The effect of protocatechuic acid on neuropathic pain and possible mechanism.

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.

Antinociception Induced by Moringa Stenopetela (Baker f.) Cufod. Leaves Extract and Possible Mechanisms of Action

Moringa stenopetala (Baker f.) Cufod., is an endemic species growing in the south of Ethiopia. M. stenopetala is often consumed as food and used in traditional medicine and it has also been traditionally used for relieving of pain in Ethiopia. This study aimed to investigate the antinociceptive effect and mechanisms of action of M. stenopetala leaves methanol extract in mice. The per-oral doses of 50, 100, and 200 mg/kg of M. stenopetala extract were tested for antinociceptive action by using hot-plate, tail-immersion, and writhing tests. The possible mechanisms of in the antinociceptive action were investigated by pre-treatment with 5 mg/kg naloxone (non-selective opioid antagonist), 1 mg/kg ketanserin (5-HT2A/2C receptor antagonist), and 1 mg/kg yohimbine (α2 adrenoceptor antagonist). The methanol extract of M. stenopetala showed antinociceptive effect in all tests. The significant involvement of 5-HT2A/2C receptors and α2 adrenoceptors in antinociception induced by M. stenopetala extract in the hot-plate and tail-immersion tests, as well as significant contribution of opioid receptors and α2 adrenoceptors in writhing test, were identified. In conclusion, these findings demonstrate that the methanol extract of M. stenopetala has potential in pain management. Thisstudywillcontributetonewtherapeuticapproachesandprovideguidancefornewdrug development studies.

The anxiolytic effect of perampanel and possible mechanisms mediating its anxiolytic effect in mice.

AIMS: The aim of this study is to investigate the anxiolytic activity of perampanel, a non-competitive antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors, which is approved for partial-onset seizures in patients with epilepsy, and its mechanism of action. MAIN METHODS: The anxiolytic activity of perampanel at the doses of 0.25, 0.5, 1, 2, and 4 mg/kg intraperitoneally (i.p.) was investigated in mice using elevated plus-maze, hole-board, and open-field tests. The findings were compared to the anxiolytic activity of gamma-aminobutyric acid type A benzodiazepine (GABAA/BZ) receptor allosteric modulator diazepam (1 mg/kg, i.p.) and AMPA antagonist GYKI-53655 (5 mg/kg, i.p.). The mechanisms of action of perampanel were evaluated by pre-treatment with GABAA/BZ receptor antagonist flumazenil (3 mg/kg, i.p.), serotonin 5-hydroxytryptamine 1A (5-HT1A) antagonist WAY-100635 (1 mg/kg, i.p.), and α2-adrenoreceptor antagonist yohimbine (5 mg/kg, i.p.). KEY FINDINGS: In the elevated plus-maze and open-field tests, perampanel at the dose of 0.5 mg/kg, and in the hole-board test, at the doses of 0.25, 0.5, and 1 mg/kg demonstrated an anxiolytic effect without altering the locomotor activity. The effect of perampanel was comparable to the effect of diazepam. Stimulation of GABAA/BZ and α2-adrenergic receptors contributed to the anxiolytic effect of perampanel, since significant antagonisms were determined in various behavioral parameters by the antagonist pre-treatments. SIGNIFICANCE: AMPA antagonism is believed to provide the determined anxiolytic activity of perampanel. Increased GABAergic tonus induced by AMPA receptor antagonism along with other systems, especially the noradrenergic system, might be involved in the anxiolytic activity.

Review: The nicotinic modulation of pain.

