Fenamates Inhibit Human Sodium Channel Nav1.2 and Protect Glutamate-Induced Injury in SH-SY5Y Cells.

Voltage-gated sodium channels are crucial mediators of neuronal damage in ischemic and excitotoxicity disease models. Fenamates have been reported to have anti-inflammatory properties following a decrease in prostaglandin synthesis. Several researches showed that fenamates appear to be ion channel modulators and potential neuroprotectants. In this study, the neuroprotective effects of tolfenamic acid, flufenamic acid, and mefenamic acid were tested by glutamate-induced injury in SH-SY5Y cells. Following this, fenamates' effects were examined on both the expression level and the function of hNav1.1 and hNav1.2, which were closely associated with neuroprotection, using Western blot and patch clamp. Finally, the effect of fenamates on the expression of apoptosis-related proteins in SH-SY5Y cells was examined. The results showed that both flufenamic acid and mefenamic acid exhibited neuroprotective effects against glutamate-induced injury in SH-SY5Y cells. They inhibited peak currents of both hNav1.1 and hNav1.2. However, fenamates exhibited decreased inhibitory effects on hNav1.1 when compared to hNav1.2. Correspondingly, the inhibitory effect of fenamates was found to be consistent with the level of neuroprotective effects in vitro. Fenamates inhibited glutamate-induced apoptosis through the modulation of the Bcl-2/Bax-dependent cell death pathways. Taken together, Nav1.2 might play a part in fenamates' neuroprotection mechanism. Nav1.2 and NMDAR might take part in the neuroprotection mechanism of the fenamates. The fenamates inhibited glutamate-induced apoptosis through modulation of the Bcl-2/Bax-dependent cell death pathways.

Synthesis and characterization of bis(pyrazolyl)borate Ni(ii) complexes: ligand rearrangement and transformation.

Five examples of bis(pyrazolyl)borate Ni(ii) complexes 2-5, exhibiting C-HNi interactions, were readily prepared from the reactions of K[BBN(3-R1-4-R2-pz)2] with Ni(ii) precursors (Ni(acac)2 or NiCl2(PPh3)2) in dichloromethane or toluene. When R1 = R2 = H, complex 2a with square-planar geometry around the Ni centre and showing an unusual C-HNi anagostic interaction was obtained. In contrast, when R1 = Me, R2 = H or R1 = Me, R2 = Br, tetrahedral complexes 3 or 4 were formed preferentially with strong C-HNi agostic interactions, respectively. Additionally, some differences in the formation and transformation of 3 and 4 were also found including a 1,2-borotropic shift during the formation of 3 and a further geometrical transformation from tetrahedral 3 to square-planar 2b by the second 1,2-borotropic shift under continuous heating; in contrast, no ligand change and further conversion were found in 4. When the more hindered 3-iPr-substituted ligand 1d was introduced in the reaction, the hydrolysis and cleavage of one B-N bond in the ligand occurred, leading to the singly hydroxo-bridged complex 5. The experimental and theoretical results indicate that the preference to form a thermodynamically stable complex and then balancing with orbital energy should be the intrinsic reason for the reaction selectivity.

Fenamates inhibit human sodium channel Nav1.7 and Nav1.8.

Fenamates are N-substituted anthranilic acid derivatives, clinically used as nonsteroidal anti-inflammatory drugs (NSAIDs) in fever, pain and inflammation treatments. Previous studies have shown that they are also modulators of diverse ion channels, exhibiting either activation or inhibitory effects. However, the effects of fenamates on sodium channel subtypes are still unknown. In this study, fenamates, including mefenamic acid, flufenamic acid and tolfenamic acid, were examined by whole-cell patch clamp techniques on the sodium channels hNav1.7 and hNav1.8, which are closely associated with pain. The results showed that the mefenamic acid, flufenamic acid, and tolfenamic acid inhibited the peak currents of hNav1.7 and hNav1.8 in CHO cells stably expressing hNav1.7 and hNav1.8. However, much lighter inhibition effects of hNav1.8 were registered in the experimental system. Furthermore, the mefenamic acid, flufenamic acid and tolfenamic acid significantly affected the inactivation processes of hNav1.7 and hNav1.8 with I-V curves left-shifted to hyperpolarized direction. These data indicate that the inhibition effects of Nav1.7 and Nav1.8 by mefenamic acid, flufenamic acid and tolfenamic acid might contribute to their analgesic activity in addition to their inhibition of cyclooxygenase. These findings provide a basis for further studies in the discovery of other potential targets for NSAIDs.