Increased GABA release in the human brain cortex as a potential pathogenetic basis of hyperosmolar diabetic coma.
JOURNAL OF NEUROCHEMISTRY(2008)
Abstract
Human cerebral cortical slices preincubated with [H-3]GABA, [H-3]noradrenaline, or 5-[H-3]hydroxytryptamine and superfused with Krebs solution or Mg2+-free Krebs solution were used to investigate the influence of increased D-glucose concentrations on the release of these [H-3]-neurotransmitters evoked by high K+ content or NMDA receptor activation, respectively. An increase in level of D-glucose (normal content, 11.1 mM) by 32, 60, and/or 100 mM (a range characteristic for hyperosmolar diabetic coma) increased the [H-3]GABA release and inhibited the [3 H]noradrenaline release evoked by both methods of stimulation. The K+-induced 5-[H-3]hydroxytryptamine release was also inhibited by high D-glucose content. Blockade of GABA(B) receptors by p-(3-aminopropyl)-p-diethoxymethylphosphinic acid (CGP 35348) attenuated the inhibitory effect of high D-glucose content on the K+-evoked release of [H-3]noradrenaline and 5-[H-3]hydroxytryptamine, suggesting that the effect on monoamine release is, at least to a major part, the result of the increased GABA release and, as a consequence, of an increased GABA concentration at inhibitory GABA(B) receptors. The membrane-impermeable sorbitol mimicked the increasing effect of D-glucose on [H-3]GABA release and its inhibitory effect on 5-[H-3]hydroxytryptamine release. However, dimethyl sulfoxide, which is known to permeate rapidly through biological membranes, had no effect at concentrations equiosmolar to D-glucose. It is concluded that a reduction in brain cell volume caused by increased extracellular, compared with cytoplasmic, osmolarity is crucial for the changes in neuronal function observed at high D-glucose and sorbitol content. In view of the fact that GABA is the main inhibitory neurotransmitter in the brain, the increased GABA release may be assumed to contribute to the pathogenesis of hyperosmolar diabetic coma.
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Key words
GABA RELEASE,NORADRENALINE RELEASE,5-HYDROXYTRYPTAMINE RELEASE,HYPEROSMOLAR DIABETIC COMA,GABA(B) RECEPTORS,D-GLUCOSE
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