|Year : 2017 | Volume
| Issue : 3 | Page : 148-154
Role of methylglyoxal as a transient receptor potential ankyrin 1 agonist in colon motility disturbances associated with diabetes
Abdulmohsen Assiri1, Sara Benham2, Sara Prichard3, Chris Benham4
1 Department of Pharmacy, Armed Forces Hospital (Southern Region), Khamis Mushait, Saudi Arabia
2 Department of Pharmacology, School of Biological Sciences, Cambridge University, CB2 1PD, Cambridge, UK
3 Takeda Cambridge Limited, Cambridge, UK
4 Department of Pharmacology, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, AL10 9AB, UK
|Date of Web Publication||12-Jul-2017|
Department of Pharmacy, Armed Forces Hospital (Southern Region), 15 Khamis Mushait 62413
Introduction: Evidence has been found to suggest that methylglyoxal (MG) plays a mediating role in diabetes-related gastrointestinal conditions, and a possible mechanism relating to these conditions could be revealed by determining MG as a transient receptor potential ankyrin 1 (TRPA1) channel agonist.
Methods: Muscle strips from the distal colon of male Wistar rats were used, and organ bath was employed to gain insight into the impact of MG + TRPA1 antagonist (HC-030031).
Results: Considerable rise of spontaneous contractions for longitudinal muscle strips subjected to pre-treatment with MG were observed. The potentiation of the contractile response of control longitudinal muscle strips to electric field stimulation (EFS) took place as a consequence of pre-treatment with 10 mM MG, and maximum response values displayed a rise from 2.16 g ± 0.323 to 3.64 g ± 0.421. 10 μM HC-030031 was observed to block the improvement of EFS responses by MG, and regarding circular muscle strips, a considerable decline in the maximum relaxation response was facilitated by 10 mM MG. Specifically, this was achieved at 20 Hz from 0.26 g ± 0.036 to 0.055 g ± 0.046.
Conclusion: MG has been found to directly contract the distal colons of Wistar rats while enhancing the responses initiated as a result of carbachol and EFS. After blockading the impacts using HC-030031, evidence was found to suggest that the mediation of the impacts takes place through the activation of the TRPA1 channel, which occurs from the excretion of excitatory neurotransmitters. The findings also implicate MG in the blocking of inhibitory neurotransmission.
Keywords: Colon, contraction, HC-030031, methylglyoxal, transient receptor potential ankyrin 1
|How to cite this article:|
Assiri A, Benham S, Prichard S, Benham C. Role of methylglyoxal as a transient receptor potential ankyrin 1 agonist in colon motility disturbances associated with diabetes. J Health Spec 2017;5:148-54
|How to cite this URL:|
Assiri A, Benham S, Prichard S, Benham C. Role of methylglyoxal as a transient receptor potential ankyrin 1 agonist in colon motility disturbances associated with diabetes. J Health Spec [serial online] 2017 [cited 2017 Aug 17];5:148-54. Available from: http://www.thejhs.org/text.asp?2017/5/3/148/210430
| Introduction|| |
The first and only member of the transient receptor potential ankyrin (TRPA) group of the TRP channels is the TRPA1 channel. It is a non-selective cation channel that is permeable to calcium ions. The TRPA1 channel is expressed in sensory neurons and non-sensory tissues such as the small intestine and colon.,, Methylglyoxal (MG), a highly reactive glucose metabolite, is considered an activator of the TRPA1 channel, especially in diabetics as MG is abundantly produced when hyperglycaemia occurs. Activation of TRPA1 by MG stimulates calcium influx, and thus it may participate in cytotoxicity and prompt apoptosis. In addition, an excess quantity of MG in diabetics leads to the development of oxidative stress. Various forms of gastrointestinal tract (GIT) dysfunction affect about 75% of diabetic patients. MG could also play a key role in initiating the symptoms of irritable bowel syndrome, such as diarrhoea.
