title: Phenytoin inhibits the persistent sodium current in neocortical neurons by modifying its inactivation properties.
abstract: The persistent Na⁺ current (I(NaP)) is important for neuronal functions and can play a role in several pathologies, although it is small compared to the transient Na⁺ current (I(NaT)). Notably, I(NaP) is not a real persistent current because it undergoes inactivation with kinetics in the order of tens of seconds, but this property has often been overlooked. Na⁺ channel blockers, drugs used for treating epilepsy and other diseases, can inhibit I(NaP), but the mechanism of this action and the conditions in which I(NaP) can be actually inhibited have not been completely clarified yet. We evaluated the action of phenytoin (PHT), a prototype anti-epileptic Na⁺ channel blocker, on I(NaP) inactivation in pyramidal neurons of rat sensorimotor cortical slices at different concentrations, from 5 to 100 µM. PHT did not modify I(NaP) evoked with depolarizing voltage ramps of 50 or 100 mVs⁻¹, but decreased I(NaP) evoked by slower voltage ramps (10 mVs⁻¹). However, at all of the tested concentrations, PHT decreased I(NaP) evoked by faster ramps when they were preceded by inactivating pre-pulses. Moreover, PHT shifted towards negative potentials the voltage-dependence of I(NaP) inactivation and accelerated its kinetics of development also at depolarized potentials (+40 mV), not consistently with a simple inactivated state stabilizer. Therefore, our study shows a prominent PHT effect on I(NaP) inactivation rather than an open channel block, which is instead often implied. I(NaP) is inhibited by PHT only in conditions that induce major I(NaP) inactivation. These results highlight the importance of I(NaP) inactivation not only for physiological functions but also as drug target, which could be shared by other therapeutic drugs. Through this action PHT can reduce I(NaP)-induced long-lasting pathological depolarisations and intracellular sodium overload, whereas shorter I(NaP) actions should not be modified. These properties set the conditions of efficacy and the limits of PHT as I(NaP) inhibitor.
authors: Department of Neurophysiopathology, Epilepsy Center, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy.
authors: Elisa
authors: E
authors: Colombo
authors: Silvana
authors: S
authors: Franceschetti
authors: Giuliano
authors: G
authors: Avanzini
authors: Massimo
authors: M
authors: Mantegazza
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D007700:Kinetics; D019579:Neocortex / Q000166:cytology*; D018408:Patch-Clamp Techniques; D010672:Phenytoin / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism*; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology*
chemical_list: D015222:Sodium Channels; D061567:Voltage-Gated Sodium Channel Blockers; D010672:Phenytoin; D012964:Sodium
references: Nat Med. 2011 Apr;17(4):439-47
references: 21475241
references: Neuron. 2011 Aug 25;71(4):671-82
references: 21867883
references: Epilepsia. 2007;48 Suppl 2:51-64
references: 17571353
references: Pflugers Arch. 2010 Jun;460(1):77-86
references: 20204400
references: Eur J Neurosci. 2004 May;19(10):2769-78
references: 15147310
references: Exp Neurol. 2009 Jul;218(1):1-4
references: 19361500
references: Neurobiol Dis. 2009 Jul;35(1):91-102
references: 19409490
references: Expert Rev Clin Pharmacol. 2010 May;3(3):371-84
references: 22111617
references: J Pharmacol Exp Ther. 1998 Jan;284(1):228-37
references: 9435183
references: Lancet Neurol. 2010 Apr;9(4):413-24
references: 20298965
references: Neuron. 2002 Jun 13;34(6):877-84
references: 12086636
references: J Neurophysiol. 2011 Jan;105(1):117-29
references: 20980543
references: Eur Biophys J. 2002 Sep;31(5):323-30
references: 12202908
references: Biophys J. 1998 Feb;74(2 Pt 1):831-42
references: 9533695
references: Epilepsy Res. 2010 Nov;92(1):1-29
references: 20828990
references: Epilepsia. 2003 Dec;44(12):1601-4
references: 14636336
references: Curr Opin Neurobiol. 2003 Jun;13(3):284-90
references: 12850212
references: Epilepsia. 2007 Apr;48(4):774-82
references: 17381447
references: J Physiol. 2006 Nov 15;577(Pt 1):141-54
references: 16931548
references: J Neurosci. 2006 Mar 29;26(13):3465-73
references: 16571753
references: J Physiol. 1998 Feb 15;507 ( Pt 1):105-16
references: 9490824
references: J Physiol. 1996 May 15;493 ( Pt 1):83-97
references: 8735696
references: J Neurosci. 2005 Mar 30;25(13):3341-9
references: 15800189
references: Mol Pharmacol. 1988 Oct;34(4):557-65
references: 2845252
references: J Gen Physiol. 1977 Apr;69(4):497-515
references: 300786
references: Epilepsy Curr. 2007 Jan-Feb;7(1):15-22
references: 17304346
references: Proc Natl Acad Sci U S A. 2004 Jul 27;101(30):11147-52
references: 15263074
references: J Gen Physiol. 1999 Oct;114(4):491-509
references: 10498669
references: J Physiol. 1994 Sep 1;479 ( Pt 2):199-205
references: 7528275
references: Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15348-53
references: 11742069
references: Nat Neurosci. 1999 Feb;2(2):144-50
references: 10195198
references: J Neurophysiol. 1997 Jun;77(6):3021-34
references: 9212254
references: Mol Pharmacol. 2008 Jan;73(1):157-69
references: 17940193
references: Neuroreport. 2004 Apr 29;15(6):1049-52
references: 15076732
references: Science. 1994 Sep 16;265(5179):1724-8
references: 8085162
references: J Physiol. 2010 Feb 15;588(Pt 4):651-70
references: 20173079
references: Neuroreport. 1995 Sep 11;6(13):1778-80
references: 8541480
references: J Neurosci. 2008 Jul 16;28(29):7273-83
references: 18632931
references: Eur J Neurosci. 2000 Oct;12(10):3567-74
references: 11029626
references: J Pharmacol Exp Ther. 1999 Mar;288(3):960-8
references: 10027832
references: J Neurosci. 2011 Jul 27;31(30):10811-8
references: 21795533
references: J Physiol. 2000 Oct 15;528 Pt 2:291-304
references: 11034619
references: Annu Rev Physiol. 1996;58:349-62
references: 8815799
references: J Neurophysiol. 2006 Jun;95(6):3460-8
references: 16467432
references: Mol Pharmacol. 1994 Oct;46(4):716-25
references: 7969051
references: Brain Res. 1995 Oct 23;696(1-2):127-39
references: 8574660
references: J Neurosci. 2001 Apr 1;21(7):2268-77
references: 11264302
references: J Neurosci. 2005 Oct 19;25(42):9704-20
references: 16237175
references: Mol Pharmacol. 1997 Jun;51(6):1077-83
references: 9187275
references: Cell Biochem Biophys. 2001;35(2):171-90
references: 11892790
references: Nat Clin Pract Neurol. 2008 Mar;4(3):159-69
references: 18227822
references: Clin Exp Pharmacol Physiol. 2000 Aug;27(8):569-74
references: 10901384
references: Neuron. 2003 Jul 3;39(1):109-20
references: 12848936
references: Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18994-9
references: 19020082
references: Epilepsia. 2005 May;46(5):624-35
references: 15857426
references: J Neurosci. 2006 Mar 29;26(13):3412-22
references: 16571748