Isovaline, a rare amino acid, has anticonvulsant properties in two in vitro hippocampal seizure models by increasing interneuronal activity.

Abstract:

PURPOSE:We investigated whether RS-isovaline, a unique amino acid found in carbonaceous meteorites and presumed extraterrestrial, has anticonvulsant properties in rat hippocampal slices in vitro. METHODS:Extracellular recordings were obtained in the rat hippocampal CA1 pyramidal layer in two in vitro seizure models: perfusion of low (0.25 mm) Mg(2+) and high (5 mm) K(+) (LM/HK), or 100 μm 4-aminopyridine (4-AP). To investigate the underlying mechanisms of isovaline action, whole-cell recordings were obtained from CA1 pyramidal neurons and stratum oriens interneurons during 4-AP blockade of K(+) channels. KEY FINDINGS:Perfusion of LM/HK produced seizure-like events (SLEs) or stimulus-evoked primary afterdischarges (PADs) with amplitudes of 0.9 ± 0.1 mV lasting 80 ± 14 s. Application of isovaline (250 μm) for 20-30 min abolished SLEs and PADs or attenuated seizure amplitude and duration by 57.0 ± 9.0% and 57.0 ± 12.0%, respectively. Similar effects were seen with isovaline in the 4-AP seizure model. Isovaline alone increased interneuronal spontaneous spiking from 0.9 ± 0.3 to 3.2 ± 0.9 Hz, increased input resistance by 21.6 ± 8.1%, and depolarized the resting membrane potential by 8.0 ± 1.5 mV; no changes in the firing or electrical properties of pyramidal neurons were observed. Coapplication of 4-AP and isovaline increased interneuronal spontaneous spiking from 1.0 ± 0.6 to 2.6 ± 0.8 Hz, whereas pyramidal neuronal spiking activity decreased from 0.6 ± 0.4 to 0.2 ± 0.1 Hz. SIGNIFICANCE:Isovaline exhibited anticonvulsant properties in two hippocampal seizure models. This may lead to the development of a new class of anticonvulsants based on an unusual mechanism of action of this presumed extraterrestrial amino acid.

journal_name

Epilepsia

journal_title

Epilepsia

authors

Shin DS,Yu W,Sutton A,Calos M,Puil E,Carlen PL

doi

10.1111/j.1528-1167.2011.03260.x

subject

Has Abstract

pub_date

2011-11-01 00:00:00

pages

2084-93

issue

11

eissn

0013-9580

issn

1528-1167

journal_volume

52

pub_type

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