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Neuroprotective effects of Canagliflozin: Lessons from aged genetically diverse UM-HET3 mice
dc.contributor.authorJayarathne, Hashan S. M.
dc.contributor.authorDebarba, Lucas K.
dc.contributor.authorJaboro, Jacob J.
dc.contributor.authorGinsburg, Brett C.
dc.contributor.authorMiller, Richard A.
dc.contributor.authorSadagurski, Marianna
dc.date.accessioned2022-08-02T18:55:44Z
dc.date.available2023-08-02 14:55:39en
dc.date.available2022-08-02T18:55:44Z
dc.date.issued2022-07
dc.identifier.citationJayarathne, Hashan S. M.; Debarba, Lucas K.; Jaboro, Jacob J.; Ginsburg, Brett C.; Miller, Richard A.; Sadagurski, Marianna (2022). "Neuroprotective effects of Canagliflozin: Lessons from aged genetically diverse UM-HET3 mice." Aging Cell (7): n/a-n/a.
dc.identifier.issn1474-9718
dc.identifier.issn1474-9726
dc.identifier.urihttps://hdl.handle.net/2027.42/173068
dc.description.abstractThe aging brain is characterized by progressive increases in neuroinflammation and central insulin resistance, which contribute to neurodegenerative diseases and cognitive impairment. Recently, the Interventions Testing Program demonstrated that the anti-diabetes drug, Canagliflozin (Cana), a sodium-glucose transporter 2 inhibitor, led to lower fasting glucose and improved glucose tolerance in both sexes, but extended median lifespan by 14% in male mice only. Here, we show that Cana treatment significantly improved central insulin sensitivity in the hypothalamus and the hippocampus of 30-month-old male mice. Aged males produce more robust neuroimmune responses than aged females. Remarkably, Cana-treated male and female mice showed significant reductions in age-associated hypothalamic gliosis with a decrease in inflammatory cytokine production by microglia. However, in the hippocampus, Cana reduced microgliosis and astrogliosis in males, but not in female mice. The decrease in microgliosis was partially correlated with reduced phosphorylation of S6 kinase in microglia of Cana-treated aged male, but not female mice. Thus, Cana treatment improved insulin responsiveness in aged male mice. Furthermore, Cana treatment improved exploratory and locomotor activity of 30-month-old male but not female mice. Taken together, we demonstrate the sex-specific neuroprotective effects of Cana treatment, suggesting its application for the potential treatment of neurodegenerative diseases.Our findings demonstrate sex-specific neuroprotective effects of Canagliflozin treatment that are associated with reduced neuroinflammation, improved central insulin sensitivity, and locomotor activity in aged mice.
dc.publisherWiley Periodicals, Inc.
dc.subject.otherlongevity
dc.subject.othercanagliflozin
dc.subject.otherhippocampus
dc.subject.otherhypothalamus
dc.subject.otherinsulin
dc.subject.othermetabolism
dc.titleNeuroprotective effects of Canagliflozin: Lessons from aged genetically diverse UM-HET3 mice
dc.typeArticle
dc.rights.robotsIndexNoFollow
dc.subject.hlbsecondlevelMolecular, Cellular and Developmental Biology
dc.subject.hlbtoplevelHealth Sciences
dc.description.peerreviewedPeer Reviewed
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/173068/1/ACEL13653-sup-0001-supinfo.pdf
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/173068/2/acel13653.pdf
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/173068/3/acel13653_am.pdf
dc.identifier.doi10.1111/acel.13653
dc.identifier.sourceAging Cell
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dc.owningcollnameInterdisciplinary and Peer-Reviewed


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Remediation of Harmful Language

The University of Michigan Library aims to describe its collections in a way that respects the people and communities who create, use, and are represented in them. We encourage you to Contact Us anonymously if you encounter harmful or problematic language in catalog records or finding aids. More information about our policies and practices is available at Remediation of Harmful Language.

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