In vivo imaging reveals that pregabalin inhibits cortical spreading depression and propagation to subcortical brain structures

Abstract

Migraine is characterized by severe headaches that can be preceded by an aura likely caused by cortical spreading depression (SD). The antiepileptic pregabalin (Lyrica) shows clinical promise for migraine therapy, although its efficacy and mechanism of action are unclear. As detected by diffusion-weighted MRI (DW-MRI) in wildtype (WT) mice, the acute systemic administration of pregabalin increased the threshold for SD initiation in vivo. In familial hemiplegic migraine type 1 mutant mice expressing human mutations (R192Q and S218L) in the Ca V 2.1 (P/Q-type) calcium channel subunit, pregabalin slowed the speed of SD propagation in vivo. Acute systemic administration of pregabalin in vivo also selectively prevented the migration of SD into subcortical striatal and hippocampal regions in the R192Q strain that exhibits a milder phenotype and gain of Ca V 2.1 channel function. At the cellular level, pregabalin inhibited glutamatergic synaptic transmission differentially in WT, R192Q, and S218L mice. The study describes a DW-MRI analysis method for tracking the progression of SD and provides support and a mechanism of action for pregabalin as a possible effective therapy in the treatment of migraine.familial hemiplegic migraine type 1 | migraine | diffusion-weighted MRI | voltage-gated calcium channel | gabapentinoids

Etiology and Pharmacology of Neuropathic Pain

“…Had the drug worked extracellularly to block allodynia in vivo, it would have been washed away by the time spinal cord slices were studied and no persistent effect of the drug would be seen. This supposition is supported by detailed quantitative arguments outlined in our paper (Alles et al, 2017). These observations are congruent with those of Lana et al (2016), who showed that GBP displacement of thrombospondin 4 binding (see below) is effected at an intracellular site on a2d-1.…”

“…This was observed as an increase in the amplitude of Ca 2+ responses evoked by 35 mM K + (Lu et al, 2007;Alles et al, 2017). In addition, activated microglia-conditioned medium increased overall organotypic slice excitability, and preincubation of slices with a TrkBd5 (recombinant receptor, which sequesters BDNF) inhibited this effect (Lu et al, 2009).…”

“…This very much complicates the search for effective therapeutic targets. Although gabapentinoids may only bind to one specific target, the a2d-1 subunit of voltage-gated Ca 2+ channels (Gee et al, 1996;Field et al, 2006;Offord and Isom, 2015), this interaction has multiple consequences for synaptic transmission, neuron-selective actions, and network excitability at the spinal level (Biggs et al, 2014;Alles and Smith, 2016;Alles et al, 2017) and within higher brain centers (Suzuki et al, 2005;Eroglu et al, 2009;Suto et al, 2014;Crosby et al, 2015;Patel and Dickenson, 2016a;Bannister et al, 2017b); this multiplicity of effect may explain their therapeutic effectiveness. The appreciation of this concept has led to the evidence-based development of drugs that will affect multiple targets Zamponi et al, 2015).…”

“…Both PGB and GBP are used to treat various forms of neuropathic pain, including fibromyalgia (Moore et al, 2014). Some reports suggest they may be beneficial in postoperative pain (Dauri et al, 2009;Clarke et al, 2012), as well as in management of neurogenic overactive bladder (Carbone et al, 2006) and migraine (Calandre et al, 2010;Pizzolato et al, 2011;Cain et al, 2017). An enacarbil derivative of GBP with improved oral bioavailability is available (Cundy et al, 2004), and this has been approved for use in postherpetic neuralgia and restless legs syndrome.…”

“…More recent work from our laboratory lends support to the idea that gabapentinoids work intracellularly (Alles et al, 2017). Part of this study involved in vivo administration of GBP and study of substantia gelatinosa neurons ex vivo from animals that had received GBP.…”