Isovaline attenuates epileptiform activity and seizure behavior in 4-aminopyridine treated rats

Yu, Wilson; Smith, Autumn B.; Pilitsis, Julie G.; Shin, Damian S.

doi:10.1016/j.eplepsyres.2013.11.020

Cited by 11 publications

(6 citation statements)

References 12 publications

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“…Isovaline’s effects, particularly in the central nervous system, may depend on cellular location. For example, isovaline has anti-epileptic properties which are not likely GABA B -mediated, but instead are postulated to result from a selective enhancement of hippocampal interneuronal activity by non-synaptically increasing inhibitory input and/or eliciting a shunting phenomenon onto pyramidal neurons [ 22 , 38 ]. Our experiments demonstrated no effect of isovaline on hippocampal pyramidal neurons, but do not exclude isovaline actions on interneurons.…”

Section: Discussionmentioning

confidence: 99%

Isovaline Does Not Activate GABAB Receptor-Coupled Potassium Currents in GABAB Expressing AtT-20 Cells and Cultured Rat Hippocampal Neurons

et al. 2015

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Isovaline is a non-proteinogenic amino acid that has analgesic properties. R-isovaline is a proposed agonist of the γ-aminobutyric acid type B (GABAB) receptor in the thalamus and peripheral tissue. Interestingly, the responses to R-isovaline differ from those of the canonical GABAB receptor agonist R-baclofen, warranting further investigation. Using whole cell recording techniques we explored isovaline actions on GABAB receptors coupled to rectifying K+ channels in cells of recombinant and native receptor preparations. In AtT-20 cells transfected with GABAB receptor subunits, bath application of the GABAB receptor agonists, GABA (1 μM) and R-baclofen (5 μM) produced inwardly rectifying currents that reversed approximately at the calculated reversal potential for K+ R- isovaline (50 μM to 1 mM) and S-isovaline (500 μM) did not evoke a current. R-isovaline applied either extracellularly (250 μM) or intracellularly (10 μM) did not alter responses to GABA at 1 μM. Co-administration of R-isovaline (250 μM) with a low concentration (10 nM) of GABA did not result in a response. In cultured rat hippocampal neurons that natively express GABAB receptors, R-baclofen (5 μM) induced GABAB receptor-dependent inward currents. Under the same conditions R-isovaline (1 or 50 μM) did not evoke a current or significantly alter R-baclofen-induced effects. Therefore, R-isovaline does not interact with recombinant or native GABAB receptors to open K+ channels in these preparations.

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Section: Discussionmentioning

confidence: 99%

Isovaline Does Not Activate GABAB Receptor-Coupled Potassium Currents in GABAB Expressing AtT-20 Cells and Cultured Rat Hippocampal Neurons

et al. 2015

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“…Multiple animal models exist for studying seizure activity in vivo (Pitkänen et al, 2006 ), including application of the transient potassium current blocker, 4-aminopyridine (4-AP; Barna et al, 2000 ; Bahar et al, 2006 ; Ma et al, 2009 ; Zhao et al, 2009 , 2015 ; Medina-Ceja and Ventura-Mejía, 2010 ; Salazar and Tapia, 2012 ; Yu et al, 2014 ). We have chosen an acute, rather than chronic, focal seizure mouse model for several reasons.…”

Section: Introductionmentioning

confidence: 99%

Reduction in focal ictal activity following transplantation of MGE interneurons requires expression of the GABAA receptor Î±4 subunit

Jaiswal

Keros

Zhao

et al. 2015

Front. Cell. Neurosci.

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Despite numerous advances, treatment-resistant seizures remain an important problem. Loss of neuronal inhibition is present in a variety of epilepsy models and is suggested as a mechanism for increased excitability, leading to the proposal that grafting inhibitory interneurons into seizure foci might relieve refractory seizures. Indeed, transplanted medial ganglionic eminence interneuron progenitors (MGE-IPs) mature into GABAergic interneurons that increase GABA release onto cortical pyramidal neurons, and this inhibition is associated with reduced seizure activity. An obvious conclusion is that inhibitory coupling between the new interneurons and pyramidal cells underlies this effect. We hypothesized that the primary mechanism for the seizure-limiting effects following MGE-IP transplantation is the tonic conductance that results from activation of extrasynaptic GABAA receptors (GABAA-Rs) expressed on cortical pyramidal cells. Using in vitro and in vivo recording techniques, we demonstrate that GABAA-R α4 subunit deletion abolishes tonic currents (Itonic) in cortical pyramidal cells and leads to a failure of MGE-IP transplantation to attenuate cortical seizure propagation. These observations should influence how the field proceeds with respect to the further development of therapeutic neuronal transplants (and possibly pharmacological treatments).

