Elsevier

Brain Research

Volume 870, Issues 1–2, 7 July 2000, Pages 109-117
Brain Research

Research report
Glucocorticoids exacerbate insult-induced declines in metabolism in selectively vulnerable hippocampal cell fields

https://doi.org/10.1016/S0006-8993(00)02407-0Get rights and content

Abstract

Glucocorticoids (GCs), the adrenal steroids released during stress, can compromise the ability of hippocampal neurons to survive necrotic neurological insults. This GC-induced endangerment has energetic facets, in that it can be attenuated with energy supplementation. In the present report, we studied the effects of GCs on the metabolic response of specific hippocampal cell fields to necrotic insults. We used silicon microphysiometry, which allows indirect measurement of metabolism in real time in tissue explants. Aglycemia caused a significant decline in metabolism in dentate gyrus explants, but not in CA1 or CA3 explants. When coupled with our prior report of cyanide disrupting metabolism only in CA1 explants, and the glutamatergic excitotoxin kainic acid disrupting metabolism only in CA3 explants, this demonstrates that microphysiometry can detect the selective regional vulnerability that characterizes the hippocampal response to these necrotic insults. We then examined the effects of GCs on the response to these insults, monitoring explants taken from rats that were adrenalectomized, intact, or treated with corticosterone (the GC of rats) that produced circulating levels equivalent to those of major stressors. Increased exposure to GCs worsened the decline in metabolism in dentate gyrus explants induced by hypoglycemia, and in CA1 explants induced by cyanide (after eliminating the effects of glial release of lactate for the support of neuronal metabolism). Thus, GCs worsen the metabolic consequences of necrotic insults in hippocampal explants.

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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