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Nefopam is more potent than carbamazepine for neuroprotection against veratridine in vitro and has anticonvulsant properties against both electrical and chemical stimulation

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Summary.

Nefopam (NEF) is a known analgesic that has recently been shown to be effective in controlling both neuropathic pain and convulsions in rodents. In this study we compared nefopam to carbamazepine (CBZ), a reference antiepileptic drug (AED), for their ability to protect cerebellar neuronal cultures from neurodegeneration induced by veratridine (VTD). Furthermore, we tested nefopam for protection against both, maximal electroshock-induced seizures (MES), and isoniazid-induced seizures in mice. Both NEF and CBZ were effective in preventing both signs of excitotoxicity and neurodegeneration following exposure of cultures to 5 µM veratridine for 30 min and 24 h, respectively. Concentrations providing full neuroprotection were 500 µM CBZ and 50 µM NEF, while the concentration providing 50% neuroprotection was 200 µM for CBZ and 20 µM for NEF. Neither NEF nor CBZ reduced excitotoxicity following direct exposure of cultures to glutamate, but CBZ failed to reduce increases in intracellular calcium following stimulation of L-type voltage sensitive calcium channels. In vivo, NEF (20 mg/kg i.p.) significantly reduced MES and fully prevented MES-induced terminal clonus (TC). In comparison, NEF was significantly more effective than CBZ in preventing MES, although both drugs were equally effective against MES-induced TC. Furthermore, nefopam provided protection against isoniazid-induced seizures at doses similar to those protecting against MES.

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References

  • S Ahmad LJ Fowler PS Whitton (2005) ArticleTitleLamotrigine, carbamazepine and phenytoin differentially alter extracellular levels of 5-hydroxytryptamine, dopamine and amino acids Epilepsy Res 63 141–149 Occurrence Handle15777732 Occurrence Handle10.1016/j.eplepsyres.2005.02.002 Occurrence Handle1:CAS:528:DC%2BD2MXjtF2hs74%3D

    Article  PubMed  CAS  Google Scholar 

  • P Alfonsi F Adam A Passard B Guignard DI Sessler M Chauvin (2004) ArticleTitleNefopam, a nonsedative benzoxazocine analgesic, selectively reduces the shivering threshold in unanesthetized subjects Anesthesiology 100 37–43 Occurrence Handle14695722 Occurrence Handle10.1097/00000542-200401000-00010 Occurrence Handle1:CAS:528:DC%2BD3sXhtVWhtb7J

    Article  PubMed  CAS  Google Scholar 

  • AF Ambrosio AP Silva JO Malva P Soares-da-Silva AP Carvalho CM Carvalho (1999) ArticleTitleCarbamazepine inhibits L-type Ca2+ channels in cultured rat hippocampal neurons stimulated with glutamate receptor agonists Neuropharmacology 38 1349–1359 Occurrence Handle10471089 Occurrence Handle10.1016/S0028-3908(99)00058-1 Occurrence Handle1:CAS:528:DyaK1MXltlKktL8%3D

    Article  PubMed  CAS  Google Scholar 

  • JP Belleville F Dorey JW Bellville (1979) ArticleTitleEffects of nefopam on visual tracking Clin Pharmacol Ther 26 457–463 Occurrence Handle487693 Occurrence Handle1:STN:280:DyaL3c%2Fitlaktw%3D%3D

    PubMed  CAS  Google Scholar 

  • R Bernasconi P Martin AF Steulet C Portet T Leonhardt M Schmutz (1992) ArticleTitleEffects of benzodiazepine receptor ligands with different intrinsic activities on seizures induced by inhibition of GAD Epilepsy Res Suppl 8 87–96

    Google Scholar 

  • GE Biella A Groppetti A Novelli MT Fernández-Sánchez B Manfredi ML Sptgiu (2003) ArticleTitleNeuronal sensitization and its behavioral correlates in a rat model of neuropathy are prevented by a cyclic analog of orphenadrine J Neurotrauma 20 593–601 Occurrence Handle12906743 Occurrence Handle10.1089/089771503767168519

