|Year : 2023 | Volume
| Issue : 5 | Page : 315-321
The effect of protocatechuic acid on neuropathic pain and possible mechanism
Melda Ozgurbuz Cici1, Nurcan Bektas2
1 Department of Pharmacology, Faculty of Pharmacy, Yeditepe University, Istanbul, Turkey
2 Department of Pharmacology, Faculty of Pharmacy, Anadolu University, Eskişehir, Turkey
|Date of Submission||06-May-2021|
|Date of Decision||06-Aug-2023|
|Date of Acceptance||29-Aug-2023|
|Date of Web Publication||02-Nov-2023|
Department of Pharmacology, Faculty of Pharmacy, Anadolu University, Eskişehir 26470
Source of Support: None, Conflict of Interest: None
OBJECTIVES: The goal of the research is to investigate the protocatechuic acid (PCA) potential action, a phenolic acid derivative, on pain induced by neuropathy and to determine its efficacy on activation of KATP type channels and A1 receptors.
MATERIALS AND METHODS: Neuropathic pain by cause of sciatic nerve damage was induced in Sprague-Dawley rats. Anti-allodynic and anti-hyperalgesic effects were evaluated with von Frey apparatus and Hargreave's plantar test apparatus, respectively. The effects of PCA at the doses of 75, 150 and 300 mg/kg, carbamazepine at the doses of 50 and 100 mg/kg, combination of low effective doses of PCA and carbamazepine were tested. Pretreatments 3 μg/kg DPCPX as adenosine A1 receptor antagonist and 60.7 nmol glibenclamide as KATP channel blocker were applied for mechanistic studies.
RESULTS: PCA showed anti-allodynic and anti-hyperalgesic effects without impairing locomotor activity. In addition, the combination treatment was found to be more effective than the separate individual treatments of drugs. KATP channel activation related with A1 receptor stimulation makes a significant contribution to the anti-allodynia and anti-hyperalgesia induced by PCA.
CONCLUSIONS: It can be said that PCA has similar effects with carbamazepine, which is used in clinical practice, and that PCA can take place as an adjuvant drug in neuropathic pain with the combination group. In addition, it is seen that the undesirable effects that drugs can cause alone can be avoided and a more effective treatment potential can be created with multiple mechanisms.
Keywords: Adenosine A1 receptor, KATP channels, mechanical allodynia, protocatechuic acid, thermal hyperalgesia
|How to cite this article:|
Cici MO, Bektas N. The effect of protocatechuic acid on neuropathic pain and possible mechanism. Indian J Pharmacol 2023;55:315-21
| » Introduction|| |
Neuropathy-induced pain is defined by the development of hyperalgesia and allodynia. It occurs mostly by a trauma, inflammation, or other diseases of nervous system. Current pharmacological approaches such as antidepressants and anticonvulsants provide a 30%–50% reduction in neuropathic pain symptoms in approximately 50% of patients. In additio, synergistic combinations of agents allow avoidance of side effects of drugs alone, as well as more effective treatment with a multitarget mechanism. Therefore, new drug research and also the studies about combination drug treatment strategies continues to increase due to complications including efficacy, undesirable effects, and tolerability problems.
Protocatechuic acid (PCA) is an anti-oxidant phenolic substance with various pharmacological activities, including antidiabetic, anti-inflammatory, anti-apoptotic, antihyperlipidemic, and neuroprotective activities. It has been clearly demonstrated that PCA is effective in acute pain in minimal number studies.,
KATP type K+ channels are a notable target in pain relief because they have an important role in the organizing of neuronal excitability. Another target mechanism known to be activated by the antiepileptic drug carbamazepine, used in the treatment of pain induced by neuropathy, is adenosine A1 receptors (A1Rs).
