Antiepileptic Drugs on Calcium Currents Recorded from Cortical and PAG Neurons: Therapeutic Implications for Migraine

Abstract

Cortex and periaqueductal grey (PAG) play a major role in the pathophysiology of migraine. Some antiepileptic drugs (AEDs) influence the activity of these structures by modulating high-voltage-activated (HVA) Ca(2+) channels and are effective in migraine prevention. The aim of the present study was to investigate the expression of total HVA Ca(2+) channels in cortical and PAG neurons and to study the differential action of AEDs on these channels. Isolated neurons were visually identified based on morphological criteria. HVA currents were recorded by whole-cell patch-clamp technique. The distribution ratio of L-, N-, P-, Q- and R-type HVA Ca(2+) channels was different between cortical and PAG neurons. In particular, we found that P- and Q-type HVA Ca(2+) channels were more expressed in PAG neurons than in cortical cells, whereas L- and R-type HVA Ca(2+) channels showed an opposite distribution. Interestingly, N-type HVA Ca(2+) channels were equally distributed in these two neuronal populations. A differential sensitivity to AEDs of HVA Ca(2+) channels located on cortical and PAG neurons was observed for topiramate (TPM), but not for lamotrigine (LTG) or levetiracetam (LEV). In fact, whereas both LTG and LEV were equally effective and potent in inhibiting HVA Ca(2+) currents in the two neuronal populations, TPM showed a much higher potency and efficacy in blocking these currents in PAG neurons than in cortical pyramidal cells. TPM, in fact, inhibited N-, P- and L-type channels in PAG neurons, whereas in cortical neurons this AED modulated only P- and L-type channels. Unlike the other AEDs investigated, valproic acid did not affect HVA Ca(2+) currents in cortical and PAG neurons. The negative modulation of specific subtypes of HVA Ca(2+) channels by various AEDs can restore normal electrical activity in target brain areas such as cortex and PAG, providing interesting therapeutic approaches in migraine prevention.

The Synaptic Vesicle Glycoprotein 2A Ligand Levetiracetam Inhibits Presynaptic Ca2+ Channels through an Intracellular Pathway

“…LEV was reported to inhibit Ca V 2.2 and Ca V 2.1 (P/Q type) subunits (Surges et al, 2008). In general, such effects were measured in response to shortterm LEV application and were reported to produce small irreversible reductions in Ca 2ϩ current (Lukyanetz et al, 2002;Pisani et al, 2004;Costa et al, 2006;Martella et al, 2008); our data, which showed no short-term LEV effects, are in disagreement with those studies. However, Niespodziany et al (2001) investigated the time dependence of LEV effects on Ca V channels, and their finding that LEV required Ն30 min of perfusion to cause significant inhibition correlates well with our data.…”

“…Although LEV did not affect Na ϩ -and low-voltageactivated Ca V channels (Zona et al, 2001), it was reported to inhibit high-voltage-activated Ca V channels; those effects occurred in response to short-term LEV application (Lukyanetz et al, 2002;Pisani et al, 2004;Costa et al, 2006;Martella et al, 2008), although one study reported that LEV action on Ca V channels required prolonged exposure . LEV inhibition of delayed rectifier K ϩ channels also was reported (Madeja et al, 2003).…”

Where does a migraine attack originate? In the brainstem

“…The increased iron deposition in the PAG supported the possibility of repeated activation (chronic daily headache) of the antinociceptive network (Del Rio and Linera 2004). Activation of the PAG was blocked by a triptan (Bartsch et al 2004;Jeong et al 2008), and antiepileptic drugs which are effective in migraine might modulate the function of PAG neurones (Martella et al 2008). Patients with familial hemiplegic migraine carry mis-sense gene (CACNA1A) mutations which encode the a1A subunit of the voltagegated Ca 2?…”

Anti-Obesity Therapy: from Rainbow Pills to Polyagonists

“…Topiramate is a sulphamate-substituted monosaccharide derived from D-fructose (Privitera, 1997;Shank and Maryanoff, 2008;Edvinsson and Linde, 2010) and is commonly used to treat epilepsy (Langtry et al, 1997;Privitera, 1997) and migraine (Storey et al, 2001;Adelman et al, 2008;Edvinsson and Linde, 2010;Linde et al, 2013). The use of topiramate for these clinical applications seems to reside in its ability to selectively decrease CNS neuronal activity via inhibition of certain neuronal Ca 2+ channels (Martella et al, 2008) as well as to modulate central glutamate and GABA signaling (White et al, 2000;Edvinsson and Linde, 2010). When used as monotherapy, placebo-subtracted weight loss induced by topiramate typically ranges between 3.8% and 6.5% depending on the dose (Aronne et al, 2013).…”