    Article  PubMed  Google Scholar 

  • WA Catterall (1987) ArticleTitleCommon modes of drug action on Na+ channels: local anesthetics, antiarrythmics and anticonvulsants Trends Pharmacol Sci 8 57–65 Occurrence Handle10.1016/0165-6147(87)90011-3 Occurrence Handle1:CAS:528:DyaL2sXhs1yhu78%3D

    Article  CAS  Google Scholar 

  • G De Sarro C Ascioti ED di Paola MJ Vidal A De Sarro (1992) ArticleTitleEffects of antiepileptic drugs, calcium channel blockers and other compounds on seizures induced by activation of voltage dependent L calcium channel in DBA/2 mice Gen Pharmacol 23 1205–1216 Occurrence Handle1283140 Occurrence Handle1:CAS:528:DyaK3sXpsVWqsQ%3D%3D

    PubMed  CAS  Google Scholar 

  • NW Dunham TS Miya (1957) ArticleTitleA note on a simple apparatus for detecting neurological deficit in rats and mice J Am Pharmaceut Assoc 46 208–209 Occurrence Handle1:STN:280:DyaG1c%2FksV2htw%3D%3D Occurrence Handle10.1002/jps.3030460322

    Article  CAS  Google Scholar 

  • E Esposito S Romandini E Merlo-Pich T Mennini R Samanin (1986) ArticleTitleEvidence of the involvement of dopamine in the analgesic effect of nefopam Eur J Pharmacol 128 157–164 Occurrence Handle3098570 Occurrence Handle10.1016/0014-2999(86)90762-4 Occurrence Handle1:CAS:528:DyaL28Xls1CqsrY%3D

    Article  PubMed  CAS  Google Scholar 

  • OB Fasmer OG Berge HA Jørgensen K Hole (1987) ArticleTitleAntinoceptive effects of (±)-, (+)- and (−) nefopam in mice J Pharm Pharmacol 39 508–511 Occurrence Handle2886617 Occurrence Handle1:CAS:528:DyaL2sXkvV2rsr0%3D

    PubMed  CAS  Google Scholar 

  • MT Fernández V Zitko S Gascón A Novelli (1991) ArticleTitleThe marine toxin okadaic acid is a potent neurotoxin for cultured cerebellar neurons Life Sci 49 PL157–PL162 Occurrence Handle1658510 Occurrence Handle10.1016/0024-3205(91)90398-U

    Article  PubMed  Google Scholar 

  • MT Fernández-Sánchez R Díaz-Trelles A Groppetti B Manfredi AT Brini G Biella ML Sotgiu A Novelli (2001) ArticleTitleNovel effect of nefopam preventing cGMP increase, oxygen radical formation and neuronal death induced by veratridine Neuropharmacology 41 935–942 Occurrence Handle11747898 Occurrence Handle10.1016/S0028-3908(01)00139-3

    Article  PubMed  Google Scholar 

  • MT Fernández-Sánchez R Díaz-Trelles A Groppetti B Manfredi AT Brini G Biella ML Sotgiu A Novelli (2002) ArticleTitleNefopam, an analogue of orphenadrine, protects against both NMDA receptor-dependent and independent veratridine-induced neurotoxicity Amino Acids 23 31–36 Occurrence Handle12373515 Occurrence Handle10.1007/s00726-001-0106-6 Occurrence Handle1:CAS:528:DC%2BD38Xns1Gnsrc%3D

    Article  PubMed  CAS  Google Scholar 

  • NB Finnerup H Gottrup TS Jensen (2002) ArticleTitleAnticonvulsants in central pain Expert Opin Pharmacother 3 1411–1420 Occurrence Handle12387687 Occurrence Handle10.1517/14656566.3.10.1411 Occurrence Handle1:CAS:528:DC%2BD38XnvFOhtrc%3D