According to the data above, the potential effect of 75, 150 and 300 mg/kg p.o. doses of PCA on neuropathic pain was determined and the relationship of this activity with KATP channels and A1Rs was evaluated. Pain induced by neuropathy was constituted by sciatic nerve damage and the findings were evaluated in comparison to results of reference drug, carbamazepine. The participation of KATP channel activation and also A1R stimulation to the activities of PCA were examined using the glibenclamide (60.7 nmol, i.pl.) and DPCPX (3 μg/kg, i.pl.), respectively. In addition, it is also among the aims to evaluate the advantage of a combined use of carbamazepine and PCA with a combination group.
| » Materials and Methods|| |
PCA (Santa Cruz Biotechnology, Dallas, USA), Ketamine (Richter Pharma AG, Wels, Austria), Xylazine (Biovet, Ankara, Turkey), Carbamazepine (Sigma, St. Louis, MO, USA), KATP channel blocker Glibenclamide (Sigma), A1Rs antagonist DPCPX (Abcam, Istanbul Turkey).
Sprague-Dawley female adult rats (200–250 g) were used (n = 8 per group). Animals housed in adequately-ventilated areas set on a 12-h daytime/night time cycle at 22 ± 1°C. A few days before the experiments, they were moved to the experimental room under the same conditions and were accustomed to the experiment environment. Standard pellets and tap water were provided for feeding ad libitum. The experimental procedures were adhered to principles embraced by Experimental Animal Care and Use Guide. The procedures were agreed by the Local Ethics Committee of Anadolu University (No: 2018-41, September 11, 2018).
Experimental groups and drug administrations
Pain thresholds against to thermal and mechanical stimulus of rats were detected before the surgical procedure in order to determine the development of neuropathy due to chronic constriction injury (CCI). The animals were separated into 12 groups to evaluate the anti-hyperalgesic and anti-allodynic activities. One group was subjected to sham operation without damaging the nerve. Seven days after, the thermal and mechanical thresholds were measured again for evaluating effects of operations and were saved as baseline values. The drug doses administered were selected based on similar studies.,, Drug applications were made as followed [Table 1].
In order to evaluate locomotor activity with the activity cage, two separate groups (13th and 14th groups) with neuropathy model were formed. One group was administered with vehicle while the other group was administered with 300 mg/kg PCA which was found effective in the mechanistic studies.
Chronic constriction injury-induced neuropathy model
90 mg/kg i.p. ketamine and 10 mg/kg i.p. xylazine were applied for anesthetizing rats. Then, the right hind leg of the rat was fixed to form a right angle with the femur and about one cm incision was made to this leg along its longitudinal axis, distal to the hip and four mm to the femur. In order to reveal the sciatic nerve, the tissue and muscle layer on the upper part of the nerve are separated. Four loose knots are located on the nerve with 4/0 silk catgut (Dogsan, Trabzon, Turkey) unilaterally with equal intervals. In order to keep the knots in the appropriate position, a second knot was tied on each knot and the free ends were cut to one mm. Incision then sutured with 40 mm disposable suture (Pegelak, Dogsan, Istanbul, Turkey) and sterilized with iodine solution. After the operation, the animals were taken into separate cages and carefully observed until they came out of anesthesia and rested for the development of neuropathy for a week before drug administration.
Evaluation of pain thresholds
Electronic von Frey – Mechanical allodynia
Pain thresholds against mechanical stimulus were measured with the electronic von Frey device (Ugo Basile, No: 38450, Varese, Italy). The device sensor provides a continuous application of force using a metal filament tip over its entire force capacity (1 = 1000 gf) and automatically records the animal response. Each rat was placed in special plastic cages of the device and kept for 15–30 min to adapt to the conditions. Mechanical stimulation was applied with an increasing force perpendicular to the hind paw (mid-plantar) of the rat by means of a filament with a diameter of 0.5 mm. The power (grams = gf) in which the paw withdrawal took place was automatically recorded by the device. Three consecutive measurements for each rat were made and the average of the withdrawal latency against to stimuli was counted. In order not to damage the paw tissue, the force cut-off point was determined as 50 g.
Plantar test – Thermal hyperalgesia
Pain thresholds against thermal stimulus were measured with Hargreaves apparatus (Ugo-Basile, No: 37370). Before starting the test, the animals were placed in special cages of the device and kept for 15–30 min in order to acclimate to the environment. The movable radiant heat apparatus was placed under the glass base to coincide with the mid-plantar facet of the animal's hind paw. Reflex movements of the rat's paw were gauged as the withdrawal latency against to the radiant heat stimuli and recorded automatically. Three consecutive measurements were made and paw withdrawal time for each rat was calculated by taking the average of these values. In order not to damage the paw tissue, the cut-off time point was determined as 20 s.
