Research reportGlucocorticoids exacerbate insult-induced declines in metabolism in selectively vulnerable hippocampal cell fields
Introduction
Glucocorticoids (GCs), the adrenal steroids released during stress, can have adverse effects in the nervous system if secreted or administered in excess. Exposure to excessive GCs or to stress for hours to days compromises the ability of neurons to survive in vitro and in vivo models of necrotic insults (i.e. hypoxia–ischemia, excitotoxicity and energy deprivation). These “endangering” GC effects are most pronounced in the hippocampus, with its high concentrations of corticosteroid receptors and sensitivity to GCs (reviewed in [32]).
A central dogma exists regarding the mechanisms by which such necrotic insults are damaging. This involves the excessive accumulation of synaptic excitatory amino acids (EAA) neurotransmitters, the resulting excessive post-synaptic mobilization of free cytosolic calcium, and the activation of calcium-dependent oxygen radical formation and cytoskeletal degradation [15]. GCs worsen this degenerative cascade in an energy-dependent manner. The steroid accelerates the decline in ATP concentrations in hippocampal cells during insults [14], [38]. This, in turn, compromises the costly task of containing EAA and calcium fluxes during these insults. Thus, GCs exacerbate the accumulation of extracellular EAAs, of cytosolic calcium, of oxygen radicals and of cytoskeletal degradation during these insults. Moreover, these GC effects can be blunted by supplementation with excess energy, evidence of the energetic nature of these GC actions [5], [6], [7], [17], [18], [22], [23], [24], [35], [36], [37]. As one possible cause of the effects of GCs upon hippocampal energetics, the steroid can inhibit glucose uptake and utilization [4], [8], [9], [10], [41].
The effects of GCs upon hippocampal ATP concentrations during insults suggests that the steroid should exacerbate the effects of insults upon hippocampal metabolism as well. Silicon microphysiometry can measure extracellular acidification rates in real time. Since the products of cellular metabolism include lactic acid and carbon dioxide, the amount of metabolites extruded extracellularly can serve as an indirect measure of cellular metabolism [21]. We originally adapted microphysiometry for use in neuronal monolayer cultures [28], [39] and, more recently, for use with explants from specific hippocampal cell fields from adult brain [1]. We now use microphysiometry to demonstrate the ability of GCs to worsen the disruptive metabolic effects of necrotic insults in specific hippocampal cell fields.
Section snippets
Buffers/reagents
Dulbecco’s modified Eagle’s medium (DMEM: Gibco, Grand Island, NY, USA) was used for hippocampal dissection and microphysiometric procedures in the aglycemia and hypoglycemia experiments.
Earle’s balanced salt solution without bicarbonate (EBSS; Gibco, Grand Island, NY, USA) was used for experiments with metabolic toxins. While the buffering capacity of DMEM was reduced by the substitution of 2.5 g of NaCl for every 3.7 g of NaHCO3, EBSS’ buffering capacity was reduced by omission of
Results
“Basal” metabolic rates (i.e. the final twenty min during which rates had stabilized prior to the experimental manipulation) did not differ significantly by hippocampal cell field or by GC-status (data not shown).
We previously demonstrated that microphysiometry with adult hippocampal cell field explants could replicate features of the selective vulnerability that characterizes the hippocampus in vivo [1]. Specifically, we observed that exposure to cyanide significantly altered metabolic rate in
Discussion
As reviewed, GCs can compromise the ability of hippocampal neurons to survive necrotic insults. While these endangering GC actions arise in part from some non-energetic effects (reviewed in [3]), disruptive GC effects on metabolism appear contributory as well. As evidence, (a) GCs inhibit glucose transport and utilization and accelerate the decline in ATP concentrations during hippocampal insults [4], [8], [9], [10], [14], [38], [41]; (b) energy supplementation lessens the exacerbative effects
Acknowledgements
Support was provided by Grant sponsor: NIH, Grant number: RO1 MH53814 and the Adler Foundation to RS, OA and TB, and a U.R.O. grant to LF. We are grateful to the Molecular Devices Corporation for the gift of the Cytosensor silicon microphysiometer, and to Pierre Magistretti for manuscript assistance.
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