Pain is a physiological unpleasant sensation that associated with actual or potential tissue damage and affects the major part of human population. Numerous modulatory system control pain through a complex process. The drugs that regulate the modulators involving in this process are currently available; however, the studies to understand the process and develop new agents are still going on. In this review, it is aimed to relay information about how nicotinic receptors contribute the pain modulation. It is obvious that a wide variety of nicotinic receptors is located in both peripheral and central areas. Among these receptors α7, α4ß2 and α9α10 receptor subtypes draw attention in terms of pain modulation. The fact that different receptor subtypes involve in different processes of different pain conditions leads to provide beneficial results from the agonism of α7, α4ß2 and antagonism of α9α10. The major restraint of the usage of nAChR agonists is their adverse effects. However, nowadays, the side effects are reduced by the clinical developments. Additionally, positive allosteric modulators that amplify the effectiveness of nAChR ligands are in demand.

Evaluation of wound healing effect of chitosan-based gel formulation containing vitexin.

Acute or chronic wounds are one of the most common health problems worldwide and medicinal drugs or traditional remedies are often used in wound healing. Further studies regarding wound treatment are rapidly continuing. Vitexin is a phenolic compound, which is found in many medicinal plants, has different pharmacological effects such as anti-inflammatory, analgesic and antioxidant. In the present study, it is aimed to investigate the wound healing effect of formulation prepared as chitosan-based gel with vitexin in vivo and in vitro. Cytotoxicity and wound healing assays were used for in vitro and excisional wound model is used for in vivo studies. Extracted tissues from wound area were histologically examined. Wound healing process was monitored on 7, 14 and 21st days. When wound construction was evaluated, chitosan-based gel formulation containing vitexin demonstrated significant effect compared to control group. Histological examinations demonstrated that skin regeneration was promoted by vitexin formulation. Significant cell proliferation was observed with vitexin/chitosan dispersion in the wound healing assay performed with NIH 3T3 and HaCaT cells. In conclusion, our test substance chitosan-based gel formulation containing vitexin significantly accelerated wound healing both in vivo and in vitro.

Cannabinoid system involves in the analgesic effect of protocatechuic acid.

BACKGROUND: Protocatechuic acid is an antioxidant which is shown to have analgesic activity in limited studies. However, the mechanisms of action remain unclear. OBJECTIVES: It is aimed to investigate the possible contribution of cannabinoid system that supresses the nociceptive process by the activation of CB1 and CB2 receptors in central and peripheral levels of pain pathways, to the analgesic activity of protocatechuic acid. METHODS: The analgesic activity of protocatechuic acid was determined at the doses of 75, 150 and 300 mg/kg (i.p.) by acetic acid-induced writhing and tail-immersion tests in mice. The results were compared to the analgesic effect of 300 mg/kg (i.p.) dipyrone and non-specific CB receptor agonist 5 mg/kg (i.p.) WIN 55,212-2. For investigating the contribution of cannabinoid system to protocatechuic acid analgesia; pre-treatment with 8 mg/kg (i.p.) CB1 antagonist AM251 and 8 mg/kg (i.p.) CB2 antagonist AM630 were performed separately before 300 mg/kg protocatechuic acid administration. RESULTS: It was determined that protocatechuic acid has dose-dependent analgesic effect independently from locomotor activity and is comparable with effects of dipyrone and WIN 55,212-2. Pre-treatment with CB1 receptor antagonist AM251 significantly antagonized the protocatechuic acid-induced analgesia in the tail-immersion and writhing tests, whereas pre-treatment of CB2 receptor antagonist AM630 was found to be effective only in the tail-immersion test. CONCLUSION: It is concluded that cannabinoid modulation contributes to the analgesic effect of protocatechuic acid in spinal level rather than peripheral. CB1 receptor stimulation rather than CB2 receptor stimulation mediates the analgesic effect of protocatechuic acid in both levels, especially peripheral. Graphical abstract Protocatechuic acid inhibits pain response via cannabinoidergic system.

The possible mechanisms of protocatechuic acid-induced central analgesia.

