Hypoglycemia Enhances Ionotropic But Reduces Metabotropic Glutamate Responses in Substantia Nigra Dopaminergic Neurons

Abstract

It is widely accepted that energy deprivation causes a neuronal death that is mainly determined by an increase in the extracellular level of glutamate. Consequently an excessive membrane depolarization and a rise in the intracellular concentration of sodium and calcium are produced. In spite of this scenario, the function of excitatory and inhibitory amino acids during an episode of energy failure has not been studied yet at a cellular level. In a model of cerebral hypoglycemia in the rat substantia nigra pars compacta, we measured neuronal responses to excitatory amino acid agonists. Under single-electrode voltage-clamp mode at -60 mV, the application of the ionotropic glutamate receptor agonists N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, kainate, and the metabotropic group I agonist (S)-3,5-dihydroxyphenilglycine (DHPG) produced reversible inward currents in the dopaminergic cells. In addition, an outward current was caused by the superfusion of the metabotropic GABA(B) agonist baclofen. Glucose deprivation enhanced the inward responses caused by each ionotropic glutamate agonist. In contrast, hypoglycemia depressed the DHPG-induced inward current and the baclofen-induced outward current. These effects of hypoglycemia were reversible. To test whether a failure of the Na(+)/K(+) ATPase pump could account for the modification of the agonist-induced currents during hypoglycemia, we treated the midbrain slices with strophanthidin (1-3 microM). Strophanthidin enhanced the inward currents caused by glutamate agonists. However, it did not modify the GABA(B)-induced outward current. Our data suggest that glucose deprivation enhances the inward current caused by the stimulation of ionotropic glutamate receptors while it dampens the responses caused by the activation of metabotropic receptors. Thus a substantial component of the augmented neuronal response to glutamate, during energy deprivation, is very likely due to the failure of Na(+) and Ca(2+) extrusion and might ultimately favor excitotoxic processes in the dopaminergic cells.

Severe Hypoglycemia in a Juvenile Diabetic Rat Model: Presence and Severity of Seizures Are Associated with Mortality

“…The downregulation of K ATP channels that impair potassium buffering has been postulated to enhance excitability [32]. The decrease in intracellular ATP impairs the activity of the Na + /K + -ATPase and thus the cell’s ability to restore intracellular potassium and extracellular sodium levels, leading to an enhanced glutamate receptor function [60]. This is further exacerbated by the increase in excitatory amino acids such as glutamate and aspartate as well as ammonia [54], [61] that has been correlated with the onset of seizures [25].…”

Ferulic acid inhibits nitric oxide-induced apoptosis by enhancing GABAB1 receptor expression in transient focal cerebral ischemia in rats

“…Thus, the enhancement of GABA B1 receptor expression at 3 h of reperfusion might be the early beneficial action of FA against p38 MAP kinase-mediated NO-induced apoptosis at 24 h of reperfusion. The collateral circulation is built up for the preferential protection of the penumbra area after initial cerebral ischemia; however, adenosine triphosphate (ATP) depletion and energy failure, which lead to suppression of GABA B -mediated hyperpolarization, rapidly occur within 30 min after ischemia, and the brain energy state returns to nearly normal throughout the infarct territory upon reperfusion [37][38][39] . Experimental studies have elucidated that the GABA B agonist effectively reduces glutamate release in response to GABA B receptor expression in the ischemic area 20 to 40 min after cerebral ischemia [36] ; FA and its metabolites are sharply decreased in plasma and rapidly excreted in urine 0.5 to 1.5 h after administration of FA in rats [40] .…”

Enhanced [3H] Glutamate Binding in the Cerebellum of Insulin-Induced Hypoglycaemic and Streptozotocin-Induced Diabetic Rats

“…Severe hypoglycaemia with brain dysfunction limits intensified therapy in patients with insulindependent diabetes mellitus, despite evidence that such therapy reduces the risk of chronic complications of the disease (Maran et al 1994). It is widely accepted that energy deprivation causes a neuronal death that is mainly determined by an increase in the extracellular level of glutamate (Marinelli et al 2001). Glutamate which causes excitotoxic neuronal damage, increases calcium influx through NMDA receptors in post synaptic neurons, leading to phospholipase A2 mediated arachidonic acid release (Miriam et al 1996).…”

“…As in brain injury associated with ischaemia and neurodegenerative conditions, altered neurotransmitter action appears to play a role in hypoglycaemic brain injury (Aral et al 1998;Auer 1991;Auer and Seisjo 1993). Attention has been focussed on glutamate as a potential mediator of hypoglycaemic brain injury (Aral et al 1998;Cavaliere et al 2001;Marinelli et al 2001). Severe hypoglycaemia triggers a cascade of events in vulnerable neurons that may culminate in cell death even after glucose normalization (Sang et al 2003(Sang et al , 2004(Sang et al , 2005(Sang et al , 2007.…”