PubMed Health⌕ Search

Biomedical subjects

R M Sapolsky

Publications and source records attributed to R M Sapolsky.

At least 19 recordsLinked to original sources
PubMed1999

In vivo characterization of 11beta-hydroxysteroid dehydrogenase in rat hippocampus using glucocorticoid neuroendangerment as an endpoint.

11beta-Hydroxysteroid dehydrogenase (11beta-HSD) is the enzyme responsible for the interconversion of corticosterone (CORT) to 11-dehydrocorticosterone (11-DHC). CORT is an adrenal hormone secreted during the stress response and it has widespread effects in many different target tissues. In addition, CORT can exacerbate damage caused by neurological insults, such as kainic acid-induced seizures. In addition to its protective role in the kidney, 11beta-HSD is also thought to play a role in steroid regulation in the brain. However, it is not known whether the enzyme is acting in vivo as a reductase or a dehydrogenase. If the enzyme is working as a reductase, converting 11-DHC to CORT, it has the potential to exacerbate neurotoxicity due to other agents. On the other hand, 11beta-HSD could be neuroprotective if the enzyme is acting as a dehydrogenase, deactivating CORT by converting it into 11-DHC. To characterize the enzyme in vivo, we have utilized glucocorticoid neuroendangerment in the hippocampus as an indirect assay of 11beta-HSD function. We have shown that 11-DHC can exacerbate kainic acid toxicity in adrenalectomized (ADX) rats and this exacerbation is blocked by the 11beta-HSD antagonist, carbenoxolone; these findings suggest that 11beta-HSD is working as a reductase in ADX rats. The presumptive reductase activity found in ADX rats was derived from both hippocampal and peripheral forms of the enzyme. In the presence of physiological levels of glucocorticoids, reductase activity was decreased and no dehydrogenase activity was detected. The present study demonstrates that 11beta-HSD reductase activity, both in vivo and in vitro, occurs only in the presence of low levels of circulating glucocorticoids.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1998

Glucocorticoids interact with gp120 in causing neurotoxicity in striatal cultures.

A significant subset of HIV-positive patients suffer from AIDS-Related Dementia Complex (ADC), an array of neurologic and neuropsychologic impairments. The HIV coat protein gp120 has been implicated in the deleterious neurologic consequences of HIV infection, damaging neurons through a glutamatergic and calcium-dependent pathway. We have previously reported that glucocorticoids, the adrenal steroids secreted during stress, can exacerbate the neurotoxic and calcium-mobilizing effects of gp120 in hippocampal and cortical cultures. Because both the symptomatology of ADC, as well as the neuropathologic profile of post-mortem HIV brains suggests an involvement of the striatum, we examined whether glucocorticoids could also augment the damaging effects of gp120 in primary striatal cultures. We observe that neither gp120 nor the glucocorticoid corticosterone, when administered alone, cause neurotoxicity or mobilization of free cytosolic calcium; however, a combination of the two caused significant toxicity and neuron death. This, along with our prior findings of gp120-glucocorticoid interactions, is striking, given the heavy clinical use of synthetic glucocorticoids for management of pulmonary complications of HIV infection.

AIDS Dementia Complex↗
PubMed1998

Glucocorticoids may alter antioxidant enzyme capacity in the brain: kainic acid studies.

Glucocorticoids (GCs) predispose hippocampal neurons to damage during metabolic stressors. One component of hippocampal GC-endangerment may be changes in neuronal defenses against oxidative challenge. Previous experiments showed a decrease in basal levels of copper/zinc superoxide dismutase (Cu/Zn SOD) and glutathione peroxidase (GSPx) in the brain of rats treated with GCs [L. McIntosh, K. Hong, R. Sapolsky, Glucocorticoids may alter antioxidant enzyme capacity in the brain: baseline studies, 1997.]. In this study we administered the excitotoxin kainic acid (KA) to generate reactive oxygen species (ROS) in the brain, and monitored the activity of four antioxidant enzymes over 24 h in GC-free and GC-supplemented rats. We tested the response pattern in three regions of the brain (hippocampus, cortex, cerebellum) and the liver as a peripheral control. In the hippocampus, KA induced Cu/Zn SOD and catalase, but GCs prevented the induction of catalase and maintained the lowered GSPx activity seen previously in the baseline studies. In the cortex, KA induced Cu/Zn SOD, Mn SOD and catalase activity, but there was no significant GC effect. There was no response to KA in the cerebellum, but GCs decreased GSPx activity. In the liver, KA produced a rise in Cu/Zn SOD and catalase activity, and GC-treated animals showed a slower return to baseline. These experiments indicate that the impairment of antioxidant enzyme defenses, particularly the hippocampal peroxidases, could be a component of GC-mediated neuroendangerment.

