Partial Deficiency or Short-Term Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1 Improves Cognitive Function in Aging Mice

Sooy, Karen; Webster, Scott P.; Noble, June; Binnie, Margaret; Walker, Brian R.; Seckl, Jonathan R.; Yau, Joyce L.W.

doi:10.1523/jneurosci.2783-10.2010

Cited by 77 publications

(90 citation statements)

References 37 publications

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“…Similar to other HSD1 inhibitors (Yeh et al, 2006), A-918446 and A-801195 robustly decrease cortisol formation in brain ex vivo tissue preparations. Although cognitive enhancement with HSD inhibitors in rodents has been shown after several days of treatment in older subjects (Sooy et al, 2010), these studies are the first to show that acute treatment with HSD1 inhibitors can improve cognitive performance. While young animals do not represent a model of AD, it is of interest to observe the glucocorticoid modulation can impact performance in otherwise healthy subjects.…”

Section: Discussionmentioning

confidence: 88%

Acute Inhibition of 11β-Hydroxysteroid Dehydrogenase Type-1 Improves Memory in Rodent Models of Cognition

Mohler¹,

Browman²,

Roderwald³

et al. 2011

J. Neurosci.

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Mounting evidence suggests excessive glucocorticoid activity may contribute to Alzheimer's disease (AD) and age-associated memory impairment. 11␤-hydroxysteroid dehydrogenase type-1 (HSD1) regulates conversion of glucocorticoids from inactive to active forms. HSD1 knock-out mice have improved cognition, and the nonselective inhibitor carbenoxolone improved verbal memory in elderly men. Together, these data suggest that HSD1 inhibition may be a potential therapy for cognitive deficits, such as those associated with AD. To investigate this, we characterized two novel and selective HSD1 inhibitors, A-918446 and A-801195. Learning, memory consolidation, and recall were evaluated in mouse 24 h inhibitory avoidance. Inhibition of brain cortisol production and phosphorylation of cAMP response element-binding protein (CREB), a transcription factor involved in cognition, were also examined. Rats were tested in a short-term memory model, social recognition, and in a separate group cortical and hippocampal acetylcholine release was measured via in vivo microdialysis. Acute treatment with A-801195 (10 -30 mg/kg) or A-918446 (3-30 mg/kg) inhibited cortisol production in the ex vivo assay by ϳ35-90%. Acute treatment with A-918446 improved memory consolidation and recall in inhibitory avoidance and increased CREB phosphorylation in the cingulate cortex. Acute treatment with A-801195 significantly improved short-term memory in rat social recognition that was not likely due to alterations of the cholinergic system, as acetylcholine release was not increased in a separate set of rats. These studies suggest that selective HSD1 inhibitors work through a novel, noncholinergic mechanism to facilitate cognitive processing.

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Section: Discussionmentioning

confidence: 88%

Acute Inhibition of 11β-Hydroxysteroid Dehydrogenase Type-1 Improves Memory in Rodent Models of Cognition

Mohler¹,

Browman²,

Roderwald³

et al. 2011

J. Neurosci.

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“…Indeed, Holmes et al (2010) showed that an increased hippocampal expression of 11b-HSD1 was responsible for memory impairments in mice. Partial deficiency or short-term inhibition of 11b-HSD1 improves cognitive function in ageing mice (Sooy et al 2010). The fact that vitamin A deficiency induces anatomic and phenotypic changes comparable with those in neurodegeneration (Ghenimi et al 2009) could be partly linked to an increase in 11b-HSD1 expression at the central level.…”

Section: Discussionmentioning

confidence: 99%

Vitamin A regulates hypothalamic–pituitary–adrenal axis status in LOU/C rats

Marissal-Arvy¹,

Hamiani²,

Richard³

et al. 2013

Journal of Endocrinology

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The aim of this study was to explore the involvement of retinoids in the hypoactivity and hyporeactivity to stress of the hypothalamic-pituitary-adrenal (HPA) axis in LOU/C rats. We measured the effects of vitamin A deficiency administered or not with retinoic acid (RA) on plasma corticosterone in standard conditions and in response to restraint stress and on hypothalamic and hippocampal expression of corticosteroid receptors, corticotropinreleasing hormone and 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) in LOU/C rats. Interestingly, under control conditions, we measured a higher plasma concentration of retinol in LOU/C than in Wistar rats, which could contribute to the lower basal activity of the HPA axis in LOU/C rats. Vitamin A deficiency induced an increased HPA axis activity in LOU/C rats, normalized by RA administration. Compared with LOU/C control rats, vitamin A-deficient rats showed a delayed and heightened corticosterone response to restraint stress. The expression of corticosteroid receptors was strongly decreased by vitamin A deficiency in the hippocampus, which could contribute to a less efficient feedback by corticosterone on HPA axis tone. The expression of 11b-HSD1 was increased by vitamin A deficiency in the hypothalamus (C62.5%) as in the hippocampus (C104.7%), which could lead to a higher production of corticosterone locally and contribute to alteration of the hippocampus. RA supplementation treatment restored corticosterone concentrations and 11b-HSD1 expression to control levels. The high vitamin A status of LOU/C rats could contribute to their low HPA axis activity/reactivity and to a protective effect against 11b-HSD1-mediated deleterious action on cognitive performances during ageing.

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“…In these tissues, increased local GC activation is postulated to contribute to the increased risk of fracture and osteoporosis and impaired cognitive function associated with aging. Improved cognition and increased long-term potentiation have been reported in aged 11β-HSD1 KO mice relative to age-matched controls (32), with improved memory consolidation, recall, and social recognition also reported following treatment with specific 11β-HSD1 inhibitors (33,34).…”

Section: Figurementioning

confidence: 91%

11β-Hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects

Tiganescu

Tahrani²,

Morgan³

et al. 2013

J. Clin. Invest.

119

120

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Glucocorticoid (GC) excess adversely affects skin integrity, inducing thinning and impaired wound healing. Aged skin, particularly that which has been photo-exposed, shares a similar phenotype. Previously, we demonstrated age-induced expression of the GC-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in cultured human dermal fibroblasts (HDFs). Here, we determined 11β-HSD1 levels in human skin biopsies from young and older volunteers and examined the aged 11β-HSD1 KO mouse skin phenotype. 11β-HSD1 activity was elevated in aged human and mouse skin and in PE compared with donor-matched photo-protected human biopsies. Age-induced dermal atrophy with deranged collagen structural organization was prevented in 11β-HSD1 KO mice, which also exhibited increased collagen density. We found that treatment of HDFs with physiological concentrations of cortisol inhibited rate-limiting steps in collagen biosynthesis and processing. Furthermore, topical 11β-HSD1 inhibitor treatment accelerated healing of full-thickness mouse dorsal wounds, with improved healing also observed in aged 11β-HSD1 KO mice. These findings suggest that elevated 11β-HSD1 activity in aging skin leads to increased local GC generation, which may account for adverse changes occurring in the elderly, and 11β-HSD1 inhibitors may be useful in the treatment of age-associated impairments in dermal integrity and wound healing.

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Partial Deficiency or Short-Term Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1 Improves Cognitive Function in Aging Mice

Cited by 77 publications

References 37 publications

Acute Inhibition of 11β-Hydroxysteroid Dehydrogenase Type-1 Improves Memory in Rodent Models of Cognition

Acute Inhibition of 11β-Hydroxysteroid Dehydrogenase Type-1 Improves Memory in Rodent Models of Cognition

Vitamin A regulates hypothalamic–pituitary–adrenal axis status in LOU/C rats

11β-Hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects

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