Effects of a new potent analog of tocainide on hNav1.7 sodium channels and in vivo neuropathic pain models

Ghelardini, Carla; Desaphy, Jean-François; Muraglia, Marilena; Corbo, Filomena; Matucci, Rosanna; Dipalma, Antonella; Bertucci, Carlo; Pistolozzi, Marco; Nesi, Mascia; Norcini, Monica; Franchini, Carlo; Camerino, Diana Conte

doi:10.1016/j.neuroscience.2010.05.019

Cited by 38 publications

(25 citation statements)

References 40 publications

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“…Drugs that target Na v 1.7 activity could, thus, prove useful in conjunction with existing therapies. Na v -specific blockers are already in clinical use as local anaesthetics and, more recently, Na v 1.7-specific inhibitors are being developed for the treatment of pain (Bregman et al, 2011;Chowdhury et al, 2011;Clare, 2010;Ghelardini et al, 2010). Given its functional significance and marked upregulation in tumour tissue, we suggest that Na v 1.7 represents an important new target for therapeutic intervention and/or as a diagnostic and/or prognostic marker in NSCLC.…”

Section: -Test) Continuous Lines Indicatementioning

confidence: 96%

Functional expression of the voltage-gated sodium channel, Nav1.7, underlies epidermal growth factor-mediated invasion in human [R1.S1] non-small cell lung cancer cells

Campbell¹,

Main²,

FitzGerald³

2013

Journal of Cell Science

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SummaryVarious ion channels are expressed in human cancers where they are intimately involved in proliferation, angiogenesis, invasion and metastasis. Expression of functional voltage-gated Na + channels (Na v ) is implicated in the metastatic potential of breast, prostate, lung and colon cancer cells. However, the cellular mechanisms that regulate Na v expression in cancer remain largely unknown. Growth factors are attractive candidates; they not only play crucial roles in cancer progression but are also key regulators of ion channel expression and activity in non-cancerous cells. Here, we examine the role of epidermal growth factor receptor (EGFR) signalling and Na v in non-small cell lung carcinoma (NSCLC) cell lines. We show unequivocally, that functional expression of the a subunit Na v 1.7 promotes invasion in H460 NSCLC cells. Inhibition of Na v 1.7 activity (using tetrodotoxin) or expression (by using small interfering RNA), reduces H460 cell invasion by up to 50%. Crucially, non-invasive wild type A549 cells lack functional Na v , whereas exogenous overexpression of the Na v 1.7 a subunit is sufficient to promote TTX-sensitive invasion of these cells. EGF/EGFR signalling enhances proliferation, migration and invasion of H460 cells but we find that, specifically, EGFR-mediated upregulation of Na v 1.7 is necessary for invasive behaviour in these cells. Examination of Na v 1.7 expression at mRNA, protein and functional levels further reveals that EGF/ EGFR signalling via the ERK1/2 pathway controls transcriptional regulation of channel expression to promote cellular invasion. Immunohistochemistry of patient biopsies confirms the clinical relevance of Na v 1.7 expression in NSCLC. Thus, Na v 1.7 has significant potential as a new target for therapeutic intervention and/or as a diagnostic or prognostic marker in NSCLC.

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Section: -Test) Continuous Lines Indicatementioning

confidence: 96%

Functional expression of the voltage-gated sodium channel, Nav1.7, underlies epidermal growth factor-mediated invasion in human [R1.S1] non-small cell lung cancer cells

Campbell¹,

Main²,

FitzGerald³

2013

Journal of Cell Science

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“…8 Multiple lines of evidence show that they have been implicated in the development of inflammatory pain 9,10 and neuropathic pain. [11][12][13] Furthermore, dysregulation of VGSCs in injured sensory neurons is also involved in the development of painful peripheral neuropathy in a rat model of diabetes. [14][15][16][17] However, roles for Na V 1.7 and Na V 1.8 in colonic hypersensitivity in streptozotocin (STZ)-induced diabetic rats remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Colonic Hypersensitivity and Sensitization of Voltage-gated Sodium Channels in Primary Sensory Neurons in Rats with Diabetes