Animals↗
PubMed1998

Glucocorticoids may alter antioxidant enzyme capacity in the brain: baseline studies.

Glucocorticoids (GCs), the adrenal steroids secreted during stress, have been shown to increase the vulnerability of hippocampal neurons to metabolic insults, potentially by altering the neuronal defense capacity against oxidative damage. These experiments assessed the effect of long term in vivo GC supplementation on basal activity of the antioxidant enzymes copper/zinc superoxide dismutase (Cu/Zn SOD), manganese superoxide dismutase (Mn SOD), catalase, and glutathione peroxidase (GSPx). Kinetic enzyme studies were done using brain tissue from the hippocampus, cortex, cerebellum, and also from liver as a peripheral control. Cu/Zn SOD activity was significantly lower in all brain regions of GC-treated rats, but higher in the liver. Mn SOD activity was unaffected by treatment. Catalase in the brain appeared largely unaffected by GC treatment, although liver catalase was significantly decreased. GSPx activity was significantly decreased by GCs at high peroxide levels in all tissues. These results indicate that the presence of GCs may lower the antioxidant capacity of tissues in a region-specific manner, and that the deficit may not appear until the tissue is challenged with supranormal levels of oxidative products (as seen with GSPx).

Animals↗
PubMed1998

Darting terrestrial primates in the wild: a primer.

While a goal of many field primatologists is to observe subjects in as undisturbed a setting as possible, it is often necessary to anesthetize animals for any of a variety of reasons. In this paper, we review techniques for anesthetizing wild primates, based on our experience with more than a thousand such procedures carried out on baboons in East Africa. We consider the following: 1) rationales for anesthetizing a wild primate; 2) systems for the delivery of anesthetic and choice of anesthetic; 3) the darting process itself and issues relevant to the period between darting and the safe removal of the animal; 4) handling of an anesthetized primate; 5) medical complications associated with darting; 6) when to reanesthetize an animal; 7) the process of recovery from anesthesia and release of an awake animal; 8) safety issues for humans. The range of information that can be obtained through field anesthetizations, when carried out successfully, as well as the potential benefit for the animals involved, can be enormous. However, this process is not trivial from the standpoint of the dangers involved to both the subjects and to humans and because of the potential disruption of social behavior to the group. As such, anesthetizations in the field should not be carried out without a strong rationale and without a tremendous priority given to the safety and care of all involved.

Anesthetics↗
PubMed1998

Gene therapy with HSP72 is neuroprotective in rat models of stroke and epilepsy.

Brain areas damaged by stroke and seizures express high levels of the 72-kd heat shock protein (HSP72). Whether HSP72 represents merely a marker of stress or plays a role in improving neuron survival in these cases has been debated. Some induced tolerance experiments have provided correlative evidence for a neuroprotective effect, and others have documented neuroprotection in the absence of HSP72 synthesis. We report that gene transfer therapy with defective herpes simplex virus vectors overexpressing hsp72 improves neuron survival against focal cerebral ischemia and systemic kainic acid administration. HSP72 overexpression improved striatal neuron survival from 62.3 to 95.4% in rats subjected to 1 hour of middle cerebral artery occlusion, and improved survival of hippocampal dentate gyrus neurons after systemic kainic acid administration, from 21.9 to 64.4%. We conclude that HSP72 may participate in processes that enhance neuron survival during transient focal cerebral ischemia and excitotoxin-induced seizures.

