PMID- 23796540
OWN - NLM
STAT- MEDLINE
DCOM- 20131028
LR  - 20130823
IS  - 1471-4159 (Electronic)
IS  - 0022-3042 (Linking)
VI  - 126
IP  - 5
DP  - 2013 Sep
TI  - A novel anticonvulsant modulates voltage-gated sodium channel inactivation and 
      prevents kindling-induced seizures.
PG  - 651-61
LID - 10.1111/jnc.12352 [doi]
AB  - Here, we explore the mechanism of action of isoxylitone (ISOX), a molecule 
      discovered in the plant Delphinium denudatum, which has been shown to have 
      anticonvulsant properties. Patch-clamp electrophysiology assayed the activity of 
      ISOX on voltage-gated sodium channels (VGSCs) in both cultured neurons and brain 
      slices isolated from controls and rats with experimental epilepsy(kindling 
      model). Quantitative transcription polymerase chain reaction (qRT-PCR) (QPCR) 
      assessed brain-derived neurotrophic factor (BDNF) mRNA expression in kindled 
      rats, and kindled rats treated with ISOX. ISOX suppressed sodium current (I(Na)) 
      showing an IC50 value of 185 nM in cultured neurons. ISOX significantly slowed 
      the recovery from inactivation (ISOX tau = 18.7 ms; Control tau = 9.4 ms; p < 0.001). 
      ISOX also enhanced the development of inactivation by shifting the Boltzmann 
      curve to more hyperpolarized potentials by -11.2 mV (p < 0.05). In naive and 
      electrically kindled cortical neurons, the IC50 for sodium current block was 
      identical to that found in cultured neurons. ISOX prevented kindled stage 5 
      seizures and decreased the enhanced BDNF mRNA expression that is normally 
      associated with kindling (p < 0.05). Overall, our data show that ISOX is a potent 
      inhibitor of VGSCs that stabilizes steady-state inactivation while slowing 
      recovery and enhancing inactivation development. Like many other sodium channel 
      blocker anti-epileptic drugs, the suppression of BDNF mRNA expression that 
      usually occurs with kindling is likely a secondary outcome that nevertheless 
      would suppress epileptogenesis. These data show a new class of anti-seizure 
      compound that inhibits sodium channel function and prevents the development of 
      epileptic seizures.
CI  - (c) 2013 International Society for Neurochemistry.
FAU - Ashraf, Muhammad N
AU  - Ashraf MN
AD  - H.E.J. Research Institute of Chemistry, International Center for Chemical and 
      Biological Sciences, University of Karachi, Karachi, Pakistan.
FAU - Gavrilovici, Cezar
AU  - Gavrilovici C
FAU - Shah, Syed U Ali
AU  - Shah SU
FAU - Shaheen, Farzana
AU  - Shaheen F
FAU - Choudhary, Muhammad I
AU  - Choudhary MI
FAU - Rahman, Atta-ur
AU  - Rahman AU
FAU - Fahnestock, Margaret
AU  - Fahnestock M
FAU - Simjee, Shabana U
AU  - Simjee SU
FAU - Poulter, Michael O
AU  - Poulter MO
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130722
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (1,3,5,5-trimethyl-2-cyclohexen-1-ylidine-2-propanone)
RN  - 0 (Anticonvulsants)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Cyclohexenes)
RN  - 0 (Ketones)
RN  - 0 (RNA, Messenger)
RN  - 0 (Sodium Channels)
SB  - IM
MH  - Animals
MH  - Anticonvulsants/*pharmacology
MH  - Brain-Derived Neurotrophic Factor/biosynthesis/genetics
MH  - Cells, Cultured
MH  - Cyclohexenes/chemistry/*pharmacology
MH  - Delphinium/chemistry
MH  - Dose-Response Relationship, Drug
MH  - Electrodes, Implanted
MH  - Electrophysiological Phenomena
MH  - Isomerism
MH  - Ketones/chemistry/*pharmacology
MH  - Kindling, Neurologic/*drug effects
MH  - Male
MH  - RNA, Messenger/biosynthesis/genetics
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Real-Time Polymerase Chain Reaction
MH  - Seizures/physiopathology/*prevention & control
MH  - Sodium Channels/*drug effects
OTO - NOTNLM
OT  - Isoxylitones [E/Z]
OT  - brain-derived neurotrophic factor
OT  - electrophysiology
OT  - steady-state inactivation
EDAT- 2013/06/26 06:00
MHDA- 2013/10/29 06:00
CRDT- 2013/06/26 06:00
PHST- 2013/04/23 00:00 [received]
PHST- 2013/06/06 00:00 [revised]
PHST- 2013/06/10 00:00 [accepted]
PHST- 2013/06/26 06:00 [entrez]
PHST- 2013/06/26 06:00 [pubmed]
PHST- 2013/10/29 06:00 [medline]
AID - 10.1111/jnc.12352 [doi]
PST - ppublish
SO  - J Neurochem. 2013 Sep;126(5):651-61. doi: 10.1111/jnc.12352. Epub 2013 Jul 22.