Song

Zhang

et al. 2015

J Neurogastroenterol Motil

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Background/AimsPatients with long-standing diabetes often demonstrate intestinal dysfunction and abdominal pain. However, the pathophysiology of abdominal pain in diabetic patients remains elusive. The purpose of study was to determine roles of voltage-gated sodium channels in dorsal root ganglion (DRG) in colonic hypersensitivity of rats with diabetes. MethodsDiabetic models were induced by a single intraperitoneal injection of streptozotocin (STZ; 65 mg/kg) in adult female rats, while the control rats received citrate buffer only. Behavioral responses to colorectal distention were used to determine colonic sensitivity in rats. Colon projection DRG neurons labeled with DiI were acutely dissociated for measuring excitability and sodium channel currents by whole-cell patch clamp recordings. Western blot analysis was employed to measure the expression of Na V 1.7 and Na V 1.8 of colon DRGs. ResultsSTZ injection produced a significantly lower distention threshold than control rats in responding to colorectal distention. STZ injection also depolarized the resting membrane potentials, hyperpolarized action potential threshold, decreased rheobase and increased frequency of action potentials evoked by 2 and 3 times rheobase and ramp current stimulation. Furthermore, STZ injection enhanced neuronal sodium current densities of DRG neurons innervating the colon. STZ injection also led to a significant upregulation of Na V 1.7 and Na V 1.8 expression in colon DRGs compared with age and sex-matched control rats. ConclusionsOur results suggest that enhanced neuronal excitability following STZ injection, which may be mediated by upregulation of Na V 1.7 and Na V 1.8 expression in DRGs, may play an important role in colonic hypersensitivity in rats with diabetes.

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“…Making the alkyl chain even longer seemed to be unnecessary due to local irritative effect and poor aqueous solubility, previously reported for the similar structures with longer N-alkyl chain in the pyrrolidine ring [22]. The cyclohexyl substituted derivatives 4n and 4o demonstrated practically the same level and duration of anaesthesia as their corresponding n-butyl analogues 4c, e. Interestingly, despite recent reports [25][26][27] on high in vitro sodium channel blocking potential of 2,6-xylidine analogue of 4m -NeP1 ( Fig. 1), introduction of a N-benzyl moiety into the pyrrolidine ring of ortho-toluidine derivative appeared to abolish anaesthetic activity.…”

Section: Surface Local Anaesthetic Activitymentioning

confidence: 75%

Synthesis, local anaesthetic and antiarrhythmic activities of N-alkyl derivatives of proline anilides

Kalinin¹,

Pantsurkin²,

Syropyatov³

et al. 2013

European Journal of Medicinal Chemistry

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We describe here the design, synthesis and evaluation of in vivo local anaesthetic and antiarrhythmic activities of a series of N-alkylproline anilides. Most of the compounds demonstrated surface anaesthetic activity higher than that of lidocaine, ropivacaine and bupivacaine. We established that the local anaesthetic activity was sensitive to structural variations in the substitution pattern at the aromatic ring and the type of alkyl group at the proline nitrogen atom. Some of the prepared N-alkylproline anilides possessed significant antiarrhythmic activity with higher therapeutic indexes than the reference drugs.

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Effects of a new potent analog of tocainide on hNav1.7 sodium channels and in vivo neuropathic pain models

Cited by 38 publications

References 40 publications

Functional expression of the voltage-gated sodium channel, Nav1.7, underlies epidermal growth factor-mediated invasion in human [R1.S1] non-small cell lung cancer cells

Functional expression of the voltage-gated sodium channel, Nav1.7, underlies epidermal growth factor-mediated invasion in human [R1.S1] non-small cell lung cancer cells

Colonic Hypersensitivity and Sensitization of Voltage-gated Sodium Channels in Primary Sensory Neurons in Rats with Diabetes

Synthesis, local anaesthetic and antiarrhythmic activities of N-alkyl derivatives of proline anilides

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