Animals↗
PubMed1998

Basolateral amygdala lesions block the disruptive effects of long-term adrenalectomy on spatial memory.

The present study examined, in rats with N-methyl-D-aspartate-induced lesions of the basolateral amygdala, the effects of long-term adrenalectomy (i.e. 12-13 weeks) on memory for spatial and cued learning in a water maze. In sham amygdala-lesioned rats, adrenalectomy induced impairments in acquisition and retention performance for the spatial, but not the cued water-maze task. The adrenalectomized rats sustained selective degeneration and death of granule cells in the dentate gyrus dorsal blade. Continuous supplementation of the animals' drinking water with an extremely low dose of corticosterone (20 microg/ml) did not block the retention deficit, but blocked the acquisition deficit and the dentate gyrus neurodegenerative changes. The finding that the memory impairments and dentate gyrus neurodegeneration are dissociable supports the view that the adrenalectomy-induced memory effects are due to the loss of activational effects of circulating adrenal hormones at the time of learning. In adrenalectomized rats which received corticosterone as well as those which did not, lesions of the basolateral amygdala blocked the impairing effects of adrenalectomy on spatial learning and memory. However, the basolateral amygdala lesions did not affect the neurodegenerative changes in the dentate gyrus. In conclusion, the present findings provide further evidence that the basolateral amygdala is involved in regulating stress hormone effects on learning and memory.

Adrenalectomy↗
PubMed1998

Gene transfer of calbindin D28k cDNA via herpes simplex virus amplicon vector decreases cytoplasmic calcium ion response and enhances neuronal survival following glutamatergic challenge but not following cyanide.

Excitatory amino acid overstimulation of neurons can lead to a marked rise in cytoplasmic Ca2+ concentration ([Ca2+])i) and be followed by neuron death from hours to days later. If the rise in [Ca2+]i is prevented, either by removing Ca2+ from the extracellular environment or by placing Ca2+ chelators in the cytosol of the stimulated cells, the neurotoxicity associated with excitotoxins can be ameliorated. We have recently shown that neurons infected with a herpes simplex virus amplicon vector expressing cDNA for calbindin D28k responded to hypoglycemia with decreased [Ca2+]i and increased survival relative to controls. We now report that vector-infected neurons respond to glutamatergic insults with lower [Ca2+]i than controls and with increased survival. Infected neurons exposed to sodium cyanide did not respond with lower [Ca2+]i than controls, nor did they demonstrate increased survival postinsult. We examine these results in light of our earlier report and in the context of the potential of vectors like this for neuronal gene therapy.

Animals↗
PubMed1998

Energy dependency of glucocorticoid exacerbation of gp120 neurotoxicity.

The HIV envelope glycoprotein, gp120, a well documented neurotoxin, may be involved in AIDS-related dementia complex. gp120 works through an NMDA receptor- and calcium-dependent mechanism to damage neurons. We have previously demonstrated that both natural and synthetic glucocorticoids (GCs) exacerbate gp120-induced neurotoxicity and calcium mobilization in hippocampal mixed cultures. GCs, steroid hormones secreted during stress, are now shown to work in conjunction with gp120 to decrease ATP levels and to work synergistically with gp120 to decrease the mitochondrial potential in hippocampal cultures. Furthermore, energy supplementation blocked the ability of GCs to worsen gp120's effects on neuronal survival and calcium mobilization. A GC-induced reduction in glucose transport in hippocampal neurons, as previously documented, may contribute to this energetic dependency. These results may have clinical significance, considering the common treatment of severe cases of Pneumocystis carinii pneumonia, typical of HIV infection, with large doses of synthetic GCs.

Adenosine Triphosphate↗
PubMed1997

Application of silicon microphysiometry to tissue slices: detection of metabolic correlates of selective vulnerability.