In diabetics, colon dysfunction has been increasingly attributed to the damage caused by oxidative stress and apoptosis to the enteric nervous system. Inhibitory neuronal populations in the colon of diabetics are reduced, and implicitly, nitric oxide synthesis is low. However, another study showed that enhanced excitability, rather than damaged inhibitory control, mechanisms are the more likely cause for the increased spontaneous activity seen in diabetic colons.
The functions of the GIT are not only regulated by nerves but also by the enteroendocrine cells. The most prevalent of these cells found in the gut are enterochromaffin (EC) cells, which contain more than 90% of the serotonin in the body. It is widely acknowledged that the secretion of serotonin from EC cells is caused by increasing the concentration of intracellular calcium. Although TRPA1 is expressed in the mucosa, smooth muscle and the epithelial cells of the GIT, it is expressed in a higher amount in EC cells. TRPA1 agonists such as allyl isothiocyanate (AITC) raise the concentration of intracellular calcium in EC cells and hence increase the secretion of serotonin. The contractile functions of the GIT are activated by serotonin, which stimulates the 5-HT3 receptors found in the submucosal plexus (SMP) and in myenteric primary intrinsic afferent neurons. The investigation of the response of GIT contractility to MG was prompted by the anticipated presence of TRPA1 channels in EC cells within the gut and myenteric neurons.
Investigating the impact of cholinergic nerves on TRPA1 agonist (AITC)-evoked contractility of the colon was done with the aid of the muscarinic antagonist atropine. In the proximal colon, the presence of atropine had no effect on AITC-evoked contractile responses, but in the distal colon, atropine reduced AITC-evoked contractile responses.
This research was carried out to investigate the extent to which colon motility is affected by increased levels of MG (functioning as a TRPA1 agonist) and to provide an interpretation of the mechanisms underpinning the anticipated alterations in colon motility.
| Subjects and Methods|| |
Adult male Wistar rats with a weight of 0.25 – 0. 45 kg were kept in plastic containers with a sawdust surface covering, under closely regulated conditions. Up to the day on which the experiments were conducted, the rats were put on a laboratory diet (5LF5) and were provided a constant water source. The method by which the rats were euthanised was carbon dioxide asphyxiation with subsequent cervical dislocation. This study used the minimum number of rats possible, which were killed with the approval of a committee for animal care and in conformance with the norms stipulated by the UK Home Office and the UK Animal (Scientific Procedures) Act 1986. A midline abdominal incision was made to extract the entire portion of the rat intestine, which were placed into oxygenated Krebs–Henseleit solution, equilibrated with 95% O2 and 5% CO2. Diabetic rat distal colon segments were used in a set of experiments. To induce diabetes in the rats, a single streptozotocin injection (65 mg/kg, intraperitoneal) was administered to the rats. In the first 48 h following the injection, 2% sucrose water was given to the rats to avoid hypoglycaemia. A serum glucose level of ≥300 mg/dL was used as a confirmation test to verify the development of diabetes.
Tissue setup and tension measurements
Longitudinal muscle strips were prepared by employing the affixed mesenteric membrane as a marker to position the colon segments perpendicularly. Subsequently, scissors were used to open the colon segment along the mesenteric membrane to create a sheet. Longitudinal muscle strips about 1 cm in length and 0.3 cm in width were obtained by making a vertical cut in the muscle sheet. Both extremities of the longitudinal muscle strip were then tied with a thread, followed by placing the tissue in a 15 mL tissue bath containing Krebs–Henseleit solution (95% O2 and 5% CO2) at a temperature of 37°C. At the bottom of the bath, there was a hook to which the loop of the thread was tied, while the longer thread was attached to the isometric force transducer hook that was linked to an amplifier and a computer. The positioning of the tissue was outside the aeration stream, to minimise artefacts produced by aeration during force measurements. The isometric force transducer was held by a racking device, which steadily increased the applied force until the tissue was subjected to almost 1 g of tension.