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“…Our recent paper expanded on our in vitro study by examining whether isovaline effects on SLEs and PADs translated to behavioral and electrophysiological outcomes in vivo [8] . To be consistent with our in vitro study, we injected a single intraperitoneal (IP) dose of 4-AP to elicit generalized convulsions and epileptiform activity in rats [16][17][18] .…”

Section: Research Highlightmentioning

confidence: 99%

“…In contrast, isovaline had no direct effect on pyramidal neuron firing at baseline levels during aCSF perfusion. However, we noted that isovaline attenuated pyramidal neuronal hyperactivity during low Mg 2+ /high K + or 4-AP treatment, presumably from increased inhibitory drive from interneurons.Our recent paper expanded on our in vitro study by examining whether isovaline effects on SLEs and PADs translated to behavioral and electrophysiological outcomes in vivo [8] . To be consistent with our in vitro study, we injected a single intraperitoneal (IP) dose of 4-AP to elicit generalized convulsions and epileptiform activity in rats [16][17][18] .…”

mentioning

confidence: 99%

“…Now, more recent AEDs are being developed with novel chemical structures and mechanisms (see review [6] ). Here, we discuss our research of isovaline in in vitro and in vivo models of epilepsy [7,8] to raise awareness that this amino acid provides antiepileptic efficacy through a novel mechanism. As a consequence, isovaline could represent a new class of drugs for the treatment of epilepsy.…”

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confidence: 99%

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Isovaline: A unique amino acid with antiepileptic drug properties

Shin

2014

Mol Cell Epilepsy

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Current anti-epileptic drugs (AEDs) primarily act by decreasing excitation or increasing inhibition of the neuronal network. This is achieved by inactivating Na+ or Ca 2+ ion channels and decreasing glutamate release or by enhancing GABAergic influence. Despite using these AEDs, approximately 30% of epileptic patients remain intractable. As a consequence, there is a clear need to develop new AEDs that may work via novel mechanisms to provide greater efficacy. With this in mind, we investigated whether isovaline, a unique amino acid with a similar chemical structure to glycine and GABA, could fill this role. Previously, we showed that isovaline attenuated seizure-like events (SLEs) in vitro via a novel mechanism. In this research highlight, we discuss our latest published findings which demonstrate the efficacy of isovaline in an in vivo rat model of epilepsy. Epilepsy is one of the most common neurological disorders in the world, affecting sixty-five million people worldwide [1] . Anti-epileptic drugs (AEDs) are the preferred treatment option for managing epilepsy disorders since they are more pragmatic than other proposed treatments such as surgical resection or electrical stimulation. Older AEDs such as phenytoin, valproate and phenobarbital primarily act on voltage-gated ion channels [2,3] or GABA A receptors [4] ; however, these drugs do not provide adequate seizure control in 30% of epileptic patients and poignantly underscores the considerable need for new and improved AEDs [5] . In achieving these goals, 2 nd generation AEDs were developed which expanded upon the mechanism(s) thought to underlie the older generation AEDs, but possessed slightly different toxicity and drug-interaction profiles. Now, more recent AEDs are being developed with novel chemical structures and mechanisms (see review [6] ). Here, we discuss our research of isovaline in in vitro and in vivo models of epilepsy [7,8] to raise awareness that this amino acid provides antiepileptic efficacy through a novel mechanism. As a consequence, isovaline could represent a new class of drugs for the treatment of epilepsy. KeywordsIsovaline is a non-proteinogenic amino acid initially identified in the Murchison carbonaceous meteorite. This amino acid is present as a racemic mixture, which is unlike most proteinogenic amino acids which are predominantly S-enantiomers [9,10] . Notably, the chirality of amino acids is known to have significant pathophysiological effects [11] although it's unclear what importance this has for isovaline in AED efficacy since our research only focused on its natural form. Prior to our investigation of isovaline for AED utility, this amino acid was investigated for its effects on nociception [12][13][14] . More specifically, Puil and colleagues at the University of British Columbia injected mice with strychnine into the lumbar intrathecal space, or administered formalin, RESEARCH HIGHLIGHTWilson Yu, et al.Isovaline is antiepileptic in rats 2 glutamate, or prostaglandin E2 into the hindpaw to elicit acute and chronic pain ...

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Isovaline attenuates epileptiform activity and seizure behavior in 4-aminopyridine treated rats

Cited by 11 publications

References 12 publications

Isovaline Does Not Activate GABAB Receptor-Coupled Potassium Currents in GABAB Expressing AtT-20 Cells and Cultured Rat Hippocampal Neurons

Isovaline Does Not Activate GABAB Receptor-Coupled Potassium Currents in GABAB Expressing AtT-20 Cells and Cultured Rat Hippocampal Neurons

Reduction in focal ictal activity following transplantation of MGE interneurons requires expression of the GABAA receptor Î±4 subunit

Isovaline: A unique amino acid with antiepileptic drug properties

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