Levetiracetam as Adjunctive Therapy for Refractory Anxiety Disorders

Kinrys, Gustavo; Worthington, John J.; Wygant, Lisa E; Nery, Fernanda Sampaio; Reese, Hannah E.; Pollack, Mark H.

doi:10.4088/jcp.v68n0705

Cited by 18 publications

(10 citation statements)

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“…Currently marketed as Keppra®, levetiracetam is FDA-approved for the treatment of epilepsy (reviewed in [1]), though it also shows promise in the treatment of anxiety disorders [2], [3], [4], pain [5], [6], [7], dyskinesias [8], [9], [10], [11], [12], and post-traumatic stress disorder [3]. The protein receptor for levetiracetam is Synaptic Vesicle Protein 2A (SV2A) [13], a membrane glycoprotein specific to the secretory vesicles of neurons and endocrine cells in vertebrates [14].…”

Section: Introductionmentioning

confidence: 99%

Levetiracetam Reverses Synaptic Deficits Produced by Overexpression of SV2A

et al. 2011

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Levetiracetam is an FDA-approved drug used to treat epilepsy and other disorders of the nervous system. Although it is known that levetiracetam binds the synaptic vesicle protein SV2A, how drug binding affects synaptic functioning remains unknown. Here we report that levetiracetam reverses the effects of excess SV2A in autaptic hippocampal neurons. Expression of an SV2A-EGFP fusion protein produced a ∼1.5-fold increase in synaptic levels of SV2, and resulted in reduced synaptic release probability. The overexpression phenotype parallels that seen in neurons from SV2 knockout mice, which experience severe seizures. Overexpression of SV2A also increased synaptic levels of the calcium-sensor protein synaptotagmin, an SV2-binding protein whose stability and trafficking are regulated by SV2. Treatment with levetiracetam rescued normal neurotransmission and restored normal levels of SV2 and synaptotagmin at the synapse. These results indicate that changes in SV2 expression in either direction impact neurotransmission, and suggest that levetiracetam may modulate SV2 protein interactions.

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Section: Introductionmentioning

confidence: 99%

Levetiracetam Reverses Synaptic Deficits Produced by Overexpression of SV2A

et al. 2011

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“…Levetiracetam is a Food and Drug Administration-approved treatment for epilepsy (reviewed in Ref. 11) that also shows promise in the treatment of anxiety disorders (27,28,47), pain (12,13,36), dyskinesias (7,32,40,43,48), and posttraumatic stress disorder (28). Thus SV2 represents a vesicle protein whose action is likely to play an important (and targetable) regulatory action at synapses.…”

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confidence: 99%

SV2 regulates neurotransmitter release via multiple mechanisms

Nowack¹,

Yao²,

Custer

et al. 2010

American Journal of Physiology-Cell Physiology

122

116

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Nowack A, Yao J, Custer KL, Bajjalieh SM. SV2 regulates neurotransmitter release via multiple mechanisms. Am J Physiol Cell Physiol 299: C960 -C967, 2010. First published August 11, 2010 doi:10.1152/ajpcell.00259.2010.-Among the proteins that mediate calcium-stimulated transmitter release, the synaptic vesicle protein 2 (SV2) stands out as a unique modulator specific to the neurons and endocrine cells of vertebrates. In synapses, SV2 regulates the expression and trafficking of the calcium sensor protein synaptotagmin, an action consistent with the reduced calcium-mediated exocytosis observed in neurons lacking SV2. Yet SV2 contains amino acid motifs consistent with it performing other actions that could regulate presynaptic functioning and that might underlie the mechanism of drug action. To test the role of these functional motifs, we performed a mutagenic analysis of SV2A and assessed the ability of mutant SV2A proteins to restore normal synaptic transmission in neurons from SV2A/B knockout mice. We report that SV2A-R231Q, harboring a mutation in a canonical transporter motif, restored normal synaptic depression (a measure of release probability and signature deficit of neurons lacking SV2). In contrast, normal synaptic depression was not restored by SV2A-W300A and SV2A-W666A, harboring mutations of conserved tryptophans in the 5th and 10th transmembrane domains. Although they did not rescue normal neurotransmission, SV2A-W300A and SV2A-W666A did restore normal levels of synaptotagmin expression and internalization. This indicates that tryptophans 300 and 666 support an essential action of SV2 that is unrelated to its role in synaptotagmin expression or trafficking. These results indicate that SV2 performs at least two actions at the synapse that contribute to neurotransmitter release. synapse; neurotransmission; exocytosis THE CALCIUM-REGULATED SECRETION of neurotransmitters is a specialized form of membrane fusion that requires regulatory proteins that are unique to transmitter-containing vesicles. One of these is synaptic vesicle protein 2 (SV2), a membrane glycoprotein expressed exclusively in neurons and endocrine cells. SV2 is the binding site of a class of drugs typified by levetiracetam (5,17,26,29,31). Levetiracetam is a Food and Drug Administration-approved treatment for epilepsy (reviewed in Ref. 11) that also shows promise in the treatment of anxiety disorders (27, 28, 47), pain (12, 13, 36), dyskinesias (7,32,40,43,48), and posttraumatic stress disorder (28). Thus SV2 represents a vesicle protein whose action is likely to play an important (and targetable) regulatory action at synapses.SV2 is essential for normal neurotransmission. Neurons lacking SV2A and SV2B demonstrate reduced neurotransmission and reduced synaptic depression (8 -10, 22, 41, 44). These phenotypes reflect reduced release probability due to impaired ability of vesicles to fuse in response to elevated cytoplasmic calcium. This effect occurs after vesicle docking (10) and before formation of the SNARE (soluble N-ethylmaleimidese...

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“…For issues with anxiety, the calcium channel modulating drug pregabalin was shown to be more effective than alprazolam for anxiety symptoms at one week of use [192]. Also, leviracetam has also been shown to have anxiolytic properties [193] [194]. The gammaaminobu-tyric acid (GABA) reuptake inhibitor tiagabine has been shown to decrease symptoms of anxiety and improved sleep with the same efficiency as paroxetine in a 10…”

Section: Psychiatric Pharmaceutical Considerationsmentioning

confidence: 99%