Biomedical subjects
RM Sapolsky
Publications and source records attributed to RM Sapolsky.
McEwen-Induced Modulation of Endocrine History: A Partial Review.
In endless facets of physiology, there are points of homeostatic balance, such that too much or too litttle of something can both be deleterious (i.e., an "inverse U" pattern). This is particularly true when considering glucocorticoids (GCs), the adrenals steroid secreted during stress. In the first part of this paper, I review a number of realms in which a paucity and an excess of GCs are both damaging. Some findings are classical (for example, concerning GC effects upon body weight), while some are quite recent and have considerable implications for both physiology and pathophysiology (for example, inverse U's of GC actions in the realm of immunity and neuronal survival). The second part of the review considers the far thornier issue of how such inverse U's of GC actions are generated on a cellular and molecular level. One solution that has evolved, primarily in the hippocampus within the nervous system, involves the presence of two different types of receptors for GCs within the same cells; so long as the two receptors have very different affinities and mediate opposing effects on some cellular endpoint, an inverse U will emerge. The second solution, found in a number of peripheral tissues, involves GCs having opposing effects on the amount of some signal being generated (e.g., an immune cytokine) and the sensitivity of target tissues to that signal; under conditions that appear to be physiologically relevant, inverse U's emerge from this pattern as well. The final section of this review considers the enormous role played by Bruce McEwen in the emergence of this literature. I suggest that while much of this obviously has to do with the facts that have come from his group, another substantial contribution is from his steadying and supportive personality, the veritable embodiment of homeostatic balance.
Stress, Glucocorticoids, and Damage to the Nervous System: The Current State of Confusion.
An extensive literature demonstrates that glucocorticoids (GCs), the adrenal steroids secreted during stress, can have a broad range of deleterious effects in the brain. The actions occur predominately, but not exclusively, in the hippocampus, a structure rich in corticosteroid receptors and particularly sensitive to GCs. The first half of this review considers three types of GC effects: a) GC-induced atrophy, in which a few weeks' exposure to high GC concentrations or to stress causes reversible atrophy of dendritic processes in the hippocampus; b) GC neurotoxicity where, over the course of months, GC exposure kills hippocampal neurons; c) GC neuroendangerment, in which elevated GC concentrations at the time of a neurological insult such as a stroke or seizure impairs the ability of neurons to survive the insult. The second half considers the rather confusing literature as to the possible mechanisms underlying these deleterious GC actions. Five broad themes are discerned: a) that GCs induce a metabolic vulnerability in neurons due to inhibition of glucose uptake; b) that GCs exacerbate various steps in a damaging cascade of glutamate excess, calcium mobilization and oxygen radical generation. In a review a number of years ago, I concluded that these two components accounted for the deleterious GC effects. Specifically, the energetic vulnerability induced by GCs left neurons metabolically compromised, and less able to carry out the costly task of containing glutamate, calcium and oxygen radicals. More recent work has shown this conclusion to be simplistic, and GC actions are shown to probably involve at least three additional components: c) that GCs impair a variety of neuronal defenses against neurologic insults; d) that GCs disrupt the mobilization of neurotrophins; e) that GCs have a variety of electrophysiological effects which can damage neurons. The relevance of each of those mechanisms to GC-induced atrophy, neurotoxicity and neuroendangerment is considered, as are the likely interactions among them.