Based on the thresholds obtained from the behavioral experiments, the percentage of maximum possible effect (% MPE) was determined as below:
MPE % = ([threshold measured postdrug-threshold measured predrug]/[cut-off value-threshold measured predrug]) × 100
The increase in the MPE % data was evaluated as anti-allodynic and anti-hyperalgesic activity, respectively.
Activity cage in the form of a plexiglass cage was used (Ugo-Basile, No: 47420). The infrared rays produced by the pieces on two opposite vertical sides of the device are interrupted by the horizontal and vertical motions of the animal and the interruptions are recorded. Movements of rats were recorded for 15 min.
Data analysis was performed with GraphPad Prism ver. 5.0 package program. For statistical evaluation of neuropathy development and activity cage results, Student's t-test was applied. One-way ANOVA with Tukey Honestly Significant Difference (HSD) test for evaluation of the action studies was performed. Two-way ANOVA with Bonferroni test for evaluation of the mechanistic experiments was performed. All data were indicated as mean ± (standard error of mean) and the level of significance was adjusted at P < 0.05.
| » Results|| |
Development of experimental neuropathy
As expected, the mechanical and thermal pain thresholds were not statistically change in the sham group. Lower thermal and mechanical pain thresholds were obtained from animals with nerve damaged (Data not shown). Animals that did not develop neuropathy (only two of animals) were excluded from the study and two animals were included in the study by ethical approval to preserve the number of animals in the groups.
Assessment of anti-allodynic activity
Increases in MPE % values of all groups were found to be statistically significant (***P < 0.001) when compared with the control group. It was determined that the MPE% value of the combination group was significantly (+++P < 0.001 and &&&P < 0.001) enhanced when compared to the groups administered alone [Figure 1].
|Figure 1: Maximum possible effect % values calculated from the mechanical allodynia thresholds of the groups administered with 75, 150 and 300 mg/kg protocatechuic acid, 50 and 100 mg/kg carbamazepine, and combination of 50 mg/kg carbamazepine with 150 mg/kg protocatechuic acid. ***P < 0.001; significance in comparison to the control, &&&P < 0.001; significance in comparison to 50 mg/kg carbamazepine, +++P < 0.001; significance in comparison to 150 mg/kg protocatechuic acid. One-way ANOVA with Tukey Honestly Significant Difference multiple comparison test were performed using ± standard error of mean values (n = 8). MPE = Maximum possible effect|
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Assessment of anti-hyperalgesic activity
MPE % values of all groups were found to be significantly (**P < 0.01, ***P < 0.001, ***P < 0.001, *P < 0.05, ***P < 0.001 and ***P < 0.001, respectively) increased in comparison to the control group. It was determined that the MPE% value of the combination group was enhanced significantly (&&&P < 0.001) when compared with the group in which 50 mg/kg carbamazepine was administered alone, but not 150 mg/kg PCA. While the effect of 150 and 300 mg/kg PCA was similar to that of 100 mg/kg carbamazepine, the effect of PCA at the dose of 300 mg/kg was significantly higher (&P < 0.05) compared to the effect of 50 mg/kg carbamazepine [Figure 2].
|Figure 2: Maximum possible effect % values calculated from the thermal hyperalgesia thresholds of the groups administered with 75, 150 and 300 mg/kg protocatechuic acid, 50 and 100 mg/kg carbamazepine, and combination of 50 mg/kg carbamazepine with 150 mg/kg protocatechuic acid. *P < 0.05, **P < 0.01, ***P < 0.001; significance in comparison to the control, &P < 0.05, &&&P < 0.001; significance in comparison to 50 mg/kg carbamazepine. One-way ANOVA with Tukey Honestly Significant Difference multiple comparison test were performed using ± standard error of mean values (n = 8). MPE = Maximum possible effect|
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The participation of KATP channels
Although glibenclamide pretreatment significantly (&&&P < 0.001) decreased both mechanical and thermal thresholds, the effects of PCA were remained significant (+++P < 0.001) [Figure 3].