It is aimed to investigate the central antinociceptive effect of protocatechuic acid and the involvement of stimulation of opioidergic, serotonin 5-HT2A/2C, α2-adrenergic and muscarinic receptors in protocatechuic acid-induced central analgesia in mice. Time-dependent antinociceptive effects of protocatechuic acid at the oral doses of 75, 150 and 300 mg/kg were tested in hot-plate (integrated supraspinal response) and tail-immersion (spinal reflex) tests in mice. To investigate the mechanisms of action; the mice administered 300 mg/kg protocatechuic acid (p.o.) were pre-treated with non-specific opioid antagonist naloxone (5 mg/kg, i.p.), serotonin 5-HT2A/2C receptor antagonist ketanserin (1 mg/kg, i.p.), α2-adrenoceptor antagonist yohimbine (1 mg/kg, i.p.) and non-specific muscarinic antagonist atropine (5 mg/kg, i.p.), respectively. The antinociceptive effect of protocatechuic acid was observed at the doses of 75, 150 and 300 mg/kg in tail-immersion test, at the doses of 150 and 300 mg/kg in hot-plate test at different time interval. The enhancement in the latency of protocatechuic acid-induced response to thermal stimuli was antagonized by yohimbine, naloxone and atropine in tail-immersion test, while it was antagonized only by yohimbine and naloxone pretreatments in hot-plate test. These results indicated that protocatechuic acid has the central antinociceptive action that is probably organized by spinal mediated cholinergic and opiodiergic, also spinal and supraspinal mediated noradrenergic modulation. However, further studies are required to understand how protocatechuic acid organizes the interactions of these modulatory systems. As a whole, these findings reinforce that protocatechuic acid is a potential agent that might be used for pain relief. Additionally, the clarification of the effect and mechanisms of action of protocatechuic acid will contribute to new therapeutic approaches and provide guidance for new drug development studies.

Valnoctamide: The effect on relieving of neuropathic pain and possible mechanisms.

The purpose of this study is to assess the possible anti-allodynic and antihyperalgesic effect of valnoctamide, an amide derivative of valproic acid, at the doses of 40, 70 and 100 mg/kg (i.p.) in neuropathic pain model induced by chronic constriction injury in rats, by using dynamic plantar test and plantar test (Hargreaves method), and to evaluate that the possible role of certain serotonin, noradrenergic, opioid and GABAergic receptors by pre-treatment with 1 mg/kg (i.p.) ketanserin, yohimbine, naloxone and 0.5 mg/kg (i.p.) bicuculline, respectively. 70 and 100 mg/kg valnoctamide significantly increased the mechanical and thermal thresholds decreasing with the development of neuropathy and demonstrated anti-allodynic and antihyperalgesic activity. Limited contribution of serotonin 5-HT2A/2C receptors and α2-adrenoceptors, and significant contribution of GABAA and opioid receptors to the anti-allodynic activity have been identified whereas remarkable contribution of opioid receptors and significant contribution of serotonin 5-HT2A/2C receptors, α2-adrenoceptors, GABAA receptors to the antihyperalgesic activity have been identified. Based upon these findings and considering that valnoctamide has safer side-effect profile, it is possible to say that valnoctamide is a potential agent that might be used alone or in combination with the other effective therapies in the alleviating of neuropathic pain.

The imidazoline receptors and ligands in pain modulation.

Pain is an unpleasant experience and effects daily routine negatively. Although there are various drugs, many of them are not entirely successful in relieving pain, since pain modulation is a complex process involving numerous mediators and receptors. Therefore, it is a rational approach to identify the factors involved in the complex process and develop new agents that act on these pain producing mechanisms. In this respect, the involvement of the imidazoline receptors in pain modulation has drawn attention in recent years. In this review, it is aimed to focus on the imidazoline receptors and their ligands which contribute to the pain modulation. It is demonstrated that imidazoline-2 (I2) receptors are steady new drug targets for analgesics. Even if the mechanism of I2 receptor is not well known in the modulation of pain, it is known that it plays a role in tonic and chronic pain but not in acute phasic pain. Moreover, the I2 receptor ligands increase the analgesic effects of opioids in both acute and chronic pain and prevent the development of opioid tolerance. So, they are valuable for the chronic pain treatment and also therapeutic coadjuvants in the management of chronic pain with opiate drugs due to the attenuation of opioid tolerance and addiction. Thus, the use of the ligands which bind to the imidazoline receptors is an effective strategy for relieving pain. This educational forum exhibits the role of imidazoline receptors and ligands in pain process by utilizing experimental studies.