    Article  PubMed  CAS  Google Scholar 

  • RW Fuller HD Snoddy (1993) ArticleTitleEvaluation of nefopam as a monoamine uptake inhibitor in vivo in mice Neuropharmacology 32 995–999 Occurrence Handle7507578 Occurrence Handle10.1016/0028-3908(93)90064-A Occurrence Handle1:CAS:528:DyaK2cXksFOjtA%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • JC Gasser JW Bellville (1975) ArticleTitleRespiratory effects of nefopam Clin Pharmacol Ther 18 175–179 Occurrence Handle1097153 Occurrence Handle1:CAS:528:DyaE2MXlt1KntLs%3D

    PubMed  CAS  Google Scholar 

  • HU Gerbershagen E Schaffner (1979) ArticleTitleRespiratory effect of nefopam Clin Ther 2 IssueIDSuppl B 17 39–42

    Google Scholar 

  • F Guirimand X Dupont D Bouhassira L Brasseur M Chauvin (1999) ArticleTitleNefopam strongly depresses the nociceptive flexion (R(III)) reflex in humans Pain 80 399–404 Occurrence Handle10204754 Occurrence Handle10.1016/S0304-3959(98)00238-3 Occurrence Handle1:CAS:528:DyaK1MXht1OksLw%3D

    Article  PubMed  CAS  Google Scholar 

  • RC Heel RN Brogden GE Pakes TM Speight GS Avery (1980) ArticleTitleNefopam: a review of its pharmacological properties and therapeutic efficacy Drugs 19 249–267 Occurrence Handle6991238 Occurrence Handle1:CAS:528:DyaL3cXktFyksLg%3D

    PubMed  CAS  Google Scholar 

  • S Hunskaar OB Fasmer OJ Broch K Hole (1987) ArticleTitleInvolvement of central serotonergic pathways in nefopam-induced antinoception Eur J Pharmacol 138 77–82 Occurrence Handle2442003 Occurrence Handle10.1016/0014-2999(87)90339-6 Occurrence Handle1:CAS:528:DyaL2sXkvV2kur8%3D

    Article  PubMed  CAS  Google Scholar 

  • J Ichikawa HY Meltzer (1999) ArticleTitleValproate and carbamazepine increase prefrontal dopamine release by 5-HT1A receptor activation Eur J Pharmacol 380 R1–R3 Occurrence Handle10513560 Occurrence Handle10.1016/S0014-2999(99)00517-8 Occurrence Handle1:CAS:528:DyaK1MXms1Oks7k%3D

    Article  PubMed  CAS  Google Scholar 

  • J Ichikawa J Dai HY Meltzer (2005) ArticleTitleLithium differs from anticonvulsant mood stabilizers in prefrontal cortical and accumbal dopamine release: role of 5-HT(1A) receptor agonism Brain Res 1049 182–190 Occurrence Handle15936730 Occurrence Handle10.1016/j.brainres.2005.05.005 Occurrence Handle1:CAS:528:DC%2BD2MXntVGhtbw%3D

    Article  PubMed  CAS  Google Scholar 

  • DR Jasinski KL Preston (1987) ArticleTitleA comparative assay of nefopam, morphine and d-amphetamine Psychopharmacology 91 273–278 Occurrence Handle3104949 Occurrence Handle10.1007/BF00518176 Occurrence Handle1:CAS:528:DyaL2sXitVOnu7Y%3D

    Article  PubMed  CAS  Google Scholar 

  • JPY Kao AT Harootunian RY Tsien (1989) ArticleTitlePhotochemically generated cytosolic calcium pulses and their detection by Fluo-3 J Biol Chem 264 8179–8184 Occurrence Handle2498309 Occurrence Handle1:CAS:528:DyaL1MXksFemtLk%3D

