Age-Dependent Anti-migraine Effects of Valproic Acid and Topiramate in Rats

Background: Valproic acid (VPA) and topiramate (TPM), initially developed as antiepileptics, are approved for migraine prophylaxis in adults but not children. The differences in their antimigraine mechanism(s) by age remain unclear.Methods: A migraine model induced by intra-cisternal (i.c.) capsaicin instillation in pediatric (4–5 weeks) and adult (8–9 weeks) rats was pretreated with VPA (30, 100 mg/kg) or TPM (10, 30, 100 mg/kg). Noxious meningeal stimulation by the irritant capsaicin triggered trigeminovascular system (TGVS) activation mimicking migraine condition, which were assessed peripherally by the depletion of calcitonin gene-related peptide (CGRP) in sensory nerve fibers of the dura mater, the increased CGRP immunoreactivity at trigeminal ganglia (TG) and centrally by the number of c-Fos-immunoreactive (c-Fos-ir) neurons in the trigeminocervical complex (TCC). Peripherally, CGRP released from dural sensory nerve terminals of TG triggered pain signal transmission in the primary afferent of trigeminal nerve, which in turn caused central sensitization of the TGVS due to TCC activation and hence contributed to migraine.Results: In the VPA-treated group, the central responsiveness expressed by reducing the number of c-Fos-ir neurons, which had been increased by i.c. capsaicin, was significant in pediatric, but not adult, rats. Inversely, VPA was effective in peripheral inhibition of elevated CGRP immunoreactivity in the TG and CGRP depletion in the dura mater of adult, but not pediatric, rats. In TPM group, the central responsiveness was significant in both adult and pediatric groups. Peripherally, TPM significantly inhibited capsaicin-induced CGRP expression of TG in adult, but not pediatric, rats. Interestingly, the capsaicin-induced depletion of CGRP in dura was significantly rescued by TPM at high doses in adults, but at low dose in pediatric group.Conclusion: These results suggest VPA exerted peripheral inhibition in adult, but central suppression in pediatric migraine-rats. In contrast, TPM involves both central and peripheral inhibition of migraine with an optimal therapeutic window in both ages. These findings may clarify the age-dependent anti-migraine mechanism of VPA and TPM, which may guide the development of new pediatric anti-migraine drugs in the future

Plasma Calcitonin Gene-Related Peptide: A Potential Biomarker for Diagnosis and Therapeutic Responses in Pediatric Migraine

Background: Plasma calcitonin gene-related peptide (CGRP) plays a key role in the migraine pathophysiology. This study aimed to investigate its role in predicting diagnosis and outcome of pharmacotherapy in pediatric migraine.Methods: We prospectively recruited 120 subjects, who never took migraine-preventive agents in a pediatric clinic, including 68 patients with migraine, 30 with non-migraine headache (NM), and 22 non-headache (NH) age-matched controls. Short-term therapeutic response was measured for at least 2 weeks after the start of therapy. Responders were defined with >50% headache reduction. Plasma CGRP concentrations were measured by ELISA.Results: In the migraine group, more patients required acute therapy, as compared to the NM group (62/68, 91% vs. 5/30, 15%, p = 0.001). The mean plasma CGRP level in migraineurs either during (291 ± 60 pg/ml) or between (240 ± 48) attacks was higher than in NM patients (51 ± 5 pg/ml, p = 0.006 and 0.018, respectively) and NH controls (53 ± 6 pg/ml, p = 0.016 and 0.045, respectively). Forty-seven patients (69%) needed preventive treatments and had higher plasma CGRP levels (364 ± 62 pg/ml, n = 47) than those not (183 ± 54 pg/ml, n = 21) (p = 0.031). Topiramate responders had higher plasma CGRP levels than non-responders (437 ± 131 pg/ml, n = 14 vs. 67 ± 19 pg/ml, n = 6, p = 0.021). Survival curves of plasma CGRP levels also showed those with higher CGRP levels responded better to topiramate. Differences were not found in the other preventives.Conclusion: The plasma CGRP level can differentiate migraine from non-migraine headache. It may also serve as a reference for the therapeutic strategy since it is higher in patients requiring migraine prevention and responsive to short-term topiramate treatment. These results are clinically significant, especially for the young children who cannot clearly describe their headache symptoms and may provide new insights into the clinical practice for the diagnosis and treatment of pediatric migraine