|Figure 3: (a and b) The effect of preadministration of 60.7 nmol glibenclamide, KATP channel antagonist, before protocatechuic acid (300 mg/kg) administration on the thresholds of mechanical allodynia and thermal hyperalgesia. ***P < 0.001; significance in comparison to the alone vehicle group, &&&P < 0.001; significance in comparison to alone 300 mg/kg protocatechuic acid group, +++P < 0.001; significance in comparison to glibenclamide pretreated vehicle group. Two-way ANOVA with Bonferroni test were applied using ± standard error of mean values (n = 8). MPE = Maximum possible effect|
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The participation of adenosine A1 receptors
Although DPCPX preadministration significantly (&&P < 0.01 and &P < 0.05) reversed the mechanical and thermal thresholds, respectively, the effects of PCA remained significant (+++P < 0.001 and ++P < 0.01) [Figure 4].
|Figure 4: (a and b) The effect of 3 μg/kg preadministration of adenosine A1R antagonist DPCPX before 300 mg/kg protocatechuic acid administration on the thresholds of mechanical allodynia and thermal hyperalgesia. ***P < 0.001; significance in comparison to the alone vehicle group, &P < 0.05, &&P < 0.01; significance in comparison to alone 300 mg/kg protocatechuic acid group, ++P < 0.01, +++P < 0.001; significance in comparison to DPCPX pretreated vehicle group. Two-way ANOVA followed by Bonferroni test were applied using ± standard error of mean values (n = 8). MPE = Maximum possible effect|
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Effect on locomotor activity
The administration of PCA at the dose of 300 mg/kg caused no alteration in the horizontal (a) and vertical (b) motions [Figure 5].
|Figure 5: (a and b) The action of protocatechuic acid (300 mg/kg) on locomotion in activity cage experiments. Student's t-test was applied using ± standard error of mean values (n = 8)|
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| » Discussion|| |
In order to evaluate the allodynia and hyperalgesia, different pathological features of neuropathic pain, a reliable and easily repeatable model for peripheral neuropathy, CCI model was preferred. It was found that the thresholds against painful stimuli decreased on the 7th day and thermal hyperalgesia and mechanical allodynia developed which indicate neuropathic pain.
Symptoms of neuropathic pain of a neurological origin are usually managed by relieving allodynia and hyperalgesia in the patients. Mechanical allodynia is the sensation of pain caused by harmless stimuli such as light touch. It is stated that light touch which may cause spinal hyprerexcitability and mechanoreceptor inputs from Aβ fibers are perceived as pain. In addition, Aβ fibers may cause allodynia with the restructuring of the dorsal horn caused by degeneration in C fibers. It is valued that thermal stimulation is transmitted to the medulla spinalis with high-threshold, unmyelinated C fibers. Due to the differences in the pathways of painful thermal and mechanical stimuli, the mechanisms involved in these pathways, nociceptors, and fibers involved in transmission, not every drug may be similarly effective on both pathological events. First of all, it should be noted that females complain of chronic pain more than males and it is known that female rats are sensitive to neuropathic pain models. Therefore, female rats were preferred in this experimental study and the results were satisfactory. PCA was determined to have both dose-dependently anti-allodynic and anti-hyperalgesic actions in female rats. The detected efficacy of PCA was compared with the efficacy of 50 and 100 mg/kg carbamazepine which is an anticonvulsant agent and is also used in neuropathic pain control. While the anti-allodynic actions of 150 and 300 mg/kg PCA was comparable to that of 50 mg/kg carbamazepine, the anti-hyperalgesic actions were comparable to that of 100 mg/kg carbamazepine. Moreover, the anti-hyperalgesic action of PCA at the dose of 300 mg/kg was observed high than that of 50 mg/kg carbamazepine. Although carbamazepine is used clinically in neuropathic pain, it has many side effects that reduce patient compliance. For this reason, studies have turned to discovering drugs with safer side effect profiles and specification for the indication. In addition, an application that allows safer treatment is the use of combined drugs by taking advantage of the synergism between them. In this study, 150 mg/kg PCA was combined with 50 mg/kg carbmazepine to evaluate the possible synergism between PCA and carbamazepine. It was determined that combined drug therapy provided a more significant anti-allodynic and also anti-hyperalgesic effect compared to 150 and 300 mg/kg PCA and 50 and 100 mg/kg carbamazepine treatment. Based on these data, it can be thought that the use of PCA in combination with carbamazepine in the medication of neuropathic pain might be beneficial in avoiding dose-related side effects of carbamazepine. In addition, pain relieving drugs are preferred to act on neuropathic pain independently of locomotor activity. Data obtained from the activity cage of PCA at a dose of 300 mg/kg, which was determined to have a high analgesic effect, showed that locomotor activity remained unchanged. It may be said that the detected analgesic activity of PCA is not related to locomotor activity and also does not decrease or increase locomotor activity as a side effect. This result provides an advantage to the analgesia of PCA.