    PubMed  CAS  Google Scholar 

  • M Kito M Maehara K Watanabe (1994) ArticleTitleAntiepileptic drugs – calcium current interaction in cultured human neuroblastoma cells Seizure 3 141–149 Occurrence Handle8081641 Occurrence Handle10.1016/S1059-1311(05)80205-5 Occurrence Handle1:STN:280:DyaK2czmtlSktA%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • S Kochen B Giagante S Oddo (2002) ArticleTitleSpike-and-wave complexes and seizure exacerbation caused by carbamazepine Eur J Neurol 9 41–47 Occurrence Handle11784375 Occurrence Handle10.1046/j.1468-1331.2002.00317.x Occurrence Handle1:STN:280:DC%2BD38%2FlvVOhtA%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • BK Koe (1976) ArticleTitleMolecular geometry of inhibitors of the uptake of catecholamines and serotonin in synaptosomal preparations of rat brain J Pharmacol Exp Ther 199 649–661 Occurrence Handle994022 Occurrence Handle1:CAS:528:DyaE2sXotlGisw%3D%3D

    PubMed  CAS  Google Scholar 

  • J Kornhuber CG Parsons S Hartmann W Retz S Kamolz J Thome P Riederer (1995) ArticleTitleOrphenadrine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: binding and patch clamp studies J Neural Transm 102 237–246 Occurrence Handle10.1007/BF01281158 Occurrence Handle1:CAS:528:DyaK28Xhs1Kmu78%3D

    Article  CAS  Google Scholar 

  • GG Mather R Labroo ME Le Guern F Lepage JM Gillardin RH Levy (2000) ArticleTitleNefopam enantiomers: preclinical pharmacology/toxicology and pharmacokinetic characteristics in healthy subjects after intravenous administration Chirality 12 153–159 Occurrence Handle10689295 Occurrence Handle10.1002/(SICI)1520-636X(2000)12:3<153::AID-CHIR9>3.0.CO;2-V Occurrence Handle1:CAS:528:DC%2BD3cXhslKqs7Y%3D

    Article  PubMed  CAS  Google Scholar 

  • S Mignani GA Bohme G Birraux A Boireau P Jimonet D Damour A Genevois-Borella MW Debono J Pratt M Vuilhorgne F Wahl JM Stutzmann (2002) ArticleTitle9-Carboxymethyl-5H,10H-imidazo[1,2-a] indeno[1,2-e]pyrazin-4one-2-carbocylic acid (RPR117824): selective anticonvulsive and neuroprotective AMPA antagonist Bioorg Med Chem 10 1627–1637 Occurrence Handle11886824 Occurrence Handle10.1016/S0968-0896(01)00431-X Occurrence Handle1:CAS:528:DC%2BD38XhslSktrw%3D

    Article  PubMed  CAS  Google Scholar 

  • T Murakami M Okada Y Kawata G Zhu A Kamata S Kaneko (2001) ArticleTitleDetermination of effects of antiepileptic drugs on SNAREsmediated hippocampal monoamine release using in vivo microdialysis Br J Pharmacol 134 507–520 Occurrence Handle11588104 Occurrence Handle10.1038/sj.bjp.0704285 Occurrence Handle1:CAS:528:DC%2BD3MXnvV2ktbo%3D

    Article  PubMed  CAS  Google Scholar 

  • A Novelli JA Reilly PG Lypsko RC Henneberry (1988) ArticleTitleGlutamate becomes neurotoxic via the NMDA receptor when intracellular energy levels are reduced Brain Res 451 205–212 Occurrence Handle2472189 Occurrence Handle10.1016/0006-8993(88)90765-2 Occurrence Handle1:CAS:528:DyaL1cXktlentLo%3D

    Article  PubMed  CAS  Google Scholar 

  • A Novelli R Díaz-Trelles A Groppetti MT Fernández-Sánchez (2006) ArticleTitleNefopam inhibits calcium influx, cGMP formation, and NMDA receptor-dependent neurotoxicity following activation of voltage sensitive calcium channels Amino Acids 30 183–191

    Google Scholar 

  • PI Pillans DJ Woods (1995) ArticleTitleAdverse reactions associated with nefopam NZ Med J 108 382–384 Occurrence Handle1:STN:280:DyaK28%2Fjtlynug%3D%3D

