2-deoxy-d-glucose protects hippocampal neurons against excitotoxic and oxidative injury: Evidence for the involvement of stress proteins

Abstract

Food restriction can extend life span in rodents and was recently reported to increase the resistance of neurons in the brain to excitotoxic and metabolic insults. In principle, administration to ad libitum fed rodents of an agent that reduces glucose availability to cells should mimick certain aspects of food restriction. We now report that administration of 2-deoxy-D-glucose (2DG), a non-metabolizable analog of glucose, to adult rats results in a highly significant reduction in seizure-induced spatial memory deficits and hippocampal neuron loss. Pretreatment of rat hippocampal cell cultures with 2DG decreases the vulnerability of neurons to excitotoxic (glutamate) and oxidative (Fe2+) insults. The protective action of 2DG is associated with decreased levels of cellular oxidative stress and enhanced calcium homeostasis. 2DG treatment increased levels of the stress-responsive proteins GRP78 and HSP70 in hippocampal neurons, without affecting levels of Bcl-2 or GRP75, suggesting that mild reductions in glucose availability can increase neuronal resistance to oxidative and metabolic insults by a mechanism involving induction of stress proteins. Our findings establish cell culture and in vivo models of "chemical food restriction" which may prove useful in elucidating mechanisms of neuroprotection and in developing preventive approaches for neurodegenerative disorders that involve oxidative stress and excitotoxicity.

Mood stabilizing drug lithium increases expression of endoplasmic reticulum stress proteins in primary cultured rat cerebral cortical cells

“…GRP78 binds Ca 2+ , folds damaged proteins (Bole et al, 1986;Lee, 1987), and has been found to inhibit oxyradical accumulation (Liu et al, 1998;Yu et al, 1999;Lee et al, 1999). In cultured rat hippocampal neurons, it has been reported that pretreatment with 2-deoxy-d-glucose, an inducer of GRP78 expression, inhibited cell death and reactive oxygen species accumulation, and stabilized mitochondrial transmembrane potential after cells have been challenged by glutamate and oxidant FeSO 4 .…”

Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems

“…Associated with the neuroprotective effect of IF was increased levels of the stress resistance proteins and brain-derived neurotrophic factor ( BDNF) [41,42]. Interestingly, administration of 2-deoxy-d-glucose (2DG; a nonmetabolizable glucose analog) to rats, which mimics some aspects of CR, also increases the production of stress resistance proteins in brain cells [43]. The latter findings suggested the possibility that IF would increase the resistance of neurons to a stroke because data from other studies have shown that protein chaperones and BDNF can reduce ischemic brain damage [43][44][45][46].…”

“…Interestingly, administration of 2-deoxy-d-glucose (2DG; a nonmetabolizable glucose analog) to rats, which mimics some aspects of CR, also increases the production of stress resistance proteins in brain cells [43]. The latter findings suggested the possibility that IF would increase the resistance of neurons to a stroke because data from other studies have shown that protein chaperones and BDNF can reduce ischemic brain damage [43][44][45][46]. We therefore subjected rats that had been maintained for 3 months on either an IF or a control diet to transient middle cerebral artery occlusion, a model of ischemic stroke [41].…”

“…In particular, levels of the protein chaperones heat-shock protein 70 and glucose-regulated protein 78 were increased in brain cells of rats maintained on an IF regimen or administered with 2DG [41][42][43]. The increased production of BDNF in brain cells of rodents on IF also likely results from a cellular stress response because BDNF expression is known to be increased by several different types of mild stress [25,40].…”

Molecular Bases of Caloric Restriction Regulation of Neuronal Synaptic Plasticity

“…When rodents were administered with 2-DG for 2 weeks, neurons in their brains exhibited an increased resistance to dysfunction and death in experimental models relevant to the pathogenesis of AD, PD, and stroke [88,89,122]. More interestingly, the mechanism whereby 2-DG supplementation protects neurons may be similar to that of CR because levels of some stress-induced proteins, heat shock protein 70 and glucose-regulated protein 78, are increased in neurons of rats and mice given 2-DG [88,89,122]. Although prolonged treatment of 2-DG has shown similar neuronal protection to that produced by CR, few studies has been performed in order to determinate nociception.…”