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Background Brain injury is the main cause of high mortality and disability after successful cardiopulmonary resuscitation (CPR) from sudden cardiac arrest (CA). The transient receptor potential M4 (TRPM4) channel is a novel target for ameliorating blood–brain barrier (BBB) disruption and neuroinflammation. Herein, we tested whether flufenamic acid (FFA), which is reported to block TRPM4 with high potency, could confer neuroprotection against brain injury secondary to CA/CPR and whether its action was exerted by blocking the TRPM4 channel. Methods Wild-type (WT) and Trpm4 knockout ( Trpm4 −/− ) mice subjected to 10-min CA/CPR were randomized to receive FFA or vehicle once daily. Post-CA/CPR brain injuries including neurologic deficits, survival rate, histological damage, edema formation, BBB destabilization and neuroinflammation were assessed. Results In WT mice subjected to CA/CPR, FFA was effective in improving survival and neurologic outcome, reducing neuropathological injuries, attenuating brain edema, lessening the leakage of IgG and Evans blue dye, restoring tight junction protein expression and promoting microglia/macrophages from the pro-inflammatory subtype toward the anti-inflammatory subtype. In comparison to WT mice, Trpm4 −/− mice exhibited less neurologic deficiency, milder histological impairment, more BBB integrity and more anti-inflammatory microglia/macrophage polarization. As expected, FFA did not provide a benefit of superposition compared with vehicle in the Trpm4 −/− mice after CA/CPR. Conclusions FFA mitigates BBB breach and modifies the functional status of microglia/macrophages, thereby improving survival and neurologic deficits following CA/CPR. The neuroprotective effects occur at least partially by interfering with the TRPM4 channel in the neurovascular unit. These results indicate the significant clinical potential of FFA to improve the prognosis for CA victims who are successfully resuscitated.

Mutations in five different genes encoding connexin channels cause eleven clinically defined human skin diseases. Keratitis ichthyosis deafness (KID) syndrome is caused by point mutations in the GJB2 gene encoding Connexin 26 (Cx26) which result in aberrant activation of connexin hemichannels. KID syndrome has no cure and is associated with bilateral hearing loss, blinding keratitis, palmoplantar keratoderma, ichthyosiform erythroderma and a high incidence of childhood mortality. Here, we have tested whether a topically applied hemichhanel inhibitor (flufenamic acid, FFA) could ameliorate the skin pathology associated with KID syndrome in a transgenic mouse model expressing the lethal Cx26-G45E mutation. We found that FFA blocked the hemichannel activity of Cx26-G45E in vitro, and substantially reduced epidermal pathology in vivo, compared to untreated, or vehicle treated control animals. FFA did not reduce the expression of mutant connexin hemichannel protein, and cessation of FFA treatment allowed disease progression to continue. These results suggested that aberrant hemichannel activity is a major driver of skin disease in KID syndrome, and that the inhibition of mutant hemichannel activity could provide an attractive target to develop novel therapeutic interventions to treat this incurable disease.

Burns are soft tissue injuries that require particular care for wound healing. Current tissue engineering approaches are aimed at identifying the most efficient treatment combinations to restore the tissue properties and function by using adapted scaffolds or delivery platforms for tissue repair and regeneration by triggering molecules. To reduce the inflammation associated with skin burns, the addition of an anti-inflammatory factor in these scaffolds would greatly increase the quality of the therapy. Therefore, this study is aimed at obtaining and validating a novel multiparticulate system based on a collagen matrix with controlled delivery of flufenamic acid anti-inflammatory drug for burn wound healing applications. In this work, we have characterized the properties and biocompatibility of these multiparticulate drug delivery systems (MDDS) and we have demonstrated their efficiency against burns and soft tissue lesions, particularly when the drug was microencapsulated, and thus with a controlled release. This study contributes to the advancement in therapy of burns and burn wound healing applications.

