Standardized Centella asiatica extract ECa 233 alleviates pain hypersensitivity by modulating P2X3 in trigeminal neuropathic pain.

OBJECTIVE: During oral surgery and temporomandibular joint repositioning, pain hypersensitivity often occurs due to irritation or inflammation of the nerve endings in the orofacial region. This study aimed to investigate the effects of ECa 233, a Centella asiatica-standardized extract, on the development of mechanical hyperalgesia and allodynia induced by chronic constriction injury of the infraorbital nerve in mice. METHODOLOGY: The right infraorbital nerves of the mice were ligated. Oral carbamazepine (20 mg/kg) or ECa 233 (30, 100, or 300 mg/kg) was administered daily for 21 days. Von Frey and air-puff tests were performed on both sides of the whisker pad on days 0, 7, 14, and 21. Thereafter, the expression of purinergic receptor subtype 3 (P2X3) and voltage-gated sodium channel 1.7 (NaV1.7), a transmembrane protein, in the trigeminal ganglion and c-fos immunoreactivity-positive neurons in the trigeminal nucleus caudalis was assessed. RESULTS: After 21 days of infraorbital nerve ligation, the mice showed allodynia- and hyperalgesia-like behavior, P2X3 and NaV1.7 were upregulated in the trigeminal ganglion, and nociceptive activity increased in the trigeminal nucleus caudalis. However, the oral administration of carbamazepine (20 mg/kg), ECa 233 (100 mg/kg), or ECa 233 (300 mg/kg) mitigated these effects. Nevertheless, ECa 233 failed to affect NaV1.7 protein expression. CONCLUSION: Carbamazepine and ECa 233 can prevent pain hypersensitivity in mice. Considering the side effects of the long-term use of carbamazepine, ECa 233 monotherapy or combined ECa 233 and carbamazepine therapy can be used as an alternative for regulating the development of hypersensitivity in trigeminal pain. However, further detailed clinical studies should be conducted to provide comprehensive information on the use of ECa 233.

Standardized Centella asiatica extract ECa 233 alleviates pain hypersensitivity by modulating P2X3 in trigeminal neuropathic pain

Abstract During oral surgery and temporomandibular joint repositioning, pain hypersensitivity often occurs due to irritation or inflammation of the nerve endings in the orofacial region. Objective: This study aimed to investigate the effects of ECa 233, a Centella asiatica-standardized extract, on the development of mechanical hyperalgesia and allodynia induced by chronic constriction injury of the infraorbital nerve in mice. Methodology: The right infraorbital nerves of the mice were ligated. Oral carbamazepine (20 mg/kg) or ECa 233 (30, 100, or 300 mg/kg) was administered daily for 21 days. Von Frey and air-puff tests were performed on both sides of the whisker pad on days 0, 7, 14, and 21. Thereafter, the expression of purinergic receptor subtype 3 (P2X3) and voltage-gated sodium channel 1.7 (NaV1.7), a transmembrane protein, in the trigeminal ganglion and c-fos immunoreactivity-positive neurons in the trigeminal nucleus caudalis was assessed. Results: After 21 days of infraorbital nerve ligation, the mice showed allodynia- and hyperalgesia-like behavior, P2X3 and NaV1.7 were upregulated in the trigeminal ganglion, and nociceptive activity increased in the trigeminal nucleus caudalis. However, the oral administration of carbamazepine (20 mg/kg), ECa 233 (100 mg/kg), or ECa 233 (300 mg/kg) mitigated these effects. Nevertheless, ECa 233 failed to affect NaV1.7 protein expression. Conclusion: Carbamazepine and ECa 233 can prevent pain hypersensitivity in mice. Considering the side effects of the long-term use of carbamazepine, ECa 233 monotherapy or combined ECa 233 and carbamazepine therapy can be used as an alternative for regulating the development of hypersensitivity in trigeminal pain. However, further detailed clinical studies should be conducted to provide comprehensive information on the use of ECa 233.