Evaluation of the antithrombotic effects of Crataegus monogyna and Crataegus davisii in the carrageenan-induced tail thrombosis model.

CONTEXT: Crataegus species are widely used as herbal medicines for preventing cardiovascular diseases (CVDs). However, there are no studies on the effects of Crataegus monogyna Jacq. (Rosaceae) and C. davisii Browicz on thrombosis, which is an important mechanism in CVDs. OBJECTIVE: The purpose of this study was to investigate the antithrombotic effects of ethanol extracts of Crataegus monogyna (CMEx) and C. davisii (CDEx) leaves by using the carrageenan-induced tail thrombosis model. MATERIALS AND METHODS: The hind paw of each mouse was injected with 1% Type I carrageenan to induce thrombosis. CMEx was tested at the doses of 100, 200, and 300 mg/kg and CDEx at the dose of 50, 100, 200, and 300 mg/kg in comparison with heparin. The lengths of tail thrombosis were measured at the 24, 48, and 72 h. RESULTS: Does of 200 and 300 mg/kg CMEx showed significant effects (p < 0.01; p < 0.001) at 24 h when compared with the control group. The antithrombotic activity of 200 and 300 mg/kg CMEx showed a decrease at 48 and 72 h but the activity of 300 mg/kg dose of CMEx was still significant (p < 0.01). The activities of 50 and 100 mg/kg doses of CDEx were significant (p < 0.001; p < 0.01) between 24 and 72 h whereas 200 and 300 mg/kg CDEx did not show any significance. DISCUSSION AND CONCLUSIONS: CMEx and CDEx significantly inhibited the carrageenan-induced mouse tail thrombosis. Based on these results, it was concluded that CDEx and CMEx may potentially be used as therapeutic agents or complementary treatments against thrombosis.

Zonisamide: Antihyperalgesic efficacy, the role of serotonergic receptors on efficacy in a rat model for painful diabetic neuropathy.

AIMS: The purpose of this study was to compare the changes of antihyperalgesic effectiveness of zonisamide (25 and 50 mg/kg), an antiepileptic drug, on the early and late phases of neuropathy and to investigate the role of serotonergic descending inhibitory pain pathways in antihyperalgesic effectiveness of zonisamide in the streptozotocin-induced rat model for painful diabetic neuropathy. MAIN METHODS: The hot-plate and tail-immersion, to determine thermal thresholds, and paw pressure withdrawal tests, to determine mechanical thresholds, were performed as hyperalgesia tests. To investigate the role of serotonergic pathway, 1 mg/kg ketanserin (5-HT(2A/2C) antagonist) and ondansetron (serotonin 5-HT3 receptor antagonist) were used. KEY FINDINGS: Zonisamide enhanced pain thresholds significantly in the 3rd, 6th and 8th weeks as the reference drugs morphine (5 mg/kg) and carbamazepine (32 mg/kg, tested only in the 3rd week). There were no observed differences on the potency of antihyperalgesic effect between weeks and between doses. Each antagonist reversed the effect of zonisamide in the hot-plate and tail-immersion tests significantly, but, relatively in the paw pressure withdrawal tests. SIGNIFICANCE: These results support the role for zonisamide in the management of diabetic neuropathic pain in all phases. Serotonin 5-HT2A/2C and 5-HT3 receptors are involved in the antihyperalgesic effect of zonisamide by enhancement of thermal threshold, and partially by mechanical threshold, so they may not mediate mechanical hyperalgesia in diabetic neuropathy.

