In the rat, the hippocampus loses neurons with age, and cumulative exposure to glucocorticoids (GCs), the adrenocortical stress hormones, plays a major role in such exposure. My prior work suggests that GCs disrupt energy metabolism and thus compromise the ability of neurons to survive metabolic challenges. As evidence, varied insults that damage the hippocampus are more toxic in rates exposed to elevated GC concentrations and are less so in adrenalectomized rates. Such insults include the excittoxin kainic acid, the antimetabolite 3- acetylpyridine and hypoxia-ischemia. My proposed studies will 1) determine whether this model of GC- induced hippocampal damage applies to senescent neuron loss, 2) study the cellular mechanisms of this GC toxicity, and 3) examine the neuroendocrine consequences of the neuron loss. Part I: I will examine whether additional hippocampal insults also have their toxicities modulated by GC milieu. These will include epileptogenic excitotoxins and heavy metals. Since these acute insults may be of limited relevance to the gradual neuron loss of aging, I will then determine whether milder chronic insults also have their toxicities modulated by GCs. Part II: I will determine whether GCs are the sole damaging agents. I will expand my prior work with hippocampal neuron cultures to examine whether GCs endanger cells directly. I will study the steroidal and tissue specificity of the phenomenon, as well as identify the mediating receptors. Part III: I will study whether GCs exacerbate abnormal cellular parameters that accompany and may mediate neuron death. These will include excitatory neurotransmitter release, calcium influxes and lactic acidosis. Part IV: I will determine whether the aged hippocampus is preferentially sensitive to the synergy between GCs and varied insults, and whether GCs produce more extreme changes in the previously mentioned cellular parameters in the aged hippocampus. Part V: The hippocampus is a mediator the inhibitory negative feedback actions of GCs upon the adrenocortical axis. Using hypophysial portal cannulation methods, I will examine whether the hippocampal neuron loss of aging is associated with hypersecretion of corticotropic releasing factor or related peptides. If so, this would explain the GC hypersecretion of the aged rat which, in turn, further damages the hippocampus and impairs its function.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG006633-03
Application #
3117731
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1987-01-15
Project End
1989-12-31
Budget Start
1989-01-05
Budget End
1989-12-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
Schools of Arts and Sciences
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
McIntosh, L J; Sapolsky, R M (1996) Glucocorticoids increase the accumulation of reactive oxygen species and enhance adriamycin-induced toxicity in neuronal culture. Exp Neurol 141:201-6
Brooke, S M; Trafton, J A; Sapolsky, R M (1996) Autofluorescence as a confound in the determination of calcium levels in hippocampal slices using fura-2AM dye. Brain Res 706:283-8
Sapolsky, R; Brooke, S; Stein-Behrens, B (1995) Methodologic issues in studying glucocorticoid-induced damage to neurons. J Neurosci Methods 58:1-15
Chou, Y C; Lin, W J; Sapolsky, R M (1994) Glucocorticoids increase extracellular [3H]D-aspartate overflow in hippocampal cultures during cyanide-induced ischemia. Brain Res 654:8-14
Moghaddam, B; Bolinao, M L; Stein-Behrens, B et al. (1994) Glucocorticoids mediate the stress-induced extracellular accumulation of glutamate. Brain Res 655:251-4
Lawrence, M S; Sapolsky, R M (1994) Glucocorticoids accelerate ATP loss following metabolic insults in cultured hippocampal neurons. Brain Res 646:303-6
Stein-Behrens, B A; Lin, W J; Sapolsky, R M (1994) Physiological elevations of glucocorticoids potentiate glutamate accumulation in the hippocampus. J Neurochem 63:596-602
Raley-Susman, K M; Sapolsky, R M; Kopito, R R (1993) Cl-/HCO3- exchange function differs in adult and fetal rat hippocampal neurons. Brain Res 614:308-14
Redish, D M; Raley-Susman, K M; Sapolsky, R M (1993) Inhibition of acidification rate in cultured fibroblasts by glucocorticoids. Application of silicon microphysiometry to endocrinology. Horm Metab Res 25:264-7
Tombaugh, G C; Sapolsky, R M (1993) Endocrine features of glucocorticoid endangerment in hippocampal astrocytes. Neuroendocrinology 57:7-13

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