Preliminary study on antinociceptove effect of aqueous extract of Boesenbergia pandurata in formalin-induced nociception test in mice

Pain is an unpleasant sensation associated with body state dysfunction that negatively affects the productivity of patients. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used as over-the-counter pain reliever medication due to its cost effectiveness. However, prolonged usage of NSAIDs usually accompanied with adverse side effects such as ulcer, nausea and even kidney failure. Hence, researchers are now focused on traditional herbal research to search for potential analgesic substances that are with minimal or no adverse effects. Boesenbergia pandurata，it is also known as temu kunci in Malaysia is a perennial herb that belongs to Zingiberaceae family. Boesenbergia pandurata is widely distributed in Southeast Asia and its rhizomes are commonly used as food ingredients or as traditional medicine to treat diseases conditions such as inflammation, cancer, and fungal infection. The aim of this study is to evaluate the inhibitory effect of aqueous extract of Boesenbergia pandurata (AEBP) on formalin-induced nociception test in mice. Mice were pre-treated with AEBP via intraperitoneal injection 30 min before challenged with intraplantar injection of formalin. It was demonstrated that intraperitoneal administration of AEBP at doses (0.3, 1, 3 and 10 mg/kg) produced significant antinociceptive response in both neurogenic and inflammatory phases of pain response induced by formalin. The findings indicated preliminary study on antinociceptive effect of AEBP, but further study should be conducted to explore the exact mechanism of pain inhibition by AEBP

Plasma and urine metabolite profiling reveals the protective effect of Clinacanthus nutans in an ovalbumin-induced anaphylaxis model: ¹H-NMR metabolomics approach

The present study sought to identify the key biomarkers and pathways involved in the induction of allergic sensitization to ovalbumin and to elucidate the potential anti-anaphylaxis property of Clinacanthus nutans (Burm. f.) Lindau water leaf extract, a Southeast Asia herb in an in vivo ovalbumin-induced active systemic anaphylaxis model evaluated by 1H-NMR metabolomics. The results revealed that carbohydrate metabolism (glucose, myo-inositol, galactarate) and lipid metabolism (glycerol, choline, sn-glycero-3-phosphocholine) are the key requisites for the induction of anaphylaxis reaction. Sensitized rats treated with 2000 mg/kg bw C. nutans extract before ovalbumin challenge showed a positive correlation with the normal group and was negatively related to the induced group. Further 1H-NMR analysis in complement with Kyoto Encyclopedia of Genes and Genomes (KEGG) reveals the protective effect of C. nutans extract against ovalbumin-induced anaphylaxis through the down-regulation of lipid metabolism (choline, sn-glycero-3-phosphocholine), carbohydrate and signal transduction system (glucose, myo-inositol, galactarate) and up-regulation of citrate cycle intermediates (citrate, 2-oxoglutarate, succinate), propanoate metabolism (1,2-propanediol), amino acid metabolism (betaine, N,N-dimethylglycine, methylguanidine, valine) and nucleotide metabolism (malonate, allantoin). In summary, this study reports for the first time, C. nutans water extract is a potential anti-anaphylactic agent and 1H-NMR metabolomics is a great alternative analytical tool to explicate the mechanism of action of anaphylaxis

Activity of cardamonin on chemical model of nociception in mice

Non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are among the most widely used medication in reducing pain. Prolonged usage of these drugs leads to undesirable side effects such as gastrointestinal bleeding, respiratory depression and tolerance. Thus, there is a demand to search for new pharmacologically potent analgesic compounds with fewer or no adverse effects. Cardamonin is a naturally occurring chalcone, which are commonly found in plant kingdom. Previous reports showed that cardamonin has anti-inflammatory effects and inhibit generation of nitric oxide and prostaglandin E2 via interruption of NF-κB pathway. In the present study, we evaluated the antinociceptive property of cardamonin using acetic acid-induced abdominal writhing test in mice. Cardamonin (0.3, 1, 3 and 10 mg/kg), vehicle (10 ml/kg) or indomethacin (10 mg/kg) was administered either intraperitoneally or orally, 30 minutes or 60 minutes respectively before injection of 0.8% acetic acid. The number of abdominal writhes was recorded for 30 minutes, starting from 5 minutes after acetic acid injection. Cardamonin showed significant reduction in abdominal writhes. These findings suggested that cardamonin exerted pronounced antinociceptive activity when assessed in chemical model of nociception in mice