There are many modulator chemicals and ion channels involved in the pain and control process by regulating Aβ and C fiber conduction. It is important to elucidate various mechanisms that may play a role in relieving neuropathic pain for demonstrating the pharmacological effect profile of the active substance. In previous studies, limited data are available on the mechanisms mediating the acute analgesic activity of PCA. Arslan et al. reported that PCA exhibits an acute analgesic effect at spinal/supraspinal levels, including cholinergic, opioid, and noradrenergic systems. Neuropathic pain and its control are a complex process involving many chemicals. Therefore, pharmacological effects should be tested with different mechanism-based methods and mechanistic studies should be carried out with agonists and antagonists of the relevant systems. For elaborating the action mechanism of the effects, the influence of PCA on the KATP channel and the A1R has been investigated. Peripheral intraplantar preadministration of A1R antagonist DPCPX was performed to estimate the relationship of anti-allodynic and anti-hyperalgesic activity of PCA with A1R stimulation. It has been determined that the A1R antagonist provides an effective reversal of the effects of PCA. Therefore, it might be said that the peripheral action of PCA on neuropathic pain is accompanied by A1R stimulation. Studies have explained how central A1R activation provides pain control through various mechanisms. Peripheral mechanisms include pertussis toxin-sensitive G-protein mediated cAMP/PKA inhibition, NO/cGMP/PKG/KATP signalling pathway activation, and induction of the PLC signalling pathway. However, despite the antagonism observed in the effect, the fact that the effect of PCA continues to be significant indicates that different mechanisms are involved in the effect.
In this study, another antinociceptive mechanism investigated due to the tight relationship between them in addition to A1R stimulation in PCA-induced analgesia is KATP channel activation. For this purpose, peripheral intraplantar application of KATP channel antagonist glibenclamide was performed before PCA. Glibenclamide is known to specifically block KATP channels. It was observed that the anti-allodynic and anti-hyperalgesic actions of PCA were significantly reversed by glibenclamide. According to the data obtained, it can be said that the participation of KATP channel activation in the effect of PCA is clear. KATP channels show antinociceptive effect through both Aβ and C fibers in dorsal root ganglion neurons in neuropathic pain induced by nerve damage., Activation of these channels allows K+ ions to flow out of the cell and thus cell membrane repolarization or hyperpolarization occurs and this results in a decrease in membrane excitability and analgesia. In addition, in studies conducted with A1R agonists, it has been reported that the analgesia observed with A1R stimulation is mediated by activation of KATP channels in neurons.
| » Conclusions|| |
PCA showed anti-allodynic and anti-hyperalgesic activities similar to carbamazepine without altering locomotor activity. KATP channel activation accompanying A1R stimulation makes a significant contribution to the effects of PCA. It can be said that PCA has the potential to be used alone or as an adjunct to avoid toxicity and side effects of existing drugs alone or to enable more effective treatment with a multitarget mechanism in neuropathic pain management. However, this preclinical data should be detailed by performing new mechanistic studies in different models and animals in order to support the suggestion.
The authors also would like to thank PhD student Hazal Eken for their assistance in the pre-experimental process.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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