11β-Hydroxysteroid Dehydrogenase Inhibition Improves Cognitive Function in Healthy Elderly Men and Type 2 Diabetics
In aging humans and rodents, inter-individual differences in cognitive function have been ascribed to variations in long-term glucocorticoid exposure. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates the active glucocorticoid cortisol from circulating inert cortisone, thus amplifying i...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2004-04, Vol.101 (17), p.6734-6739 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Sandeep, Thekkepat C. Joyce L. W. Yau Alasdair M. J. Mac Lullich Noble, June Deary, Ian J. Walker, Brian R. Seckl, Jonathan R. McEwen, Bruce S. |
| description | In aging humans and rodents, inter-individual differences in cognitive function have been ascribed to variations in long-term glucocorticoid exposure. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates the active glucocorticoid cortisol from circulating inert cortisone, thus amplifying intracellular glucocorticoid levels in some tissues. We show that 11β-HSD1, but not 11β-HSD2, mRNA is expressed in the human hippocampus, frontal cortex, and cerebellum. In two randomized, double-blind, placebo-controlled crossover studies, administration of the 11β-HSD inhibitor carbenoxolone (100 mg three times per day) improved verbal fluency (P < 0.01) after 4 weeks in 10 healthy elderly men (aged 55-75 y) and improved verbal memory (P < 0.01) after 6 weeks in 12 patients with type 2 diabetes (52-70 y). Although carbenoxolone has been reported to enhance hepatic insulin sensitivity in short-term studies, there were no changes in glycemic control or serum lipid profile, nor was plasma cortisol altered. 11β-HSD1 inhibition may be a new approach to prevent/ameliorate cognitive decline. |
| doi_str_mv | 10.1073/pnas.0306996101 |
| format | Article |
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In two randomized, double-blind, placebo-controlled crossover studies, administration of the 11β-HSD inhibitor carbenoxolone (100 mg three times per day) improved verbal fluency (P < 0.01) after 4 weeks in 10 healthy elderly men (aged 55-75 y) and improved verbal memory (P < 0.01) after 6 weeks in 12 patients with type 2 diabetes (52-70 y). 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W. Yau</creatorcontrib><creatorcontrib>Alasdair M. J. Mac Lullich</creatorcontrib><creatorcontrib>Noble, June</creatorcontrib><creatorcontrib>Deary, Ian J.</creatorcontrib><creatorcontrib>Walker, Brian R.</creatorcontrib><creatorcontrib>Seckl, Jonathan R.</creatorcontrib><creatorcontrib>McEwen, Bruce S.</creatorcontrib><title>11β-Hydroxysteroid Dehydrogenase Inhibition Improves Cognitive Function in Healthy Elderly Men and Type 2 Diabetics</title><title>Proceedings of the National Academy of Sciences - PNAS</title><description>In aging humans and rodents, inter-individual differences in cognitive function have been ascribed to variations in long-term glucocorticoid exposure. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates the active glucocorticoid cortisol from circulating inert cortisone, thus amplifying intracellular glucocorticoid levels in some tissues. We show that 11β-HSD1, but not 11β-HSD2, mRNA is expressed in the human hippocampus, frontal cortex, and cerebellum. In two randomized, double-blind, placebo-controlled crossover studies, administration of the 11β-HSD inhibitor carbenoxolone (100 mg three times per day) improved verbal fluency (P < 0.01) after 4 weeks in 10 healthy elderly men (aged 55-75 y) and improved verbal memory (P < 0.01) after 6 weeks in 12 patients with type 2 diabetes (52-70 y). Although carbenoxolone has been reported to enhance hepatic insulin sensitivity in short-term studies, there were no changes in glycemic control or serum lipid profile, nor was plasma cortisol altered. 