INHIBITION OF TOLL‐LIKE RECEPTOR‐4, NUCLEAR FACTOR‐κB AND MITOGEN‐ACTIVATED PROTEIN KINASE BY LIGNOCAINE MAY INVOLVE VOLTAGE‐SENSITIVE SODIUM CHANNELS

Abstract

We have shown previously that lignocaine inhibits the upregulation of inducible nitric oxide synthase (iNOS), a crucial factor that initiates the systemic inflammatory response during sepsis, possibly through voltage-sensitive sodium channels (VSSC). Toll-like receptor-4 (TLR-4), nuclear factor (NF)-kappaB and mitogen activated protein kinases (MAPKs) participate in the upstream regulation of iNOS expression induced by endotoxin. In the present study, we investigated the effects of lignocaine in the regulation of the expression of these enzymes. The role of VSSC in the effects of lignocaine was also investigated. Confluent murine macrophages (RAW264.7 cells) were randomized to receive lipopolysaccharide (LPS; 100 ng/mL), LPS + lignocaine (50 micromol/L), LPS + tetrodotoxin (TTX; 1 micromol/L; a VSSC inhibitor), LPS + lignocaine + veratridine (Ver; 50 micromol/L; a VSSC activator) or LPS + TTX + Ver. After reacting with LPS for 0, 15, 30, 45 and 60 min, cell cultures were harvested and enzyme expression was evaluated. We found that LPS significantly increased the concentrations of TLR-4, NF-kappaB and MAPKs, including extracellular regulated kinase (ERK), c-jun N-terminal kinase (JNK) and p38 MAPK, in activated macrophages. Lignocaine and TTX significantly attenuated the effects of LPS on TLR-4, NF-kappaB, ERK and p38 MAPK expression, but not on JNK. Veratridine mitigated the effects of lignocaine and TTX. These data demonstrate that lignocaine has significant inhibitory effects on the activation of TLR-4, NF-kappaB and MAPKs in activated macrophages. Moreover, these effects involve VSSC.

The Protective Effect of Lidocaine on Septic Rats via the Inhibition of High Mobility Group Box 1 Expression and NF-κB Activation

“…Therefore, NF- κ B activation plays an important role in the inflammatory response during sepsis [21, 22]. Lee et al [23] demonstrated that the blocking of voltage-sensitive sodium channels and inhibition of p38 mitogen-activated protein kinase might be involved in the inhibitory effect of lidocaine on the NF- κ B signaling pathway in RAW264.7 cells. However, Lang et al [20] reported that lidocaine could inhibit IL-8 and IL-10 secretion from intestinal cells via the inhibition of NF- κ B activation and decreased IkappaB phosphorylation.…”

Phenytoin Effects on Proliferation and Induction of IL1<i>β</i> and PGE2 in Pediatric and Adults’ Gingival Fibroblasts

“…No study has yet reported the probable effects of phenytoin on TLR-related signals. However, based on similar pharmacologic function of phenytoin and Lignocaine, which is a Na + channel-blocker that inhibits the effects of lipopolysaccharides on mitoionic activator proteins in macrophages, one might propose that phenytoin reduces the fibroblasts-related signals [50]. By considering the hyperplasia of phenytoin-treated fibroblasts, it might be concluded that this inhibitive influence is restricted to inflammatory responses and is not related to the drug cytotoxicity.…”

Protein Kinases and Pain

“…In ATP-activated cultured rat microglia, lidocaine inhibited p38 MAPK activation and attenuated the production of proinflammatory cytokines, including TNF-, IL-1 and IL-6 (Su et al, 2010). Furthermore, lidocaine significantly inhibited LPS-induced Tolllike receptor 4, NF-κB, ERK and p38 MAPK activation, but not JNK activation in LPSstimulated murine macrophages (Lee et al, 2008).…”