Anti-allergic effect of Clinacanthus nutans aqueous extract: protection against IgE-mediated passive systemic anaphylaxis

Introduction: Anaphylaxis is a serious, rapid and potentially life-threatening allergic response involving IgE or IgG. Clinacanthus nutans, a small native shrub found in tropical Asia possess analgesic, anti-inflammatory and anti-viral activities and traditionally used for skin rashes, insect and snake-bites. In Thailand, alcoholic C. nutans extracts has been used topically for skin rashes, a symptom of allergy. Aim: To justify that C. nutans can treat skin rashes; this study investigated the anti-allergenicity of C. nutans extracts. Methods: Cytotoxicity of C. nutans extracts was evaluated by MTT on RBL-2H3. The most active C. nutans extract was determined by IgE-mediated mast cell degranulation. Acute toxicity of C. nutans aqueous extract was evaluated using female Sprague Dawley rats at 5000 mg/kg. Anti-allergenicity of C. nutans aqueous extract was studied by IgE-mediated passive systemic anaphylaxis (PSA). The release of preformed mediator (β-hexosaminidase) as well as newly synthesized mediators (TNF-α, IL-4 and LTC4) was evaluated. Results: C. nutans extracts were not cytotoxic up to 1 mg/ml (ethanolic) and 6 mg/ml (aqueous). In vitro, C. nutans aqueous extract was able to inhibit the release of preformed mediators but not newly synthesized mediators at 5 mg/ml. The ethanolic extracts were not able to inhibit all mediators tested. At 5000 mg/kg, C. nutans aqueous extract was non-toxic to the rats; no significant difference observed haematologically and biochemically. In vivo, C. nutans aqueous extract did not inhibit mediators of IgE-mediated PSA at 500 mg/kg and 2000 mg/kg. Conclusion: C. nutans aqueous extract was most active but could not inhibit mediators of IgE-mediated PSA. As anaphylaxis could be mediated by IgE orIgG, we postulate that C. nutans aqueous extract may exhibit its anti-allergenicity in IgG-mediated pathway

Zerumbone-induced antinociception: involvement of the L-arginine-nitric oxide-cGMP -PKC-K+ ATP channel pathways.

This study investigated the antinociceptive effects of zerumbone in chemical behavioural models of nociception in mice. Zerumbone given through intraperitoneal route (i.p.) produced dose-related antinociception when assessed on acetic acid-induced abdominal writhing test in mice. In addition, the i.p. administration of zerumbone exhibited significant inhibition of the neurogenic pain induced by intraplantar (i.pl.) injection of capsaicin and bradykinin. Likewise, zerumbone given by i.p. route reduced the nociception produced by i.pl. injection of glutamate and phorbol myristate acetate (PMA). The antinociception caused by zerumbone in the acetic acid test was significantly attenuated by i.p. pre-treatment of mice with l-arginine (nitric oxide precursor) and glibenclamide (ATP-sensitive K(+) channel inhibitor). However, the antinociception of zerumbone was enhanced by methylene blue (non-specific gyanylyl cyclase inhibitor). Together, these results indicate that zerumbone produces pronounced antinociception against chemical models of nociception in mice. It also strongly suggests that the l-arginine-nitric oxide-cGMP-PKC-K(+) ATP channel pathways, the TRPV1 and kinin B2 receptors play an important role in the zerumbone-induced antinociception

Antinociceptive activity of a synthetic curcuminoid analogue, 2,6-bis-(4-hydroxy-3-methoxybenzylidene)cyclohexanone, on nociception-induced models in mice.

