Neuroscience Letters 518 (2012) 36–40 Contents lists available at SciVerse ScienceDirect Neuroscience Letters j ourna l ho me p ag e: www.elsevier.com/locate/neulet Changes of the peripheral nerve excitability in vivo induced by the persistent Na + current blocker ranolazine Hiroyuki Nodera ∗ , Seward B. Rutkove Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA a r t i c l e i n f o Article history: Received 5 March 2012 Received in revised form 10 April 2012 Accepted 19 April 2012 Keywords: Axonal excitability Sensory nerve Persistent Na + current Ranolazine Slow K + current a b s t r a c t Persistent Na + current (Na p ) in the peripheral axons play an important functional role in controlling the axonal excitability. Abnormal Na p is believed to contribute to neurodegeneration and neuropathic pain, and thus it is an attractive therapeutic target. To assess the behavior of selective Na p block- ade, axonal excitability testing was performed in vivo in 10 normal male mice exposed to ranolazine by recording the tail sensory nerve action potentials (SNAPs). Twenty minutes after administering ranolazine i.p. (50 mg/kg), the following changes were observed: lower SNAP amplitudes and the need for greater stimulus currents; greater threshold changes induced by long hyperpolarizing currents; reduced accommodation to long depolarizing current along with reduced late subexcitability; and reduced strength-duration time constant. These changes are explained by the suppression of Na p leading to greater threshold currents, partial block of transient Na + current, and suppression of slow K + currents. The sup- pressed slow K + currents appear to limit the modification of the membrane excitability by ranolazine. This study confirms the utility of axonal excitability testing as a useful treatment biomarker in neurological conditions in which Na p function is being modified. © 2012 Elsevier Ireland Ltd. All rights reserved. The primary role of the vast majority of peripheral nerve Na + channels is action potential generation. In addition to these fast inactivating, transient Na + channels, up to 5% of Na + channels have distinct kinetics with slow inactivation, producing a persis- tent Na + current (Na p ) [11]. The Na p is functionally significant because abnormally increased Na p has been reported in periph- eral nerve diseases and is believed responsible for the generation of ectopic discharges manifesting as neuropathic pain and fascic- ulations [16,19,22,24]. Increased Na p not only causes symptoms, but also is believed to play a role in neurodegeneration. Exces- sive Na p increases the intracellular Na + concentration activating the Na + –Ca 2+ exchanger in reverse, leading to an influx of Ca 2+ , which in turn triggers prodegenerative pathways involving proteases and lipases, ultimately leading to mitochondrial toxicity and neuronal death [21]. Therefore, blocking Na p is an attractive therapeutic target for peripheral nerve diseases from both the symptomatic and neuroprotective standpoints. Unlike traditional Na + channel Abbreviations: HCN, hyperpolarization-activated cyclic nucleotide-gated; Ih, hyperpolarization-activated current; I/V, current–threshold relationship; Nap, per- sistent Na+ current; RC, recovery cycle; SDTC, strength-duration time constant; SNAP, sensory nerve action potential; TE, threshold electrotonus; TTX, tetrodotoxin. ∗ Corresponding author at: Department of Neurology, Beth Israel Deaconess Med- ical Center, Shapiro 8, 330 Brookline Ave, Boston, MA 02215, USA. Tel.: +1 617 667 4382; fax: +1 617 667 3175. E-mail addresses: hodera@bidmc.harvard.edu, hnodera1@yahoo.co.jp (H. Nodera). blockers that act on both transient and persistent Na + currents, a recently FDA-approved anti-anginal agent, ranolazine, selectively blocks cardiac and neuronal Na p at a therapeutic concentration [14] and has shown an antinociceptive effect [5,7]. To effectively uti- lize this or similar drugs in a wide range of neurological diseases, monitoring of Na p by an effective biomarker is needed. Axonal excitability testing is a non-invasive electrophysiologic technique that enables in vivo, real-time monitoring of membrane proper- ties including Na p [2,17]. Although others have reported on in vivo studies on non-selective blockade of Na + current [8,10,12] and the theoretical behavior of excitability parameters of blocking Na p [3] in isolation, the changes in excitability by selectively blocking Na p have not been directly measured. Therefore, the aim of the present study was to assess alterations in axonal excitability parameters in vivo with administration of ranolazine. The study was approved by the Beth Israel Deaconess Medical Center’s Institutional Animal Care and Use Committee. Ten male, 8 week-old, Swiss Webster mice (Charles River, Wilmington, MA) were studied. Electrophysiological studies were performed on the tail under 1.5% isoflurane anesthesia with the animal warmed on a heating pad to maintain a tail temperature of 32–34 ◦ C through- out the studies. Sensory nerve action potentials (SNAPs) were recorded orthodromically by placing stainless steel, 30-gage, dis- posable needle electrodes as follows: the reference and active recording needles were placed 10 mm and 20 mm from the base of the tail respectively; the cathode and anode were placed 35 mm and 45 mm respectively distal to the active recording electrode, and 0304-3940/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neulet.2012.04.050