    CAS  Google Scholar 

  • SN Piper SW Suttner CC Schmidt WH Maleck B Kumle J Boldt (1999) ArticleTitleNefopam and clonidine in the prevention of postanaesthetic shivering Anaesthesia 54 695–699 Occurrence Handle10417466 Occurrence Handle10.1046/j.1365-2044.1999.00849.x Occurrence Handle1:CAS:528:DyaK1MXlsFWntr4%3D

    Article  PubMed  CAS  Google Scholar 

  • G Rosa G Pinto P Orsi RA de Blasi G Conti R Sanita I La Rosa A Gasparetto (1995) ArticleTitleControl of post anaesthetic shivering with nefopam hydrochloride in mildly hypothermic patients after neurosurgery Acta Anaesthesiol Scand 39 90–95 Occurrence Handle7725889 Occurrence Handle1:STN:280:DyaK2M3kt12gtQ%3D%3D

    PubMed  CAS  Google Scholar 

  • JH Rosland K Hole (1990) ArticleTitleThe effect of nefopam and its enantiomers on the uptake of 5-hydroxytryptamine, noradrenaline and dopamine in crude rat brain synaptosomal preparations J Pharm Pharmacol 42 437–438 Occurrence Handle1979627 Occurrence Handle1:CAS:528:DyaK3cXlvVChsbk%3D

    PubMed  CAS  Google Scholar 

  • K Schirrmacher A Mayer J Walden R Dusing D Bingmann (1993) ArticleTitleEffects of carbamazepine on action potentials and calcium currents in rat spinal ganglion cells in vitro Neuropsychobiology 27 176–179 Occurrence Handle8232835 Occurrence Handle1:CAS:528:DyaK2cXpsFKjsA%3D%3D Occurrence Handle10.1159/000118976

    Article  PubMed  CAS  Google Scholar 

  • TB Schumacher H Beck C Steinhauser J Schramm CE Elger (1998) ArticleTitleEffects of phenytoin, carbamazepine, and gabapentin on calcium channels in hippocampal granule cells from patients with temporal lobe epilepsy Epilepsia 39 355–363 Occurrence Handle9578025 Occurrence Handle10.1111/j.1528-1157.1998.tb01387.x Occurrence Handle1:CAS:528:DyaK1cXisl2gsb0%3D

    Article  PubMed  CAS  Google Scholar 

  • M Segal D Manor (1992) ArticleTitleConfocal microscopic imaging of [Ca2+]i in cultured rat hippocampal neurons following exposure to N-methyl-D-aspartate J Physiol 448 655–676 Occurrence Handle1534370 Occurrence Handle1:CAS:528:DyaK38XhsVCnu7o%3D

    PubMed  CAS  Google Scholar 

  • M Serra MC Foddi CA Ghiani MA Melis C Motzo A Concas E Sanna G Biggio (1992) ArticleTitlePharmacology of gamma-aminobutyric acid. A receptor complex after the in vivo administration of the anxioselective and anticonvulsant beta-carboline derivative abecarnil J Pharmacol Exp Ther 263 1360–1368 Occurrence Handle1361574 Occurrence Handle1:CAS:528:DyaK3sXlt1emtA%3D%3D

    PubMed  CAS  Google Scholar 

  • A Stefani F Spadoni G Bernardi (1997) ArticleTitleVoltage-activated calcium channels: targets of antiepileptic drug therapy? Epilepsia 38 959–965 Occurrence Handle9579933 Occurrence Handle10.1111/j.1528-1157.1997.tb01477.x Occurrence Handle1:CAS:528:DyaK2sXmt1KltLg%3D

    Article  PubMed  CAS  Google Scholar 

  • EA Swinyard WC Brown LS Goodman (1952) ArticleTitleComparative assays of epileptic drugs in mice and rats J Pharmacol Exp Ther 106 319–330 Occurrence Handle13000628 Occurrence Handle1:CAS:528:DyaG3sXnsV2g

