Insulin sensitizes neural and vascular TRPV1 receptors in the trigeminovascular system

Background Clinical observations suggest that hyperinsulinemia and insulin resistance can be associated with migraine headache. In the present study we examined the effect of insulin on transient receptor potential vanilloid 1 (TRPV1) receptor-dependent meningeal nociceptor functions in rats. Methods The effects of insulin on the TRPV1 receptor stimulation-induced release of calcitonin gene related peptide (CGRP) from trigeminal afferents and changes in meningeal blood flow were studied. Colocalization of the insulin receptor, the TRPV1 receptor and CGRP was also analyzed in trigeminal ganglion neurons. Results Insulin induced release of CGRP from meningeal afferents and consequent increases in dural blood flow through the activation of TRPV1 receptors of trigeminal afferents. Insulin sensitized both neural and vascular TRPV1 receptors making them more susceptible to the receptor agonist capsaicin. Immunohistochemistry revealed colocalization of the insulin receptor with the TRPV1 receptor and CGRP in a significant proportion of trigeminal ganglion neurons. Conclusions Insulin may activate or sensitize meningeal nociceptors that may lead to enhanced headache susceptibility in persons with increased plasma insulin concentration.

TRPV1 Receptor-Mediated Hypoglycemic Mechanism of Capsaicin in Streptozotocin-Induced Diabetic Rats

Graphical AbstractSignal pathway of hypoglycemic mechanism of capsaicin in the pancreas of STZ-induced diabetic rats.

Petasin and isopetasin reduce CGRP release from trigeminal afferents indicating an inhibitory effect on TRPA1 and TRPV1 receptor channels

Background Butterbur root extract with its active ingredients petasin and isopetasin has been used in the prophylactic treatment of migraine for years, while its sites of action are not completely clear. Calcitonin gene-related peptide (CGRP) is known as a biomarker and promoting factor of migraine. We set out to investigate the impact of petasins on the CGRP release from trigeminal afferents induced by activation of the calcium conducting transient receptor potential channels (TRPs) of the subtypes TRPA1 and TRPV1. Methods We used well-established in vitro preparations, the hemisected rodent skull and dissected trigeminal ganglia, to examine the CGRP release from rat and mouse cranial dura mater and trigeminal ganglion neurons, respectively, after pre-incubation with petasin and isopetasin. Mustard oil and capsaicin were used to stimulate TRPA1 and TRPV1 receptor channels. CGRP concentrations were measured with a CGRP enzyme immunoassay. Results Pre-incubation with either petasin or isopetasin reduced mustard oil- and capsaicin-evoked CGRP release compared to vehicle in an approximately dose-dependent manner. These results were validated by additional experiments with mice expressing functionally deleted TRPA1 or TRPV1 receptor channels. Conclusions Earlier findings of TRPA1 receptor channels being involved in the site of action of petasin and isopetasin are confirmed. Furthermore, we suggest an important inhibitory effect on TRPV1 receptor channels and assume a cooperative action between the two TRP receptors. These mechanisms may contribute to the migraine prophylactic effect of petasins.

Cannabidiol induces autophagy via ERK1/2 activation in neural cells

Autophagy is a lysosomal catabolic process essential to cell homeostasis and is related to the neuroprotection of the central nervous system. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid present in Cannabis sativa. Many therapeutic actions have been linked to this compound, including autophagy activation. However, the precise underlying molecular mechanisms remain unclear, and the downstream functional significance of these actions has yet to be determined. Here, we investigated CBD-evoked effects on autophagy in human neuroblastoma SH-SY5Y and murine astrocyte cell lines. We found that CBD-induced autophagy was substantially reduced in the presence of CB1, CB2 and TRPV1 receptor antagonists, AM 251, AM 630 and capsazepine, respectively. This result strongly indicates that the activation of these receptors mediates the autophagic flux. Additionally, we demonstrated that CBD activates autophagy through ERK1/2 activation and AKT suppression. Interestingly, CBD-mediated autophagy activation is dependent on the autophagy initiator ULK1, but mTORC1 independent. Thus, it is plausible that a non-canonical pathway is involved. Our findings collectively provide evidence that CBD stimulates autophagy signal transduction via crosstalk between the ERK1/2 and AKT kinases, which represent putative regulators of cell proliferation and survival. Furthermore, our study sheds light on potential therapeutic cannabinoid targets that could be developed for treating neurodegenerative disorders.

