Impaired neuronal glucose uptake in pathogenesis of schizophrenia – Can GLUT 1 and GLUT 3 deficits explain imaging, post-mortem and pharmacological findings?

McDermott, Emma; Silva, Prasanna de

doi:10.1016/j.mehy.2005.06.022

Cited by 27 publications

(14 citation statements)

References 22 publications

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“…Also, it has been recently stated that drug-naive SZ patients and its relatives have elevated risk of diabetes and also low risk of obesity, suggesting a possible genetic predisposition to impaired glucose metabolism in this kind of patients [62]. These and other reports support the hypothesis that a failure of glucose uptake could misbalance the production of glutamate due to an inadequate glucose transport at high glucose demands leading to clinical spectrum of first onset SZ onset [63]. Thus, the altered regulation of glucose brain could constitute another dysfunctional mechanism of NMDAR in these patients.…”

Section: Discussionsupporting

confidence: 56%

From Glutamatergic Dysfunction to Cognitive Impairment: Boundaries in the Therapeutic of the Schizophrenia

Gaspar¹,

Bustamante²,

Rojo³

et al. 2012

CPB

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Cognitive deficits are trait markers in schizophrenia and the improvement of these dysfunctions has been considered as a new frontier of treatment in this disease. A current model for the patophysiology of schizophrenia states that N-methyl-D-aspartate receptor (NMDAR) hypofunction leads to a dysregulation of gamma-amino butyric acid (GABA) fast- spiking interneurons, consequently disinhibiting pyramidal glutamatergic output and disturbing signal-to-noise ratio. In this way, the modulation of the glutamate activity might constitute a highly promising target for future therapeutic interventions of this disease. In the present review, we discuss key regulatory elements for glutamatergic neurotransmission and provide new insights into their potential role in developing pharmacological treatments. Also, we emphasize the role of certain chemical families as potential sources of new lead compounds with affinity for metabotropic glutamate receptors (mGluRs) with cognitive enhancing properties.

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Section: Discussionsupporting

confidence: 56%

From Glutamatergic Dysfunction to Cognitive Impairment: Boundaries in the Therapeutic of the Schizophrenia

Gaspar¹,

Bustamante²,

Rojo³

et al. 2012

CPB

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“…However, it is important to consider mRNA changes in neurons may not have an effect on protein levels or transport activity. Interestingly, McDermott and deSilva hypothesized that genetic deficits in GLUT1/GLUT3 and poor uptake of glucose in the brain would result in a backlog effect and mild systemic hyperglycemia (52), which has been reported in schizophrenia (53, 54). Reduced glucose availability in neurons may disrupt bioenergetic coupling systems such as the glutamine/glutamate cycle, which is also perturbed in this illness (55, 56).…”

Section: Discussionmentioning

confidence: 99%

Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

et al. 2018

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Schizophrenia is a devastating illness that affects over 2 million people in the U.S. and costs society billions of dollars annually. New insights into the pathophysiology of schizophrenia are needed to provide the conceptual framework to facilitate development of new treatment strategies. We examined bioenergetic pathways in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia and control subjects using western blot analysis, quantitative real-time polymerase chain reaction, and enzyme/substrate assays. Laser-capture microdissection-qPCR was used to examine these pathways at the cellular level. We found decreases in hexokinase (HXK) and phosphofructokinase (PFK) activity in the DLPFC, as well as decreased PFK1 mRNA expression. In pyramidal neurons, we found an increase in monocarboxylate transporter 1 mRNA expression, and decreases in HXK1, PFK1, glucose transporter 1 (GLUT1), and GLUT3 mRNA expression. These results suggest abnormal bioenergetic function, as well as a neuron-specific defect in glucose utilization, in the DLPFC in schizophrenia.

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“…The reported decrease in glucose uptake mediated by stress or by high levels of GCs could place neurons in an energy-compromised environment, which could detrimentally affect neuronal responsiveness to pathophysiological events. In fact, glucose transport impairment precedes ATP depletion in brain, increasing neuronal vulnerability to excitotoxicity by compromising function of ion-motive ATPases (Mark et al, 1995), as it has been seen to occur in some neurodegenerative processes such Ab-induced toxicity, schizophrenia and others (Novelli et al, 1988;Kalaria and Harik, 1989;Sims, 1990;Mark et al, 1997;McDermott and De Silva, 2005) in which the reduction in glucose uptake occurs as an early step in the disease process prior to neuronal degeneration (Pettegrew et al, 1994;Reiman et al, 1996). On the other hand, GCs promote reduction in ATP levels (Tombaugh and Sapolsky, 1992;Lawrence and Sapolsky, 1994).…”

Section: Discussionmentioning

confidence: 99%

Effects of Peroxisome Proliferator-Activated Receptor Gamma Agonists on Brain Glucose and Glutamate Transporters after Stress in Rats

García‐Bueno

Caso

Perez‐Nievas

et al. 2006

Neuropsychopharmacol

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Repeated stress causes an energy-compromised status in the brain, with a decrease in glucose utilization by the brain cells, which might account for excitotoxicity processes seen in this condition. In fact, brain glucose metabolism mechanisms are impaired in some neurodegenerative disorders, including stress-related neuropsychopathologies. More recently, it has been demonstrated that some synthetic peroxisome proliferator-activated receptor gamma (PPARg) agonists increase glucose utilization in rat cortical slices and astrocytes, as well as inhibit brain oxidative damage after repeated stress, which add support for considering these drugs as potential neuroprotective agents. To assess if stress causes glucose utilization impairment in the brain and to study the mechanisms by which this effect is achieved, young-adult male Wistar rats (control and immobilized for 6 h during 7 or 14 consecutive days, S7, S14) were i.p. injected with the natural ligand 15-deoxy-D-12,14-prostaglandin J 2 (PGJ 2 , 120 mg/kg) or the high-affinity ligand rosiglitazone (RG, 3 mg/kg) at the onset of stress. Repeated immobilization during 1 or 2 weeks produces a decrease in brain cortical synaptosomal glucose uptake, and this effect was prevented by treatment with both natural and synthetic PPARg ligands by restoring protein expression of the neuronal glucose transporter, GLUT-3 in membrane fractions. On the other hand, treatment with PPARg ligands prevents stress-induced ATP loss in rat brain. Finally, repeated immobilization stress also produces a decrease in brain cortical synaptosomal glutamate uptake, and this effect was prevented by treatment with PPARg ligands by restoring synaptosomal protein expression of the glial glutamate transporter, EAAT2. In summary, our results demonstrate that 15d-PGJ 2 and the thiazolidinedione rosiglitazone increase neuronal glucose metabolism, restore brain ATP levels and prevent the impairment in glutamate uptake mechanisms induced by exposure to stress, suggesting that this class of drugs may be therapeutically useful in conditions in which brain glucose levels or availability are limited after exposure to stress.

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Impaired neuronal glucose uptake in pathogenesis of schizophrenia – Can GLUT 1 and GLUT 3 deficits explain imaging, post-mortem and pharmacological findings?

Cited by 27 publications

References 22 publications

From Glutamatergic Dysfunction to Cognitive Impairment: Boundaries in the Therapeutic of the Schizophrenia

From Glutamatergic Dysfunction to Cognitive Impairment: Boundaries in the Therapeutic of the Schizophrenia

Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

Effects of Peroxisome Proliferator-Activated Receptor Gamma Agonists on Brain Glucose and Glutamate Transporters after Stress in Rats

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