11β-HSD1 inhibition may be a new approach to prevent/ameliorate cognitive decline.</description><subject>Biological Sciences</subject><subject>Blood plasma</subject><subject>Cerebellum</subject><subject>Endocrinology</subject><subject>Glucocorticoids</subject><subject>Hippocampus</subject><subject>Memory</subject><subject>Messenger RNA</subject><subject>Older adults</subject><subject>Placebos</subject><subject>Type 2 diabetes mellitus</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><recordid>eNp9kM1uEzEUhS0EoqGwZoOEl2ymvXc8f16wQGlLIhWxKWvLY99JXE3skT2JOq_VB-GZmJCqFRtWVzrnO-dKh7GPCBcItbgcvE4XIKCSskLAV2yBIDGrCgmv2QIgr7OmyIsz9i6lewCQZQNv2RmWUCM2csFGxN-P2WqyMTxMaaQYnOVXtD0KG5rbia_91rVudMHz9W6I4UCJL8PGz9KB-M3em7-e83xFuh-3E7_uLcV-4j_Ic-0tv5sG4jm_crql0Zn0nr3pdJ_ow9M9Z79uru-Wq-z25_f18tttZoQUmNVQNqYyFivKrUVjtUZrm0Z3ZaWlJWihrCTlLYmyKYymkqgrZGdJdpXJpThnX0-9w77dkTXkx6h7NUS303FSQTv1r-PdVm3CQRVQIBZz_vKUNzGkFKl7jiKo4_7quL962X9OfHn6eDReaFRYq6oWher2fT_Swzijn_-PzsSnE3GfxhCfESHqHMtc_AELz53K</recordid><startdate>20040427</startdate><enddate>20040427</enddate><creator>Sandeep, Thekkepat C.</creator><creator>Joyce L. 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Mac Lullich</creatorcontrib><creatorcontrib>Noble, June</creatorcontrib><creatorcontrib>Deary, Ian J.</creatorcontrib><creatorcontrib>Walker, Brian R.</creatorcontrib><creatorcontrib>Seckl, Jonathan R.</creatorcontrib><creatorcontrib>McEwen, Bruce S.</creatorcontrib><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sandeep, Thekkepat C.</au><au>Joyce L. W. Yau</au><au>Alasdair M. J. Mac Lullich</au><au>Noble, June</au><au>Deary, Ian J.</au><au>Walker, Brian R.</au><au>Seckl, Jonathan R.</au><au>McEwen, Bruce S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>11β-Hydroxysteroid Dehydrogenase Inhibition Improves Cognitive Function in Healthy Elderly Men and Type 2 Diabetics</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><date>2004-04-27</date><risdate>2004</risdate><volume>101</volume><issue>17</issue><spage>6734</spage><epage>6739</epage><pages>6734-6739</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>In aging humans and rodents, inter-individual differences in cognitive function have been ascribed to variations in long-term glucocorticoid exposure. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates the active glucocorticoid cortisol from circulating inert cortisone, thus amplifying intracellular glucocorticoid levels in some tissues. We show that 11β-HSD1, but not 11β-HSD2, mRNA is expressed in the human hippocampus, frontal cortex, and cerebellum. In two randomized, double-blind, placebo-controlled crossover studies, administration of the 11β-HSD inhibitor carbenoxolone (100 mg three times per day) improved verbal fluency (P < 0.01) after 4 weeks in 10 healthy elderly men (aged 55-75 y) and improved verbal memory (P < 0.01) after 6 weeks in 12 patients with type 2 diabetes (52-70 y). Although carbenoxolone has been reported to enhance hepatic insulin sensitivity in short-term studies, there were no changes in glycemic control or serum lipid profile, nor was plasma cortisol altered. 11β-HSD1 inhibition may be a new approach to prevent/ameliorate cognitive decline.</abstract><pub>National Academy of Sciences</pub><pmid>15071189</pmid><doi>10.1073/pnas.0306996101</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Biological Sciences Blood plasma Cerebellum Endocrinology Glucocorticoids Hippocampus Memory Messenger RNA Older adults Placebos Type 2 diabetes mellitus |
| title | 11β-Hydroxysteroid Dehydrogenase Inhibition Improves Cognitive Function in Healthy Elderly Men and Type 2 Diabetics |
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