By positioning the strips in the direction of the longitudinal muscle fibres, it was possible to measure longitudinal muscle activity. On the other hand, to measure the response of circular muscle, strips were rotated 90° before being introduced in the bath. To induce the release of neurotransmitters, and as a substitute for neural stimulation, the strips of muscle were positioned on a plastic plate between two platinum electrodes that were connected to an electrical stimulator. The lower and upper extremities of the strip were tied with thread to, respectively, the bottom end of the plate and to the force transducer. Electrical field stimulation (0.5, 5, 10, 15 and 20 Hz, with a 0.5 ms pulse duration and a voltage of 50 V, for 10 s for every 2 min) was applied to the tissues' neurons. A 5-min break was taken after every interval, and the bath solutions were replaced. In all experiments of this study, after the tissues were hanged, 40 min of equilibration time was allowed before starting drug administration or electrical field stimulation.
The responses of longitudinal and circular distal colonic smooth muscle were recorded in grams with the use of LabScribe data software. This software received and recorded the electrical signal produced by the force transducer based on the contraction and relaxation of the colon muscles.
Physiological solution (Krebs–Henseleit solution)
The preparation of 1 L of Krebs–Henseleit solution involved dissolving 6.9 g of sodium chloride, 0.36 g of potassium chloride, 0.29 g of magnesium sulphate, 0.16 g of potassium phosphate and 2.1 g of sodium bicarbonate in approximately 800 mL of distilled water. This was followed by the addition of 2 g of glucose to the stirred water. Subsequently, prior to adding it to the solution, 0.37 g of calcium chloride was dissolved independently in approximately 100 mL of distilled water. The reason for doing this was to prevent precipitation of the solution.
The drugs used in the experiments were MG (TRPA1 agonist), HC 030031 (TRPA1 antagonist), carbachol and atropine [Table 1], all of which were obtained from Sigma-Aldrich, UK. Dimethyl sulfoxide solvent was acquired from Fisher Scientific. From a pharmacological viewpoint, neither tissue tonus nor the contraction triggered by agonists was affected by the vehicles used. The impact of a larger drug concentration on distal colon motility was examined with the help of prepared serial dilutions of every drug.
Each result is represented as the mean ± standard error of the mean, with the number of experiments mentioned with the result's associated figure. GraphPad Prism, statistical software produced by GraphPad Company which is located in (San Diego, California) was used to perform the statistical analyses. Significances by unpaired t-test were donated by * P< 0.05, ** P< 0.001 and *** P< 0.0001, as compared to control.
| Results|| |
The effect of methylglyoxal on the spontaneous activity of the rat distal colon
The spontaneous activity of longitudinal muscle strips of non-diabetic rat distal colons (control) consisted of recurrent, low frequency and high-amplitude phasic contractions alternating with small amplitude and high frequency contractions [Figure 1]a. In contrast, the strips subjected to 10 mM MG incubation exhibited a somewhat different contraction pattern, with a decrease in the interval between high amplitude contractions and an increase in the area under the curve of high-amplitude contractions; moreover, the MG triggered the formation of multi-peak, high-amplitude contractions [Figure 1]b.
|Figure 1: The spontaneous activity of longitudinal muscle strips of non-diabetic rat distal colon (a) and of rat distal colon incubated with 10 mM methylglyoxal for 60 min (b) as demonstrated by organ bath recordings. Spontaneous contraction amplitudes of control strips, strips incubated with methylglyoxal (1 mM and 10 mM) and diabetic strips are expressed in grams (c). In comparison to control, unpaired t-test significance is given by *= P < 0.05, **= P < 0.001 and ***= P < 0.0001.|
Click here to view
The frequency of contractions in the control strips was 24.6 ± 4.5 per 10 min (600 s display time), whereas the interval after which the amplitude of the contractions arrived at a stable plateau was 33.8 ± 6.4 min. A similar frequency of contractions and time to plateau were recorded in the longitudinal muscle strips incubated with 1 mM and 10 mM MG although they possessed a significantly higher amplitude of spontaneous activity (0.635 ± 0.093 g and 0.812 ± 0.089 g, respectively) as compared to the control strips (0.342 ± 0.04 g). The amplitude of spontaneous activity in diabetic tissue (0.75 ± 0.108 g) was in particular greater than that of the control tissue [Figure 1]c.
