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.

• Authors: Damian S Shin, Wilson Yu, Alex Sutton, Megan Calos, Ernest Puil, Peter L Carlen
• Journal: Epilepsia (Epilepsia) Vol. 52 Issue 11 Pg. 2084-93 (Nov 2011) ISSN: 1528-1167 [Electronic] United States
• PMID: 21906050 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.

Chemical References

• Anticonvulsants
• Convulsants
• isovaline
• 4-Aminopyridine
• Valine

Topics

• 4-Aminopyridine (pharmacology)
• Action Potentials (drug effects, physiology)
• Animals
• Anticonvulsants (therapeutic use)
• Convulsants (pharmacology)
• Dose-Response Relationship, Drug
• Hippocampus (drug effects)
• In Vitro Techniques
• Interneurons (drug effects, physiology)
• Patch-Clamp Techniques
• Pyramidal Cells (drug effects, physiology)
• Rats
• Rats, Sprague-Dawley
• Seizures (drug therapy)
• Valine (therapeutic use)