The silicon microphysiometer is a recently developed instrument which measures rates of proton efflux in real time from small numbers of cultured cells. Since the main products of cellular metabolism are lactic acid and carbon dioxide, this instrument affords an indirect but sensitive measure of cellular metabolism. We previously described the use of the instrument with primary neuronal cultures (Raley-Susman, K.M., Miller, K.R., Owicki, J.C. and Sapolsky, R.M., Effects of excitotoxin exposure on metabolic rate of primary hippocampal cultures: application of silicon microphysiometer to neurobiology, J. Neurosci., 12 (1992) 773-780). In the present report, we adapt the instrument for the indirect measurement of metabolism in tissue slices. In initial studies, we demonstrate stable measures of metabolism with low background noise in hippocampal slices. In addition, measures were relatively insensitive to slice thickness, preparation time or the possible contribution of contaminating bacteria. We then demonstrate the ability to detect metabolic correlates of selective vulnerability in individual hippocampal cell fields. Specifically, we observe a metabolic response to kainic acid that was selective for CA3-derived tissue, and a response to cyanide that was selective for CA1-derived tissue. This corresponds to the well-known vulnerability of CA3 and CA1 to excitotoxic and ischemic insults, respectively. Finally, we show that glucocorticoids, stress-sensitive steroid hormones which are known to exacerbate the toxicity in kainic acid in CA3 neurons, exacerbate the metabolic effects of this excitotoxin as well; in this case, the steroid manipulation was carried out in rats prior to killing. Thus, this instrument represents a complement to more traditional approaches for assessing metabolism in specific brain regions and it can potentially be used for a broad variety of studies with animals of differing ages and pre-mortem manipulations.

Animals↗
PubMed1997

Hypercortisolism associated with social subordinance or social isolation among wild baboons.

BACKGROUND: The phenomena of basal hypercortisolism and of dexamethasone resistance have long intrigued biological psychiatrists, and much is still unknown as to the causes and consequences of such adrenocortical hyperactivity in various neuropsychiatric disorders. We have analyzed basal cortisol concentrations and adrenocortical responsiveness to dexamethasone in a population of wild baboons living in a national park in Kenya. We tested whether social subordinance in a primate is associated with dexamethasone resistance. Furthermore, we examined whether individual differences in adrenocortical measurements were predicted by the extent of social affiliation in these animals. METHODS: Seventy yellow baboons (Papio cynocephalus) were anesthetized and injected with 5 mg of dexamethasone; the cortisol response was monitored for 6 hours. The animals were of both sexes in a range of ages and had known ranks in the dominance hierarchies within their troops. Extensive behavioral data were available for a subset of 12 adult males who were anesthetized under circumstances that also allowed for the determination of basal cortisol concentrations. RESULTS: The socially subordinate baboons were less responsive to dexamethasone than were the dominant ones; as one manifestation of this, postdexamethasone cortisol values were more than 3 times higher in the dozen lowest-ranking animals compared with the dozen highest. In addition, socially isolated males had elevated basal cortisol concentrations and showed a trend toward relative dexamethasone resistance. CONCLUSIONS: Our findings indicate that social status and degree of social affilitation can influence adrenocortical profiles; specifically, social subordinance or social isolation were associated in our study with hypercortisolism or feedback resistance.

Animals↗
PubMed1997

Styles of male social behavior and their endocrine correlates among low-ranking baboons.