The effect of methylglyoxal on carbachol-induced contractions in the rat distal colon
The contractions that carbachol triggered in the longitudinal smooth muscle of the rat distal colon displayed a direct correlation to its concentration. The minimal and maximal contractions triggered by carbachol occurred at 0.01 and 10 μM, respectively. The contraction of the longitudinal muscle to carbachol (1.38 g ± 0.214) was significantly enhanced in the presence of 1 mM MG and reached its highest point at 10 μM (2.37 g ± 0.321). In addition, the response of tissue to carbachol was considerably heightened in the presence of 10 mM of MG, producing a maximum contraction of 3.27 g ± 0.286 [Figure 2].
|Figure 2: Contraction dose–response curves of longitudinal smooth muscle of rat distal colons treated with carbachol (0.01 μM to 30 μM, displayed as 1 × 10-8 to 3 × 10-5 M) in the presence of 1 mM or 10 mM methylglyoxal. All values represent the mean ± standard error of the mean for six experiments. The mean and standard error of the mean are, respectively, indicated by markers and vertical lines. In comparison to the control, statistical significance (by unpaired t-test) is denoted as follows: *= P < 0.05, **= P < 0.001 and ***= P < 0.0001, for the 10 μM dose.|
Click here to view
The effect of methylglyoxal on electric field stimulation in the rat distal colon
Longitudinal muscle strips of rat distal colons displayed frequency-based contractions as a result of electric field stimulation (EFS) (0.5–20 Hz, 0.5 ms pulse duration, 50 V, for 10 s for every 2 min). It was established that the maximum response was obtained at 20 Hz with a maximum contraction of 2.16 g ± 0.323. No higher tissue contraction response was induced by the application of a 40 Hz electrical stimulus. Presence of 10 mM MG significantly enhanced the contractile response of the longitudinal muscle strips to EFS, with a maximum contraction of 3.64 g ± 0.421 that was achieved at 20 Hz [Figure 3].
|Figure 3: The contractile response of longitudinal smooth muscle strips of rat distal colon to electrical field stimulation (0.5–20 Hz, 0.5 ms pulse duration, 50 V, for 10 s) in the presence and absence of 10 mM methylglyoxal. All values represent the mean ± standard error of the mean for six experiments. In comparison to control, significance (by unpaired t-test) of the maximal response (at 20 Hz) is denoted as follows: *= P < 0.05.|
Click here to view
The effect of electric field stimulation on rat diabetic distal colons
The application of EFS (0.5–20 Hz, 0.5 ms pulse duration, 50 V, for 10 s every 2 min) to longitudinal smooth muscle strips from both normal and diabetic rat distal colons demonstrated that, for both tissue types, contraction increased in direct proportional to frequency. However, compared to normal distal colons, which had a maximum contraction of 1.98 g ± 0.19, EFS elicited higher responses in diabetic colons at every frequency, with a maximum contraction of 2.64 g ± 0.22 [Figure 4]. Furthermore, even though it was small (0.66 g), the discrepancy in response between diabetic and normal colons at 20 Hz was statistically significant (P < 0.0499).
|Figure 4: The contractile response of normal and diabetic rat distal colons to electric field stimulation (0.5–20 Hz, 0.5 ms pulse duration, 50 V, for 10 s). All values represent the mean ± standard error of the mean for six experiments. Statistical significance (by unpaired t-test) of the highest response achieved (at 20 Hz) is denoted as follows: *= P < 0.05.|
Click here to view
The effect of HC-030031 on electric field stimulation-triggered contraction in the presence of methylglyoxal
EFS was performed in the absence (control) and presence of 10 mM of MG; then, 10 μM of HC-030031 (selective TRPA1 antagonist) was incubated with the tissue for 30 min, and the EFS was performed again. As shown in [Figure 5], the presence of HC-030031 significantly diminished the MG-enhancement of EFS-induced contraction in the longitudinal smooth muscle of rat distal colons, with the maximum contraction being reduced from 3.783 g ± 0.421 (MG alone) to 2.723 g ± 0.22 (MG and HC-030031).