    PubMed  CAS  Google Scholar 

  • EA Swinyard AN Castellion GB Fink LS Goodman (1963) ArticleTitleSome neurophysiological and neuropharmacological characteristics of audiogenic seizure susceptible mice J Pharmacol Exp Ther 140 375–384 Occurrence Handle13979734 Occurrence Handle1:STN:280:DyaF387ntFGmsA%3D%3D

    PubMed  CAS  Google Scholar 

  • WE Tobin RH Gold (1972) ArticleTitleNefopam hydrochloride: a novel muscle relaxant J Clin Pharmacol New Drugs 12 230–238 Occurrence Handle4555883 Occurrence Handle1:STN:280:DyaE383gsFWnsg%3D%3D

    PubMed  CAS  Google Scholar 

  • SC Urwin RS Smith (1999) ArticleTitleFatal nefopam overdose Br J Anaesthesiol 83 501–502 Occurrence Handle1:STN:280:DC%2BD3c7itFertQ%3D%3D

    CAS  Google Scholar 

  • M Verleye N André I Heulard J-M Gillardin (2004) ArticleTitleNefopam blocks voltage-sensitive sodium channels and modulates glutamatergic transmission in rodents Brain Res 1013 249–255 Occurrence Handle15193535 Occurrence Handle10.1016/j.brainres.2004.04.035 Occurrence Handle1:CAS:528:DC%2BD2cXkvVKrs7o%3D

    Article  PubMed  CAS  Google Scholar 

  • C Villier MP Mallaret (2002) ArticleTitleNefopam abuse Ann Pharmacother 36 1564–1566 Occurrence Handle12243607 Occurrence Handle10.1345/aph.1C017

    Article  PubMed  Google Scholar 

  • PF Vonvoigtlander RA Lewis GL Neff Triezenberg (1983) ArticleTitleInvolvement of biogenic amines with the mechanisms of novel analgesics Prog Neuropsychopharmacol Biol Psychiatry 7 651–656 Occurrence Handle6141608 Occurrence Handle10.1016/0278-5846(83)90040-4 Occurrence Handle1:CAS:528:DyaL2cXps1Ggug%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • M Willow WA Catterall (1982) ArticleTitleInhibition of binding of [3H] batrachotoxinin A 20-a-benzoate to sodium channels by the anticonvulsant drugs dyphenylhydantoin and carbamazepine Mol Pharmacol 22 627–635 Occurrence Handle6296655 Occurrence Handle1:CAS:528:DyaL3sXitV2qs7w%3D

    PubMed  CAS  Google Scholar 

  • G Zhu M Okada T Murakami Y Kawata A Kamata S Kaneko (2002) ArticleTitleInteraction between carbamazepine, zonisamide and voltage-sensitive Ca2+ channel on acetylcholine release in rat frontal cortex Epilepsy Res 49 49–60 Occurrence Handle11948007 Occurrence Handle10.1016/S0920-1211(02)00015-3 Occurrence Handle1:CAS:528:DC%2BD38Xis1ensbg%3D

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Psychology/Psychobiology, University of Oviedo, Oviedo, Spain

    A. Novelli

  2. Department of Biochemistry and Molecular Biology, University of Oviedo, Oviedo, Spain

    A. Ferrero-Gutiérrez, A. Pérez-Gómez, C. M. Desogus & M. T. Fernández-Sánchez

  3. University Institute of Biotechnology of Asturias (IUBA), University of Oviedo, Oviedo, Spain

    A. Novelli, A. Ferrero-Gutiérrez, A. Pérez-Gómez, C. M. Desogus & M. T. Fernández-Sánchez

  4. Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Milan, Italy

    A. Groppetti

  5. Department of Pharmacological Sciences, University of Milan, Milan, Italy

    G. Rossoni & B. Manfredi

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  1. A. Novelli
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Novelli, A., Groppetti, A., Rossoni, G. et al. Nefopam is more potent than carbamazepine for neuroprotection against veratridine in vitro and has anticonvulsant properties against both electrical and chemical stimulation. Amino Acids 32, 323–332 (2007). https://doi.org/10.1007/s00726-006-0419-6

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