This study investigated the potential antinociceptive efficacy of a novel synthetic curcuminoid analogue, 2,6-bis-(4-hydroxy-3-methoxybenzylidene)cyclohexanone (BHMC), using chemical- and thermal-induced nociception test models in mice. BHMC (0.03, 0.1, 0.3 and 1.0 mg/kg) administered via intraperitoneal route (i.p.) produced significant dose-related inhibition in the acetic acid-induced abdominal constriction test in mice with an ID50 of 0.15 (0.13–0.18) mg/kg. It was also demonstrated that BHMC produced significant inhibition in both neurogenic (first phase) and inflammatory phases (second phase) of the formalin-induced paw licking test with an ID50 of 0.35 (0.27–0.46) mg/kg and 0.07 (0.06–0.08) mg/kg, respectively. Similarly, BHMC also exerted significant increase in the response latency period in the hot-plate test. Moreover, the antinociceptive effect of the BHMC in the formalin-induced paw licking test and the hot-plate test was antagonized by pre-treatment with the non-selective opioid receptor antagonist, naloxone. Together, these results indicate that the compound acts both centrally and peripherally. In addition, administration of BHMC exhibited significant inhibition of the neurogenic nociception induced by intraplantar injections of glutamate and capsaicin with ID50 of 0.66 (0.41–1.07) mg/kg and 0.42 (0.38–0.51) mg/kg, respectively. Finally, it was also shown that BHMC-induced antinociception was devoid of toxic effects and its antinociceptive effect was associated with neither muscle relaxant nor sedative action. In conclusion, BHMC at all doses investigated did not cause any toxic and sedative effects and produced pronounced central and peripheral antinociceptive activities. The central antinociceptive activity of BHMC was possibly mediated through activation of the opioid system as well as inhibition of the glutamatergic system and TRPV1 receptors, while the peripheral antinociceptive activity was perhaps mediated through inhibition of various inflammatory mediators

HEXANIC FRACTION OF TURMERIC POWDER ATTENUATES MURINE MODEL OF INDUCEDNOCICEPTION AND ITS POSSIBLE MECHANISMS OF ACTION

Background: The current study was conducted to further examine the antinociceptive activity of hexane fraction of turmeric powder (HFTP) and to elucidate the possible mechanisms of action underlying its antinociceptive activity in various experimental models of chemical- and thermal-induced nociception. Materials and Methods: Acetic acid-induced abdominal constriction, hot-plate, formalin-, capsaicin- and glutamate-induced paw licking tests in mice were employed in the antinociceptive investigation of HFTP. In all experiments, HFTP was administered intraperitoneally at the doses of 0.1, 0.5, 1.0 and 5.0 mg/kg. In a separate group of experiments, the possible sedative and toxic effects of HFTP were tested in rota rod and preliminary acute toxicity tests, respectively. Results: It was demonstrated that HFTP exerted significant dose-dependent antinociceptive responses in the acetic acid-induced abdominal constriction, hot-plate, formalin-, capsaicin- and glutamate-induced paw licking tests. It was also demonstrated that pretreatment with naloxone, produced no significant effect on the antinociception induced by HFTP. Moreover, administration of HFTP shows no significant interference in locomotor activity of the rota rod test, and in the preliminary acute toxicity test, neither abnormal behaviours nor mortality were observed. Conclusion: Together, these results indicated that HFTP-induced antinociceptive activity at doses devoid of any detectable toxicity and sedative effects exerts pronounced peripheral and central antinociceptive effects, with no involvement of opioidergic system but possibly related to its ability to interact with TRPV1 receptors and the glutamatergic system

Hematological, biochemical, histopathological and 1H-NMR metabolomics application in acute toxicity evaluation of clinacanthus nutans water leaf extract

The present study aims for the first time to provide the in vivo acute toxicological profile of the highest dose of Clinacanthus nutans (Burm. f.) Lindau water leaf extract according to the Organization for economic co-operation and development (OECD) 423 guidelines through conventional toxicity and advanced proton nuclear magnetic resonance (1H-NMR) serum and urinary metabolomics evaluation methods. A single dose of 5000 mg/kg bw of C. nutans water extract was administered to Sprague Dawley rats, and they were observed for 14 days. Conventional toxicity evaluation methods (physical observation, body and organ weight, food and water consumption, hematology, biochemical testing and histopathological analysis) suggested no abnormal toxicity signs. Serum 1H-NMR metabolome revealed no significant metabolic difference between untreated and treated groups. Urinary 1H-NMR analysis, on the other hand, revealed alteration in carbohydrate metabolism, energy metabolism and amino acid metabolism in extract-treated rats after 2 h of extract administration, but the metabolic expression collected after 24 h and at Day 5, Day 10 and Day 15 indicated that the extract-treated rats did not accumulate any toxicity biomarkers. Importantly, the outcomes further suggest that single oral administration of up to 5000 mg/kg bw of C. nutans water leaf extract is safe for consumption