|Figure 5: Effect of 10 μM HC-030031 on the contractile response of longitudinal smooth muscle strips of rat distal colons to electric field stimulation (0.5–20 Hz, 0.5 ms pulse duration, 50 V, for 10 s) in the presence of 10 mM methylglyoxal. All values represent the mean ± standard error of the mean for six experiments. In comparison to strips incubated with methylglyoxal, significance (by unpaired t-test) of the maximum response attained (at 20 Hz) is denoted as follows: *= P < 0.05.|
Click here to view
The effect of methylglyoxal on electric field stimulation-triggered contraction in the presence of atropine in longitudinal muscle strips
The contractile response of the longitudinal muscle strips to EFS was significantly decreased after incubation of the tissues with 1 μM atropine. The response obtained at 20 Hz of EFS was significantly reduced by atropine from 1.96 g ± 0.123 to 0.989 g ± 0.245. Following concomitant incubation of tissues with 1 μM atropine and 10 mM MG, longitudinal smooth muscle strips were subjected to EFS. The presence of MG countered the suppressing effect of atropine on EFS-induced contraction; the response obtained at 20 Hz of EFS in the presence of MG was increased from 0.989 g ± 0.245 (atropine alone) to 1.821 g ± 0.116 (atropine and MG) [Figure 6].
|Figure 6: Effect of 10 mM methylglyoxal on the contractile response of longitudinal smooth muscle strips of rat distal colons to electric field stimulation (0.5–20 Hz, 0.5 ms pulse duration, 50 V, for 10 s) in the presence of 1 μM atropine. All values represent the mean ± standard error of the mean for six experiments. In comparison to strips that were incubated with atropine, significance (by unpaired t-test) of the maximum response produced (at 20 Hz) is denoted as follows: *= P < 0.05.|
Click here to view
The effect of methylglyoxal on electric field stimulation-triggered relaxation in the presence of atropine in circular muscle strips
Application of 1 μM atropine to circular smooth muscle strips of rat distal colons strengthened the relaxation response of the strips to EFS. However, the addition of 10 mM MG clearly reversed the atropine-induced relaxation and significantly decreased the relaxation response achieved at 20 Hz from 0.26 g ± 0.036 (atropine alone) to 0.055 g ± 0.046 (atropine and MG), as shown in [Figure 7].
|Figure 7: Effect of 10 mM methylglyoxal on the relaxation response of circular smooth muscle strips of rat distal colons to electric field stimulation (0.5–20 Hz, 0.5 ms pulse duration, 50 V, for 10 s) in the presence of 1 μM atropine. All values represent the mean ± standard error of the mean for five experiments. In comparison to strips incubated with atropine alone, significance (by unpaired t-test) of the maximum response produced (at 20 Hz) is denoted as follows: *= P < 0.05.|
Click here to view
| Discussion|| |
Effect of methylglyoxal on rat distal colon motility
The reactive intracellular metabolite MG occurs primarily as a synthesis by-product of triose phosphates formed during glycolysis or lipid peroxidation, and it can also be found in a number of other metabolic pathways. Hyperglycaemia causes an increase in MG production and is therefore found in the plasma of individuals with diabetes. In 1990, research posited that an increase in MG levels in experimental models of diabetes was due to downregulation of the MG detoxifying glyoxalase 1 system. In diabetic patients, MG plasma levels can reach levels surpassing 800 nM., Based on these plasma levels, it can be assumed that intracellular MG levels are considerably higher. The TRPA1 channel is receptive to MG, and when TRPA1 in sensory neurons is exposed to MG, the result is uncomfortable neuropathy., However, it is increasingly believed that TRPA1 has functions outside of sensory nerve activity such as in the small intestine and colon.