Petasin and Isopetasin Reduce CGRP Release from Trigeminal Afferents Indicating an Inhibitory Effect on TRPA1 and TRPV1 Receptor Channels

Background: Butterbur root extract with its active ingredients petasin and isopetasin has been used in the prophylactic treatment of migraine for years, while its sites of action are not completely clear. Calcitonin gene-related peptide (CGRP) is known as a biomarker and promoting factor of migraine. We set out to investigate the impact of petasins on the CGRP release from trigeminal afferents induced by activation of the calcium conducting transient receptor potential channels (TRPs) of the subtypes TRPA1 and TRPV1.Methods: We used well-established in vitro preparations, the hemisected rodent skull and dissected trigeminal ganglia, to examine the CGRP release from rat and mouse cranial dura mater and trigeminal ganglion neurons, respectively, after pre-incubation with petasin and isopetasin. Mustard oil and capsaicin were used to stimulate TRPA1 and TRPV1 receptor channels. CGRP concentrations were measured with a CGRP enzyme immunoassay. Results: Pre-incubation with either petasin or isopetasin reduced mustard oil- and capsaicin-evoked CGRP release compared to vehicle in an approximately dose-dependent manner. These results were validated by additional experiments with mice expressing functionally deleted TRPA1 or TRPV1 receptor channels.Conclusions: Earlier findings of TRPA1 receptor channels being involved in the site of action of petasin and isopetasin are confirmed. Furthermore, we suggest an important inhibitory effect on TRPV1 receptor channels and assume a cooperative action between the two TRP receptors. These mechanisms may contribute to the migraine prophylactic effect of petasins.

Effect of Zanthoxylum alkylamides on glucose metabolism in streptozotocin-induced diabetic Sprague–Dawley rats

This research aimed at investigating the hypoglycemic effect of Zanthoxylum alkylamides and whether TRPV1 receptor could participate in the glucose metabolism by using streptozotocin-induced diabetic rat model. The results showed that the blood glucose measured in the Zanthoxylum alkylamides treated group (ALK) showed significantly lower values than that in the model group (Model). Significant improvements in the oral glucose tolerance as well as plasma insulin and hepatic glycogen were also observed in the ALK group, when compared to the model group. However, the improving effects of Zanthoxylum alkylamides on glucose metabolism disorder in diabetic rats were markedly inhibited by capsazepine as the TRPV1 receptor antagonist. In addition, there were significant differences in the levels of mRNA and protein of phosphoenolpyruvate carboxylase (PEPCK), gucose-6-phosphatase (G6Pase), glucokinase (GK) and cannabinoid receptor l (CB1) in the livers of the ALK group compared to model group. Meanwhile, ALK group also exhibited a remarkable increase in the pancreatic-duodenal homeobox 1 (PDX-1), glucose transporter 2 (GLUT 2), GK levels and a significant decrease in the expression levels of CB1 in the pancreas, while the presence of capsazepine would affected the expression of these genes. These findings indicate that Zanthoxylum alkylamides could ameliorate the glucose metabolism disorder in diabetic rats. Furthermore, the TRPV1 receptor could participate in regulating the expressions of genes and proteins related to glucose metabolism and insulin secretion in the liver and pancreas, and takes a role in the hypoglycemic process of Zanthoxylum alkylamides.

Recovery of Capsaicinoids and Other Phytochemicals Involved With TRPV-1 Receptor to Re-valorize Chili Pepper Waste and Produce Nutraceuticals

The hot chili pepper industry represents one of the most important staple foods in Mexico and many Asian countries. Nowadays, large amounts of waste materials are produced from the pepper supply chain that could be used as a source to obtain nutraceuticals. Among the most common and important bioactive compounds contained in pepper residues are the capsaicinoids, which are the responsible of the pungency of the pepper. Capsaicinoids, mainly capsaicin, may ameliorate obesity, gastric disorder, diabetes, cardiovascular diseases, cancer, rhinitis, asthma, immune system diseases, and important viral diseases as the recent COVID-19. The aim of this review is to review the industrial process for the extraction of capsaicinoids ingredients from pepper residues and to examine the relation of the capsaicin and other chili pepper phytochemicals to prevent and treat chronic diseases explained through the key role of the TRPV1 receptor. The extraction and incorporation of these compounds into nutraceutical formulations depend mainly on the development of new methods to improve not only the yield of a particular compound but the validation of the bioactivity and phytochemical characterization.

Structure, function, and mechanism of action of the vanilloid TRPV1 receptor

The TRPV1 receptor (transient receptor potential cation channel subfamily V member 1) is a non-selective cationic channel activated by vanilloids like capsaicin. Therefore, TRPV1 is also called a capsaicin’s receptor, which is a spicy substance found in chili peppers. The receptor is located in sensory nerve fibers and non-neuronal cells, for example in vascular endothelial and smooth muscle cells. It is thought to act as an integrator of various physical and chemical stimuli that provide heat and pain. The activation of the TRPV1 may affect at various physiological functions like release inflammatory mediators, gastrointestinal motility and temperature regulation. Numerous studies in recent years show TRPV1 plays an important role in physiology and development of pathological conditions of gastrointestinal, cardiovascular and respiratory system. These receptors are widely studied as a gripping point for new painkillers, but there are also data indicating their potential involvement in the pathomechanism of various diseases, e.g. epilepsy. TRPV1 targeting may be useful not only in paintreatment but also urinary incontinence, chronic cough or irritable bowel syndrome. The need for further investigation of the therapeutic potential of TRPV1 antagonists indicates the lack of effective drugs to treat many of these conditions. The purpose of this article is to collect and summarize knowledge about the TRPV1 receptor, its structure and mechanism of action.