Increased HDAC in association with decreased plasma cortisol in older adults with chronic fatigue syndrome

Jason, Leonard A.; Sorenson, Matthew; Sebally, Kebba; Alkazemi, Dalal; Lerch, Athena; Porter, Nicole; Kubow, Stan

doi:10.1016/j.bbi.2011.04.007

Cited by 25 publications

(28 citation statements)

References 31 publications

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“…28 Another study revealed that increased HDAC expression was associated with decreased plasma cortisol levels in older adults with chronic fatigue syndrome. 29 Whether the inhibition of HDAC6 decreases the stress response indirectly (through decreased levels of proinflammatory mediators and better bacterial clearance), or directly (effect on hypothalamus, pituitary and adrenal glands) needs to be further explored.…”

Section: Discussionmentioning

confidence: 99%

Selective histone deacetylase-6 inhibition attenuates stress responses and prevents immune organ atrophy in a lethal septic model

Zhao

Bronson

et al. 2014

Surgery

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Background An overproduction of corticosterone during severe sepsis results in increased apoptosis of immune cells, which may result in relative immunosuppression and an impaired ability to fight infections. We have previously demonstrated that administration of Tubastatin A, a selective inhibitor of histone deacetylase-6 (HDAC6), improves survival in a lethal model of cecal ligation and puncture (CLP) in mice. The purpose of this study was to characterize the effects of this treatment on sepsis-induced stress responses and immune function. Methods C57BL/6J mice were subjected to CLP, and 1 hour later given an intraperitoneal injection of either Tubastatin A dissolved in dimethyl sulfoxide (DMSO), or DMSO only. Blood samples were collected to measure the levels of circulating corticosterone and adrenocorticotropic hormone (ACTH). Thymus, and long bones (femur and tibia) were subjected to H&E staining, and immunohistochemistry was utilized to detect cleaved-caspase 3 in the splenic follicles as a measure of cellular apoptosis. Results All vehicle-treated CLP animals died within 3 days, and displayed increased corticosterone and decreased ACTH levels compared to the sham-operated group. These animals also developed atrophy of thymic cortex with a marked depletion of thymocytes. Tubastatin A treatment significantly attenuated the stress hormone abnormalities. Treated animals also had significantly lower percentages of thymic atrophy (95.0±5.0 vs. 42.5±25.3, p=0.0366), bone marrow depletion and atrophy (58.3±6.5 vs. 25.0±14.4%, p=0.0449), and cellular apoptosis in the splenic follicles (41.2±3.7 vs. 28.5±4.3 per 40× field, p=0.0354). Conclusions Selective inhibition of HDAC6 in this lethal septic model was associated with a significant blunting of the stress responses, with attenuated thymic and bone marrow atrophy, and decreased splenic apoptosis. Our findings identify a novel mechanism behind the survival advantage seen with Tubastatin A treatment.

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Section: Discussionmentioning

confidence: 99%

Selective histone deacetylase-6 inhibition attenuates stress responses and prevents immune organ atrophy in a lethal septic model

Zhao

Bronson

et al. 2014

Surgery

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“…Increased activity of HDAC 2 and 3 coincides with a decrease in plasma cortisol [14]. This theory has been cited as another possible cause of hypocortisolism found in patients.…”

Section: Cause Of the Hpa Axis Dysregulation In Cfsmentioning

confidence: 99%

A Review of Hypothalamic-Pituitary-Adrenal Axis Function in Chronic Fatigue Syndrome

2013

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Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has been found in a high proportion of chronic fatigue syndrome (CFS) patients and includes enhanced corticosteroid-induced negative feedback, basal hypocortisolism, attenuated diurnal variation, and a reduced responsivity to challenge. A putative causal role for genetic profile, childhood trauma, and oxidative stress has been considered. In addition, the impact of gender is demonstrated by the increased frequency of HPA axis dysregulation in females. Despite the temporal relationship, it is not yet established whether the endocrine dysregulation is causal, consequent, or an epiphenomenon of the disorder. Nonetheless, given the interindividual variation in the effectiveness of existing biological and psychological treatments, the need for novel treatment strategies such as those which target the HPA axis is clear.

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“…Jason, Sorenson et al (2011) recently found among an elderly sample with ME/CFS increased histone deacetylases activity, lower total antioxidant power, in the context of decreased plasma cortisol and increased plasma dehydroepiandrosterone concomitant with decreased expression of the encoding gene for the glucocorticoid receptor. Therefore, it is possible that increased HDAC activity may in turn contribute to a chronic pro-inflammatory state that may result in the expression of fatigue [30]. …”

Section: Neuroendocrine Autonomic and Immune Consequences Of Kindmentioning

confidence: 99%

An Etiological Model for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Jason¹,

Sorenson²,

Porter³

et al. 2011

Self Cite

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Kindling might represent a heuristic model for understanding the etiology of Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). Kindling occurs when an organism is exposed repeatedly to an initially sub-threshold stimulus resulting in hypersensitivity and spontaneous seizure-like activity. Among patients with ME/CFS, chronically repeated low-intensity stimulation due to an infectious illness might cause kindling of the limbic-hypothalamic-pituitary axis. Kindling might also occur by high-intensity stimulation (e.g., brain trauma) of the limbic-hypothalamic-pituitary axis. Once this system is charged or kindled, it can sustain a high level of arousal with little or no external stimulus and eventually this could lead to hypocortisolism. Seizure activity may spread to adjacent structures of the limbic-hypothalamic-pituitary axis in the brain, which might be responsible for the varied symptoms that occur among patients with ME/CFS. In addition, kindling may also be responsible for high levels of oxidative stress, which has been found in patients with ME/CFS.

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Increased HDAC in association with decreased plasma cortisol in older adults with chronic fatigue syndrome

Cited by 25 publications

References 31 publications

Selective histone deacetylase-6 inhibition attenuates stress responses and prevents immune organ atrophy in a lethal septic model

Selective histone deacetylase-6 inhibition attenuates stress responses and prevents immune organ atrophy in a lethal septic model

A Review of Hypothalamic-Pituitary-Adrenal Axis Function in Chronic Fatigue Syndrome

An Etiological Model for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

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