It has been noted in some reports that the increased motility in the colons of diabetes sufferers coincides with an increased presence of MG, but the connection has not been specifically tested. To determine whether such a connection exists, it was necessary to reproduce the diabetic state of increased MG production in mammals; to this end, distal colon longitudinal muscle strips from non-diabetic rats were incubated with MG. Even keeping in mind that the short timeframe experiments using cellular matter outside of its biological context are subject to limitations and do not completely reflect the highly complicated human body, it can still be posited that a positive result indicates a connection between elevated MG levels and colon motility. We found that increased levels of MG significantly increased spontaneous contraction of longitudinal muscle from distal rat colons, with the magnitude of the response increasing concurrently with dose. In line with this result, we found that the spontaneous activity in diabetic distal colons, which produces high and constant amounts of MG, was higher than the activity observed in control tissue [Figure 1]c. Spontaneous activity in the smooth muscle cells of the GIT has traditionally been considered to be myogenic in origin. This connection was made due to the inability of neural blockers to arrest such activity. It has been suggested that the interstitial cells of Cajal (ICC), first noted by Cajal in 1893, function as pacemaker cells, controlling the cyclical oscillation of smooth muscle cells. Two distinct types of ICCs have been identified in rat colons: ICC-Auerbach's plexus (AP) cells, which are located between the longitudinal and circular layers and are associated with the AP, and ICC-SMP cells, which are located in the submucosal surface of the circular muscle. ICC-SMP cells can be excluded as an essential factor in the stimulus of spontaneous contraction as spontaneous activity has been observed in colon strips lacking ICC-SMP cells. From the above explanation and in combination with our results, it could be concluded that TRPA1 channels in ICC-AP cells are activated by MG, which potentiates the neural signal that is transmitted from ICC-APs to smooth muscle cells, causing increased depolarisation and thus increased calcium influx, resulting in stronger contractions. However, we did not find a disparity in contraction frequency between control tissue samples and those incubated with MG. This suggests that the number of available ICC-APs is not affected by MG levels. These findings support a study done in 2003 which showed that increases in spontaneous activity in diabetic colons are probably due to higher excitability and not to reduced function of inhibitory control mechanisms.
In addition to the enhancement of spontaneous contractions, we found that MG significantly increased the contraction amplitude of longitudinal smooth muscle of rat distal colons in response to carbachol in a dose-dependent manner [Figure 2]. Similarly, MG increased the response of non-diabetic tissues to EFS [Figure 3]. In line with this result, diabetic distal colons, which produce high and constant amounts of MG, showed higher response to EFS than normal ones at all frequencies applied to the tissues [Figure 4].
One report has noted the effect of MG to activate TRPA1 channels and to raise the concentration of intracellular calcium in dorsal root ganglion neurons. This effect was also noted in human TRPA1-expressing HEK 293 cells. In our study, the role of TRPA1 channels in MG-mediated enhancement of contraction in colon tissue is supported by the use of HC-030031 (a TRPA1 antagonist). HC-030031, when tested against 48 enzymes, receptors and transporters in concentrations up to 10 μM, was found to have no significant activity against all of those proteins (MDS Pharma Service, Taipei). It is known that higher concentrations of HC-030031 (30 and 100 μM) inhibit acetylcholine-induced contractions and also have a non-specific antispasmodic effect. HC-030031 has also been proved not to block TRPV1, TRPV3, TRPV4 or TRPM8 channels , and can thus be stated to have a high selectivity profile. Based on this high selectivity profile of HC-030031, we used it to investigate whether MG exerted its effect on distal colon motility through the activation of TRPA1 channels. We found that incubation of longitudinal smooth muscle strips with 10 μM HC-030031 significantly reduced the potentiation effect of MG on the contractile response to EFS [Figure 5]. It can be concluded, therefore, that the application of MG to non-diabetic distal colon strips, or the elevated presence of MG in diabetic strips, activates TRPA1 channels and enables the influx of calcium into cells. Elevation of intracellular calcium concentration promotes the release of excitatory neurotransmitters and thus increases the response of longitudinal muscle strips of rat distal colon to carbachol and EFS.
