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

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.