Efficacy and mechanism of the antinociceptive effects of cannabidiol on acute orofacial nociception induced by Complete Freund's Adjuvant in male Mus musculus mice.

OBJECTIVES: The objectives were to investigate the efficacy and mechanisms of cannabidiol on orofacial nociception induced by Complete Freund's Adjuvant (CFA) in male Mus musculus mice. DESIGN: For the study of efficacy, mice were divided into seven groups: sham; inflammation; and cannabidiol 0.5, 1, 3, 5, and 10 mg. For the study of mechanisms of cannabidiol, mice were divided into six groups: sham, inflammation, calcitonin gene-related peptide (CGRP) antagonist with and without cannabidiol, and vanilloid receptor 1 antagonist with and without cannabidiol. Spontaneous pain-like behaviors, trigeminal nociception, and trigeminal modulating activity were investigated. RESULTS: CFA injected in the right masseter muscle significantly induced spontaneous pain-like behaviors and the trigeminal nociceptive pathway. This effect was inhibited by injection of 1, 3, 5, and 10 mg of cannabidiol. The 50 % inhibitory concentration of cannabidiol on antinociception was found to be 3 mg/kg. In addition, there was no difference in spontaneous pain-like behaviors with vanilloid receptor 1 antagonist injected before treatment with cannabidiol compared to saline control. Reduced c-fos expression was observed in the trigeminal nucleus caudalis and periaqueductal gray in the group injected with CGRP antagonist before treatment with cannabidiol. CONCLUSION: The antinociceptive effects of cannabidiol induced by acute orofacial nociception is mediated by vanilloid receptor 1 but not by CGRP. Cannabidiol can act with peripheral nonpeptidergic neurons and can be used as an alternative drug or as a synergistic medication in pain treatment.

The effects of oral Aloe vera on the efficacy of transplanted human endothelial cells and the expression of matrix metalloproteinases in diabetic wound healing.

BACKGROUND: Diabetic wounds are characterized by delayed healing and impaired angiogenesis. Aloe vera and human umbilical vein endothelial cells (HUVECs) are reported to facilitate wound healing, and the former also has hypoglycemic property. Matrix metalloproteinases are enzymes that play a role in diabetic wound pathogenesis. OBJECTIVE: To investigate whether oral Aloe vera can enhance the efficacy of HUVEC transplantation and inhibit the expression of matrix metalloproteinases in wound healing of diabetic mice. MATERIALS AND METHODS: BALB/c nude mice were randomly assigned into five groups: normal control group, diabetic group (DM), DM transplanted with HUVECs, DM treated with oral Aloe vera, and DM treated with combined HUVECs and oral Aloe vera. Diabetes was induced by streptozotocin. Bilateral full-thickness excision cutaneous wounds were created. At days 7 and 14 post-wounding, the following parameters were determined: blood glucose, wound area, wound perfusion, capillary vascularity, re-epithelialization rate and tissue VEGF levels. Tissue expressions of MMP-2 and MMP-9 were compared between the DM mice and those treated with oral Aloe vera. RESULTS: Over days 7 and 14, Aloe vera exerted glucose-lowering effect in diabetic mice. Higher wound closure rate, blood flow and capillary vascularity, and lower MMP-2 and MMP-9 expressions were observed at both time points in DM treated with Aloe vera group compared with DM group (P < 0.05). Moreover, combined therapy of HUVECs and oral Aloe vera was more effective than Aloe vera or HUVECs alone in increasing VEGF levels, capillary vascularity and wound perfusion. Blood glucose levels were negatively correlated with angiogenesis (P = 0.000. CONCLUSION: It is suggested that oral Aloe vera enhances the efficacy of HUVEC transplantation on diabetic wound angiogenesis, partly through improving glycemic control. Oral Aloe vera also promotes diabetic wound healing via inhibition of MMP-2 and MMP-9 expressions.