In light of the conclusions above, the activity of MG to increase colon motility may be specifically attributable to the release of acetylcholine, which is one of the main excitatory neurotransmitters. When tested in the presence of atropine, which has an antispasmodic effect on smooth muscle contractions, MG significantly countered the suppressive effect of atropine on EFS-induced contraction. In other words, MG still potentiates the response of longitudinal smooth muscle strips of rat distal colons to EFS even in the presence of atropine [Figure 6]. This result suggests that MG might exert its effect by stimulating the release of acetylcholine and simultaneously stimulating the release of other excitatory neurotransmitters, such as serotonin, substance P and neurokinin.
A more pronounced relaxation response is produced by circular smooth muscle strips in response to EFS, and so these were used to fully investigate the action of MG on this inhibitory contraction mechanism, which is associated with nitric oxide. In addition, atropine was used to potentiate this relaxation response of circular smooth muscle strips. MG clearly reversed the EFS (and atropine)-induced relaxation and significantly decreased the relaxation response [Figure 7]. This indicates that MG might reduce the release of nitric oxide (which is an inhibitory neurotransmitter) or possibly even destroy neurons in the enteric and autonomic nervous system that produce nitric oxide. This observation was not surprising because the reduction in inhibitory control is an important factor that cannot be overlooked, particularly in diabetics.
Impaired synthesis of nitric oxide has been associated with increased contraction in diabetic rat colon tissue. A reduction has also been observed in inhibitory neuronal populations (specifically neuronal nitric oxide synthase, expressing neurons) in the enteric nervous system of diabetic patients that accompanies a reduction in the synthesis of nitric oxide.
Collectively, all these data can be taken to indicate that MG activates TRPA1 channels, enhancing excitatory mechanisms, while also reducing the release of nitric oxide, which acts as an inhibitory neurotransmitter. Together, these actions increase contraction in longitudinal muscle strips of rat distal colon when exposed to EFS and carbachol.
The possible therapeutic value of transient receptor potential ankyrin 1 antagonists
Activation of TRPA1 channels by MG, which is abundantly produced in diabetes as a result of continuous glycolysis, leads to apoptosis, and is implicated in other cytotoxic effects in neurons that innervate the GIT. Therefore, it is tempting to speculate that TRPA1 antagonists might have helpful effects to minimise the disturbances in GIT motility associated with diabetes.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM, Högestätt ED, et al.
Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 2004;427:260-5.
Stokes A, Wakano C, Koblan-Huberson M, Adra CN, Fleig A, Turner H. TRPA1 is a substrate for de-ubiquitination by the tumor suppressor CYLD. Cell Signal 2006;18:1584-94.
Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, et al.
ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 2003;112:819-29.
Orrenius S, Zhivotovsky B, Nicotera P. Regulation of cell death: The calcium-apoptosis link. Nat Rev Mol Cell Biol 2003;4:552-65.
Miyazawa N, Abe M, Souma T, Tanemoto M, Abe T, Nakayama M, et al.
Methylglyoxal augments intracellular oxidative stress in human aortic endothelial cells. Free Radic Res 2010;44:101-7.
Bytzer P, Talley NJ, Leemon M, Young LJ, Jones MP, Horowitz M. Prevalence of gastrointestinal symptoms associated with diabetes mellitus: A population-based survey of 15,000 adults. Arch Intern Med 2001;161:1989-96.
Zhang S, Jiao T, Chen Y, Gao N, Zhang L, Jiang M. Methylglyoxal induces systemic symptoms of irritable bowel syndrome. PLoS One 2014;9:e105307.
Chandrasekharan B, Anitha M, Blatt R, Shahnavaz N, Kooby D, Staley C, et al.
Colonic motor dysfunction in human diabetes is associated with enteric neuronal loss and increased oxidative stress. Neurogastroenterol Motil 2011;23:131-8, e26.
Forrest A, Parsons M. The enhanced spontaneous activity of the diabetic colon is not the consequence of impaired inhibitory control mechanisms. Auton Autacoid Pharmacol 2003;23:149-58.
Dockray GJ. Luminal sensing in the gut: An overview. J Physiol Pharmacol 2003;54 Suppl 4:9-17.
