Somatostatin type-2 receptor activation inhibits glutamate release and prevents status epilepticus

Maxim Kozhemyakin, Karthik Rajasekaran, Marko S. Todorovic, Samuel L. Kowalski, Corinne Balint, Jaideep Kapur

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Newer therapies are needed for the treatment of status epilepticus (SE) refractory to benzodiazepines. Enhanced glutamatergic neurotransmission leads to SE, and AMPA receptors are modified during SE. Reducing glutamate release during SE is a potential approach to terminate SE. The neuropeptide somatostatin (SST) is proposed to diminish presynaptic glutamate release by activating SST type-2 receptors (SST2R). SST exerts an anticonvulsant action in some experimental models of seizures. Here, we investigated the mechanism of action of SST on excitatory synaptic transmission at the Schaffer collateral-CA1 synapses and the ability of SST to treat SE in rats using patch-clamp electrophysiology and video-EEG monitoring of seizures. SST reduced action potential-dependent EPSCs (sEPSCs) at Schaffer collateral-CA1 synapses at concentrations up to 1. μM; higher concentrations had no effect or increased the sEPSC frequency. SST also prevented paired-pulse facilitation of evoked EPSCs and did not alter action-potential-independent miniature EPSCs (mEPSCs). The effect of SST on EPSCs was inhibited by the SST2R antagonist cyanamid-154806 and was mimicked by the SST2R agonists, octreotide and lanreotide. Both SST and octreotide reduced the firing rate of CA1 pyramidal neurons. Intraventricular administration of SST, within a range of doses, either prevented or attenuated pilocarpine-induced SE or delayed the median time to the first grade 5 seizure by 11. min. Similarly, octreotide or lanreotide prevented or attenuated SE in more than 65% of animals. Compared to the pilocarpine model, octreotide was highly potent in preventing or attenuating continuous hippocampal stimulation-induced SE in all animals within 60. min of SE onset. Our results demonstrate that SST, through the activation of SST2Rs, diminishes presynaptic glutamate release and attenuates SE.

Original languageEnglish (US)
Pages (from-to)94-104
Number of pages11
JournalNeurobiology of Disease
Volume54
DOIs
StatePublished - Jun 2013

Keywords

  • Glutamate
  • Somatostatin
  • Somatostatin type 2 receptors
  • Status epilepticus
  • Synaptic transmission

ASJC Scopus subject areas

  • Neurology

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