We have previously studied the relationship between social subordinance (by approach-avoidance criteria) and physiology among male olive baboons (Papio anubis) living freely in a national park in Africa. In stable hierarchies, subordinate individuals have elevated basal glucocorticoid concentrations and a blunted glucocorticoid response to stress, as well as a prompt suppression of testosterone concentrations during stress. These facets have been interpreted as reflecting the chronic stress of social subordinance. In the present report, we find these endocrine features do not mark all subordinate individuals. Instead, endocrine profiles differed among subordinate males as a function of particular stylistic traits of social behavior. A subset of subordinate males was identified who had significantly high rates of consortships, a behavior usually shown only by high-ranking males. Such behavior predicted the beginning transition to dominance, as these males were significantly more likely than other subordinates to have moved to the dominant half of the hierarchy over the subsequent 3 years. In keeping with this theme of emerging from subordinance, these individuals had also significantly larger glucocorticoid stress-responses, another feature typical of dominant males. However, these subordinate males also had significantly elevated basal glucocorticoid concentrations; it is suggested that this reflects the stressfulness of their overt and precocious strategy of reproductive competition. In support of this, subordinate males with high rates of covert "stolen copulations" did not show elevated basal glucocorticoid concentrations. A second subset of subordinate males were the most likely to initiate fights are to displace aggression onto a third party after losing a fight. these males had significantly or near-significantly elevated testosterone concentrations, compared to the remaining subordinate cohort. Moreover, these males had significantly lower basal glucocorticoid concentrations; this echoes an extensive literature showing that the availability of a displacement behavior (whether aggressive or otherwise) after a stressor decreases glucocorticoid secretion. In support of this interpretation suggesting that it was the initiation of these aggressive acts which attenuated glucocorticoid secretion, there was no association between glucocorticoid concentrations and participation (independent of initiation) in aggressive interactions. Thus, these findings suggest that variables other than rank alone may be associated with distinctive endocrine profiles, and that even in the face of a social stressor (such as subordinance), particular behavioral styles may attenuate the endocrine indices of stress.

Aggression↗
PubMed1997

Early induction of mRNA for calbindin-D28k and BDNF but not NT-3 in rat hippocampus after kainic acid treatment.

The influence of kainic acid (KA), which induces acute seizures, on expression of mRNA for the calcium-binding protein, calbindin-D28k, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and early-response genes [c-fos, zif268 (NGFI-A), nur77 (NGFI-B)] was examined in rat hippocampus by Northern blot analysis. A significant increase (3.2-fold) in BDNF mRNA was observed 1 h after KA injection (12 mg/kg i.p.) and peak expression (9.4-fold) occurred 3 h after KA. The induction of BDNF mRNA was preceded by the induction of c-fos, mRNA (30 min after KA) and was followed by the induction of calbindin-D28k mRNA (3.5-fold 3 h after KA; a maximal response was at 3-6 h after KA). Region-specific changes, analyzed by immunocytochemistry and in situ hybridization, indicated that the most dramatic increases in calbindin protein and mRNA after KA treatment were in the dentate gyrus. Although calbindin-D28k and BDNF mRNAs were induced, a 3.4-3.8-fold decrease in NT-3 mRNA was observed by Northern analysis 3-24 h after KA treatment. Calbindin-D28k gene expression was also examined in rats with a chronic epileptic state characterized by recurrent seizures established with an episode of electrical stimulation-induced status epilepticus (SE). When these animals were examined 30 days post-SE, no changes in hippocampal calbindin-D28k mRNA were observed. Our findings suggest that the induction of calbindin-D28k mRNA (which may be interrelated to the induction of BDNF mRNA) is an early response which may not be related to enhanced neuronal activity or seizures per se, but rather to maintaining neuronal viability.

Animals↗
PubMed1997

Defective herpes simplex virus vectors expressing the rat brain stress-inducible heat shock protein 72 protect cultured neurons from severe heat shock.

Recently, preinduction of the heat shock response has been shown to protect CNS neurons undergoing various stressful insults, e.g., heat, ischemia, or exposure to excitotoxins. However, it is not known which of the proteins induced by the heat shock response mediate the protective effects. Previous correlative evidence points to a role for the highly stress-induced 72-kDa heat shock protein (hsp72). However, it is not known whether hsp72 expression alone can protect against a range of acute neuronal insults. We constructed a herpes simplex virus-1 vector carrying the rat brain stress-inducible hsp72 gene and the Escherichia coli lacZ (marker) gene. Infection with the vector caused hippocampal neurons to coexpress hsp72 and beta-galactosidase. Infection with a control vector led to marker gene expression only. Overexpression of hsp72 protected cultured hippocampal neurons against a heat shock but not against the metabolic toxin 3-nitropropionic acid or the excitotoxin glutamate. This is the first published report of protection following heat shock protein transfection in CNS neurons.

Animals↗