Nozawa K, Kawabata-Shoda E, Doihara H, Kojima R, Okada H, Mochizuki S, et al.
TRPA1 regulates gastrointestinal motility through serotonin release from enterochromaffin cells. Proc Natl Acad Sci U S A 2009;106:3408-13.
Gershon MD, Tack J. The serotonin signaling system: From basic understanding to drug development for functional GI disorders. Gastroenterology 2007;132:397-414.
Penuelas A, Tashima K, Tsuchiya S, Matsumoto K, Nakamura T, Horie S, et al.
Contractile effect of TRPA1 receptor agonists in the isolated mouse intestine. Eur J Pharmacol 2007;576:143-50.
Thornalley PJ. Pharmacology of methylglyoxal: Formation, modification of proteins and nucleic acids, and enzymatic detoxification – A role in pathogenesis and antiproliferative chemotherapy. Gen Pharmacol 1996;27:565-73.
Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001;414:813-20.
Thornalley PJ. The glyoxalase system: New developments towards functional characterization of a metabolic pathway fundamental to biological life. Biochem J 1990;269:1-11.
Han Y, Randell E, Vasdev S, Gill V, Gadag V, Newhook LA, et al.
Plasma methylglyoxal and glyoxal are elevated and related to early membrane alteration in young, complication-free patients with type 1 diabetes. Mol Cell Biochem 2007;305:123-31.
Nakayama K, Nakayama M, Iwabuchi M, Terawaki H, Sato T, Kohno M, et al.
Plasma alpha-oxoaldehyde levels in diabetic and nondiabetic chronic kidney disease patients. Am J Nephrol 2008;28:871-8.
Andersson DA, Gentry C, Light E, Vastani N, Vallortigara J, Bierhaus A, et al.
Methylglyoxal evokes pain by stimulating TRPA1. PLoS One 2013;8:e77986.
Ohkawara S, Tanaka-Kagawa T, Furukawa Y, Jinno H. Methylglyoxal activates the human transient receptor potential ankyrin 1 channel. J Toxicol Sci 2012;37:831-5.
Fernandes ES, Fernandes MA, Keeble JE. The functions of TRPA1 and TRPV1: Moving away from sensory nerves. Br J Pharmacol 2012;166:510-21.
Thuneberg L. Interstitial cells of Cajal: Intestinal pacemaker cells? Adv Anat Embryol Cell Biol 1982;71:1-130.
Plujà L, Albertí E, Fernández E, Mikkelsen HB, Thuneberg L, Jiménez M. Evidence supporting presence of two pacemakers in rat colon. Am J Physiol Gastrointest Liver Physiol 2001;281:G255-66.
Eberhardt MJ, Filipovic MR, Leffler A, de la Roche J, Kistner K, Fischer MJ, et al.
Methylglyoxal activates nociceptors through transient receptor potential channel A1 (TRPA1): A possible mechanism of metabolic neuropathies. J Biol Chem 2012;287:28291-306.
Capasso R, Aviello G, Romano B, Borrelli F, De Petrocellis L, Di Marzo V, et al.
Modulation of mouse gastrointestinal motility by allyl isothiocyanate, a constituent of cruciferous vegetables (Brassicaceae): Evidence for TRPA1-independent effects. Br J Pharmacol 2012;165:1966-77.
Eid SR, Crown ED, Moore EL, Liang HA, Choong KC, Dima S, et al
. HC-030031, a TRPA1 selective antagonist, attenuates inflammatory- and neuropathy-induced mechanical hypersensitivity. Mol Pain 2008;4:48.
McNamara CR, Mandel-Brehm J, Bautista DM, Siemens J, Deranian KL, Zhao M, et al.
TRPA1 mediates formalin-induced pain. Proc Natl Acad Sci U S A 2007;104:13525-30.
Yoneda S, Kadowaki M, Kuramoto H, Fukui H, Takaki M. Enhanced colonic peristalsis by impairment of nitrergic enteric neurons in spontaneously diabetic rats. Auton Neurosci 2001;92:65-71.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]