Investigation for anti-inflammatory and anti-thrombotic activities of methanol extract of Capparis ovata buds and fruits.

ETHNOPHARMACOLOGICAL RELEVANCE: Capparis ovata Desf. has wide natural distribution in Turkey and it is consumed in pickled form. Flower buds, root bark, and fruits of the plant are used traditionally due to their analgesic, anti-inflammatory, wound healing, anti-rheumatismal, tonic, and diuretic effects. AIM OF THE STUDY: The aim of this study was to investigate the possible anti-inflammatory and anti-thrombotic effects of methanol extracts prepared from flower buds (CBE) and fruits (CFE) of C. ovata. MATERIALS AND METHODS: Anti-inflammatory effects of CBE and CFE were assessed using carrageenan-induced and prostaglandin E2-induced mouse paw edema models. For the anti-thrombotic effect evaluation, carrageenan-induced tail thrombosis model was performed in mice. The extracts were administered intraperitonally (i.p.) at the doses of 100, 200, and 300 mg/kg. The anti-inflammatory effect of Capparis extracts were tested in comparison to 10 mg/kg diclofenac and anti-thrombotic activity to 10 and 100 IU heparin. RESULTS: CBE at the doses of 200, and 300 mg/kg and CFE at the doses of 100, 200, and 300 mg/kg showed significant anti-inflammatory activity and CFE reached therapeutic concentration early than CBE in carrageenan inflammation model. In prostaglandin E2 inflammation model, CBE and CFE exhibited significant inhibitory effects. The C. ovata extracts did not show remarkable anti-thrombotic effect. CONCLUSIONS: Based on the results obtained, it can be concluded that fruits of C. ovata have more potent anti-inflammatory effect than flower buds. It has been suggested that inhibition of cyclooxygenase pathway is one of the mechanisms of the activity. C. ovata may be potentially used as therapeutic agents for inflammatory diseases.

Effect of phenolic acids on functions of rat aorta, vas deferens and on metabolic changes in streptozotocin-induced diabetes.

OBJECTIVES: This study aimed to investigate the effects of antioxidant treatment on streptozotocin (STZ)-induced diabetic metabolic and smooth muscle (SM) complications in rats. MATERIALS AND METHODS: Threeweeks after STZ injection (i.v.), vehicle, p-OH benzoic (p-OHBA), protocatechic (PA) and gallic acids (GA) were separately administered (10 mg/kg each, i.p.) to the rats everyday for 3 weeks. Metabolic functions were observedregularly. The rats in all groups were sacrificed andaorta and Vas deferens were dissected. Theresponses of isolated organs to agonists (acetylcholine and phenylephrine) were recorded. RESULTS: Protocatechic acid prevented increase in food consumption and feces output significantly. The responses of isolated organs to agonists increased in the STZ-diabetic rats. The test drugs either prevented, exacerbated or didnot affect the SMchanges in the STZ-diabetic rats. CONCLUSIONS: It was concluded that p-OHBA, PA and GA may cause effects independently of their antioxidant effect and/or of diabeticcomplications. They may exhibit pro-oxidant activities in the experimental conditions applied.

Antithrombotic effects of ethanol extract of Crataegus orientalis in the carrageenan-induced mice tail thrombosis model.