Food allergy (FA) is a common allergic disease without any currently available effective drug therapies. Mucosal mast cells (MMCs) play a particularly important role in FA, and the increase in their cytosolic Ca 2+ concentration ([Ca 2+ ] cyt ) is considered to be a principal component of the degranulation process. However, the mechanisms governing Ca 2+ influx remain poorly understood in MMCs. Recent reports have highlighted the functions of the transient receptor potential melastatin 2 (TRPM2) channel in immunocytes, including its role in monocyte chemokine production and macrophage phagocytic activity. Although TRPM2 gene expression has been demonstrated in mast cells, the significance of such expression remains virtually unknown. In this study, we found that antigen-stimulated degranulation was significantly reduced in mucosal-type bone marrow-derived mast cells (mBMMCs) prepared from TRPM2-knockout (TRPM2-KO) mice (TRPM2-KO mBMMCs) and was suppressed following the administration of three TRPM2 inhibitors with different chemical structures, including econazole, flufenamic acid (FFA), and 2-aminoethoxydiphenyl borate. Furthermore, the antigen-stimulated increase in [Ca 2+ ] cyt was significantly decreased in TRPM2-KO mBMMCs and was also suppressed by the TRPM2 inhibitors econazole and FFA. In addition, thapsigargin-induced increase in [Ca 2+ ] cyt was significantly decreased in TRPM2-KO mBMMCs. These results suggest that TRPM2 may participate in antigen-induced extracellular Ca 2+ influx and subsequent degranulation. In addition, TRPM2 inhibitors were shown to improve food allergic reactions in a mouse model. Together, these results suggest that TRPM2 inhibitors suppress MMC degranulation via regulation of the increase in [Ca 2+ ] cyt . Thus, TRPM2 may play a key role in degranulation by modulating intracellular Ca 2+ in MMCs.

Aims: To determine the long term outcome of systemic anti-inflammatory fibrosis suppression in cases of threatened trabeculectomy bleb failure in open angle glaucoma. Methods: This prospective non-comparative case series followed 77 eyes of 63 patients which showed signs of threatened early bleb failure and were treated with oral anti-inflammatory fibrosis suppression of prednisone, a non-steroidal anti-inflammatory agent, and colchicine taken for a mean period of 6 weeks, in addition to standard postoperative topical treatment, for a mean follow up of 6 years. Results: Trabeculectomy with anti-inflammatory fibrosis suppression controlled the IOP at ≤21 mm Hg with a probability of 0.91 (95% CI: 0.81 to 1.0) at 8 years and 0.89 (95% CI: 0.56 to 1.1) at 12 years. There were no reported cases of endophthalmitis, hypotonous maculopathy, late bleb leak, or serious systemic side effects. Conclusion: Anti-inflammatory fibrosis suppression provided good control of bleb fibrosis without risk of sight threatening complications in a patient group at high risk of bleb failure.

Non-selective (NSC) cation channels participate in the Ca(2+) leak of human erythrocytes. Sustained activity of these channels triggers suicidal erythrocyte death (eryptosis), which is characterized by Ca(2+)-stimulated cell shrinkage and phosphatidylserine (PS) exposure. PS-exposing erythrocytes are rapidly cleared from circulating blood. PGE(2) activates the NSC channels, and erythrocyte PGE(2) formation is stimulated by a decrease in intra- or extracellular Cl(-) concentration. In addition, the intraerythrocytic malaria parasite Plasmodium falciparum activates the NSC channels, most probably to accomplish Na(+) and Ca(2+) entry into the erythrocyte cytosol required for parasite development. By Ca(2+) uptake the parasite maintains a low Ca(2+) concentration in the erythrocyte cytosol and thus delays the suicidal death of the host erythrocyte. Flufenamic acid has previously been shown to inhibit NSC channels. The present study thus explored the effect of flufenamic acid on erythrocyte Ca(2+) entry, on suicidal erythrocyte death and on intraerythrocytic growth of P. falciparum. Within 48 h, replacement of extracellular Cl(-) with gluconate or application of PGE(2) (50 microM) increased Fluo3 fluorescence reflecting cytosolic Ca(2+) activity, decreased forward scatter reflecting cell volume and increased annexin V binding reflecting PS exposure in FACS analysis. All those effects were significantly blunted in the presence of flufenamic acid (10 microM). Flufenamic acid (25 microM) further significantly delayed the intraerythrocytic growth of P. falciparum and the PS exposure of the infected erythrocytes. The present observations disclose a novel effect of flufenamic acid, which may allow the pharmacological manipulation of erythrocyte survival and the course of malaria.

Flufenamic acid (Arlef 100 - PD) is an anti-inflammatory analgesic offered for the relief of pain in rheumatic conditions. It should therefore be considered in comparison with established drugs which are used for this purpose, such as aspirin, phenylbutazone and the corticosteroids. Like mefenamic acid (Ponstan - PD) which we discussed in 19641 it is an anthranilic acid derivative: both drugs have similar anti-inflammatory properties but flufenamic acid is relatively more active in this respect.