal en el desarrollo de obesidad: ¿existe la obesidad salada? / Analysis of the effect of salt intake on the development of obesity: is there such a thing as "salty obesity"?

Objetivos: el transporte de la glucosa y de muchos aminoácidos en el intestino se realiza por el cotransportador SGLT1 únicamente si está unido al ion sodio. La sal aporta un ion sodio por cada molécula que se consume y en los humanos su ingesta comúnmente es de diez veces más de la cantidad necesaria y, por lo general, se acompaña de dietas ricas en carbohidratos. El presente proyecto evaluó, si el consumo abundante de sal en la dieta conlleva al desarrollo de obesidad. Este trabajo se planteó pensando en que una estrategia simple para reducir de peso sería el disminuir la cantidad de sal en los alimentos. Métodos: para corroborar la hipótesis se evaluó el efecto de la sal en la dinámica de la absorción de la glucosa en el intestino realizando curvas de tolerancia a la glucosa con sal y sin sal. También se analizó si una dieta rica en carbohidratos y sal favorece el desarrollo de obesidad en ratas wistar. Resultados: los experimentos mostraron que la ingesta de sal no influye en la dinámica de la absorción intestinal de la glucosa, ni en el desarrollo de obesidad en la rata wistar. Conclusión: el sodio que, de manera natural, recircula desde el citoplasma de los enterocitos hacia la luz del intestino mantiene saturado al cotransportador de la glucosa SGLT1 y garantiza, en todo momento, el transporte de la glucosa que se ingiere en la dieta.

Objectives: intestinal transport of glucose and many amino acids is performed by the SGLT1 cotransporter only when the latter is bound to the sodium ion. Salt contributes a sodium ion per molecule ingested. Human salt intake is often tenfold the required amount, and is generally accompanied by a carbohydrate-rich diet. The present paper evaluates whether an abundant salt intake leads to the development of obesity. It is based on the assumption that reducing the amount of salt in foods is a simple weight-loss strategy. Methods: to corroborate the hypothesis, an evaluation was conducted of the effect of salt on intestinal glucose absorption, based on tolerance curves for glucose with and without salt. An analysis was also made of whether a diet rich in carbohydrates and salt leads to the development of obesity in Wistar rats. Results: experiments showed that salt intake does not influence intestinal glucose absorption or the development of obesity in Wistar rats. Conclusion: sodium naturally recirculating from the cytoplasm of enterocytes to the intestinal lumen keeps the SGLT1 glucose cotransporter saturated and at all times ensures the transport of the glucose ingested in the diet.

Sinergismo de la cafeína sobre los efectos antinociceptivos del metamizol / Synergism of caffeine on antinociceptive effects of metamizole

BACKGROUND: Combinations of analgesic drugs have been used as an option for treating pain because some types of pain are difficult to relieve with conventional analgesics. This group of drugs has been combined with analgesics or drugs without analgesic effect and is called adjuvant. One such drug is caffeine. METHODS: We undertook the present study to analyze if caffeine is able to potentiate the antinociceptive effect of metamizole in the formalin model. RESULTS: Metamizole produced a dose-dependent antinociceptive effect with ED(50) = 329.61 mg/kg in the formalin model. Caffeine at the following doses (3.16, 10.0, 17.8 and 31.6 mg/kg) also showed antinociceptive effect. When a subeffective dose of metamizole (100 mg/kg) was combined with caffeine (3.16, 10.0, 17.8 or 31.6 mg/kg), higher antinociceptive effects were produced than the corresponding effects produced by metamizole alone. One combination presented potentiation effect; the other combination showed antinociceptive effect that was not different from the effects of metamizole alone. Two combinations showed an effect lower than the corresponding effect produced by metamizole alone. CONCLUSIONS: Adjuvant caffeine is able to change the effect of metamizole in the inflammatory pain model, in which caffeine also presents an antinociceptive effect.