INTRODUCTION: Crataegus species (common name is Hawthorn) are medicinal plants, which have flavonoids, triterpene acids, proanthocyanidins, and organic acids as main constituents, used in the treatment of cardiovascular diseases. One of the main causes of multiple cardiovascular diseases is intravascular thrombosis and current agents, which are used for the treatment and prevention of thrombosis, have some side effects. Therefore, new antithrombotic and thrombolytic agents are still needed. MATERIALS AND METHODS: Antithrombotic function of ethanol extract of Crataegus orientalis (COE) leaves was investigated in carrageenan-induced mice tail thrombosis model. Mice were injected with 40 µl (1%) carrageenan (Type I) dissolved in physiological saline by intraplantar administration in the right hind paw. After carrageenan injection, the extract was administered at the doses of 100, 200, and 300 mg/kg. Heparin was used as a positive control (10 and 100 IU). The length of tail-thrombosis was measured at 24th, 48th, and 72nd hours. RESULTS AND CONCLUSION: 100mg/kg COE and 10IU heparin were not significant when compared to control groups at the time interval (24-72 h) that results was obtained. At 24th hour, both 200 and 300 mg/kg of COE showed a significant antithrombotic activity (p<0.05 and p<0.01, respectively). However, 200 mg/kg COE lost its significance and there was a decrease in the significance values of 300 mg/kg COE (p<0.05) at 48 and 72 h. From these results, it was concluded that COE significantly inhibited carrageenan-induced mice tail thrombosis in vivo.

Antinociceptive effect of methanol extract of Capparis ovata in mice.

CONTEXT: Capparis ovata Desf. (Capparaceae) grows widely in Turkey. Flower buds and fruits of the plant are used in folk medicine for their analgesic, antirheumatismal, and diuretic effects. OBJECTIVE: This study evaluated the possible antinociceptive effect of the methanol extract of C. ovata (CME) in mice. MATERIALS: The antinociceptive effect of methanol extract, prepared with the C. ovata flower buds, was studied at the doses of 50, 100, and 200 mg/kg (i.p.) using tail-immersion, hot-plate, and writhing tests in mice. Morphine sulfate (5 mg/kg; i.p.) and dipyrone (100 mg/kg; i.p.) were used as reference analgesic agents. Naloxone (5 mg/kg; i.p.) was also tested. RESULTS: It was observed that the C. ovata extract had a significant antinociceptive effect in these tests. In the hot-plate and tail-immersion test results, the doses of 50, 100, and 200 mg/kg increased the percentage of the maximum possible effect (MPE%) value for nociception significantly according to the control value (P < 0.001). All doses of the extract decreased the number of acetic acid-induced abdominal constrictions in mice when compared with control group (P < 0.001). These effects were inhibited by pretreatment with naloxone. DISCUSSION AND CONCLUSION: Based on the results obtained, it can be concluded that CME is a potentially antinociceptive agent which acts as both at the peripheral and central levels.

Antinociceptive activity of methanol extract of fruits of Capparis ovata in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Capparis ovata Desf. and Capparis spinosa L. have wide natural distribution in Turkey and they are consumed in pickled form. Flower buds, root bark, and fruits of the plant are used in folk medicine due to their analgesic, wound healing, cell regeneration, tonic, and diuretic effects. AIM OF THE STUDY: In this study, we attempted to identify the possible antinociceptive action of methanol extract prepared from fruits of Capparis ovata. MATERIALS AND METHODS: Using tail immersion, hot plate and writhing tests, the antinociceptive effect of the methanol extract of Capparis ovata (MEC) fruits was assessed after intraperitoneal administration into mice. Morphine sulfate (5mg/kg; i.p.) and diclofenac (10mg/kg; i.p.) were used as reference analgesic agents. Naloxone (5mg/kg; i.p.) was also tested. RESULTS: MEC was studied at the doses of 50, 100, and 200mg/kg (i.p.) and exhibited significant antinociceptive activities in all tests used. The above-mentioned doses of the extract reduced the writhing responses by 32.21, 55.70, and 68.36%, respectively. MPE% were increased by 7.27, 12.07, 14.60% in the tail immersion, and 7.88, 11.71, 16.73% in the hot plate test at the tested doses, respectively. Naloxone antagonized antinociceptive effect at the doses of 100 and 200mg/kg whereas partially antagonized the effect of MEC at the dose of 50mg/kg. CONCLUSIONS: Based on the results obtained, it can be concluded that MEC has antinociceptive effects both at the peripheral and central levels.