Involvement of insulin resistance in D-galactose-induced age-related dementia in rats: Protective role of metformin and saxagliptin
Age-related dementia is one of the most devastating disorders affecting the elderly. Recently, emerging data suggest that impaired insulin signaling is the major contributor in the development of Alzheimer's dementia (AD), which is the most common type of senile dementia. In the present study,...
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| description | Age-related dementia is one of the most devastating disorders affecting the elderly. Recently, emerging data suggest that impaired insulin signaling is the major contributor in the development of Alzheimer's dementia (AD), which is the most common type of senile dementia. In the present study, we investigated the potential therapeutic effects of metformin (Met) and saxagliptin (Saxa), as insulin sensitizing agents, in a rat model of brain aging and AD using D-galactose (D-gal, 150 mg/kg/day, s.c. for 90 successive days). Six groups of adult male Wistar rats were used: normal, D-gal, Met (500 mg/kg/day, p.o), and Saxa (1 mg/kg/day, p.o) control groups, as well as D-gal/Met and D-gal/Sax treated groups. Impaired learning and memory function was observed in rats treated with D-gal using Morris water maze test. Biochemical and histopathological findings also revealed some characteristic changes of AD in the brain that include the increased content of acetylcholine, glutamate, and phosphorelated tau, as well as deposition of amyloid plaques and neurofibrillary tangles. Induction of insulin resistance in experimentally aged rats was evidenced by increased blood glycated hemoglobin, brain contents of insulin and receptors for advanced glycated end-products, as well as decreased brain insulin receptor level. Elevation of oxidative stress markers and TNF-α brain content was also demonstrated. Met and Saxa, with a preference to Met, restored the normal memory and learning functions in rats, improved D-gal-induced state of insulin resistance, oxidative stress and inflammation, and ameliorated the AD biochemical and histopathological alterations in brain tissues. Our findings suggest that D-gal model of aging results in a diminishing of learning and memory function by producing a state of impaired insulin signaling that causes a cascade of deleterious events like oxidative stress, inflammation, and tau hyper-phosphorylation. Reversing of these harmful effects by the use of insulin-sensitizing drugs like Met and Saxa suggests their involvement in alleviation insulin resistance as the underlying pathology of AD and hence their potential use as anti-dementia drugs. |
| doi_str_mv | 10.1371/journal.pone.0183565 |
| format | Article |
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Recently, emerging data suggest that impaired insulin signaling is the major contributor in the development of Alzheimer's dementia (AD), which is the most common type of senile dementia. In the present study, we investigated the potential therapeutic effects of metformin (Met) and saxagliptin (Saxa), as insulin sensitizing agents, in a rat model of brain aging and AD using D-galactose (D-gal, 150 mg/kg/day, s.c. for 90 successive days). Six groups of adult male Wistar rats were used: normal, D-gal, Met (500 mg/kg/day, p.o), and Saxa (1 mg/kg/day, p.o) control groups, as well as D-gal/Met and D-gal/Sax treated groups. Impaired learning and memory function was observed in rats treated with D-gal using Morris water maze test. Biochemical and histopathological findings also revealed some characteristic changes of AD in the brain that include the increased content of acetylcholine, glutamate, and phosphorelated tau, as well as deposition of amyloid plaques and neurofibrillary tangles. Induction of insulin resistance in experimentally aged rats was evidenced by increased blood glycated hemoglobin, brain contents of insulin and receptors for advanced glycated end-products, as well as decreased brain insulin receptor level. Elevation of oxidative stress markers and TNF-α brain content was also demonstrated. Met and Saxa, with a preference to Met, restored the normal memory and learning functions in rats, improved D-gal-induced state of insulin resistance, oxidative stress and inflammation, and ameliorated the AD biochemical and histopathological alterations in brain tissues. Our findings suggest that D-gal model of aging results in a diminishing of learning and memory function by producing a state of impaired insulin signaling that causes a cascade of deleterious events like oxidative stress, inflammation, and tau hyper-phosphorylation. Reversing of these harmful effects by the use of insulin-sensitizing drugs like Met and Saxa suggests their involvement in alleviation insulin resistance as the underlying pathology of AD and hence their potential use as anti-dementia drugs.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0183565</identifier><identifier>PMID: 28832656</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acetylcholine ; Adamantane - analogs & derivatives ; Adamantane - toxicity ; Aging ; Aging (artificial) ; Aging - pathology ; Alzheimer's disease ; Amyloid ; Animal cognition ; Animals ; Antidiabetics ; Biology and Life Sciences ; Biomarkers - metabolism ; Body Weight - drug effects ; Brain ; Brain - drug effects ; Brain - metabolism ; Brain - pathology ; Brain research ; D-Galactose ; Dementia ; Dementia - chemically induced ; Dementia - pathology ; Dementia - prevention & control ; Dementia disorders ; Diabetes ; Dipeptides - toxicity ; Drugs ; Experiments ; Galactose ; Galactose - toxicity ; Geriatrics ; Glycated Hemoglobin A - metabolism ; Hemoglobin ; Hypoglycemic Agents - therapeutic use ; Hypotheses ; Insulin ; Insulin Resistance ; Kinases ; Learning ; Locomotion - drug effects ; Male ; Medical research ; Medicine ; Medicine and Health Sciences ; Memory ; Metabolism ; Metformin ; Metformin - therapeutic use ; Nerve Tissue Proteins - metabolism ; Neurodegeneration ; Neurodegenerative diseases ; Neurofibrillary tangles ; Older people ; Oxidation resistance ; Oxidative Stress ; Pathology ; Pharmaceuticals ; Pharmacology ; Pharmacy ; Phosphorylation ; Rats ; Rats, Wistar ; Reaction Time - drug effects ; Receptors ; Research and Analysis Methods ; Rodents ; Senile plaques ; Sensitizing ; Tau protein ; Tissues ; Toxicology ; Tumor necrosis factor</subject><ispartof>PloS one, 2017-08, Vol.12 (8), p.e0183565</ispartof><rights>2017 Kenawy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Kenawy et al 2017 Kenawy et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4415-59d9d15f7ece16bc61cb390565dba286053c004bb8ab7170a90f2be389da9e9a3</citedby><cites>FETCH-LOGICAL-c4415-59d9d15f7ece16bc61cb390565dba286053c004bb8ab7170a90f2be389da9e9a3</cites><orcidid>0000-0002-2586-2104</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568415/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568415/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28832656$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ginsberg, Stephen D.</contributor><creatorcontrib>Kenawy, Sara</creatorcontrib><creatorcontrib>Hegazy, Rehab</creatorcontrib><creatorcontrib>Hassan, Azza</creatorcontrib><creatorcontrib>El-Shenawy, Siham</creatorcontrib><creatorcontrib>Gomaa, Nawal</creatorcontrib><creatorcontrib>Zaki, Hala</creatorcontrib><creatorcontrib>Attia, Amina</creatorcontrib><title>Involvement of insulin resistance in D-galactose-induced age-related dementia in rats: Protective role of metformin and saxagliptin</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Age-related dementia is one of the most devastating disorders affecting the elderly. Recently, emerging data suggest that impaired insulin signaling is the major contributor in the development of Alzheimer's dementia (AD), which is the most common type of senile dementia. In the present study, we investigated the potential therapeutic effects of metformin (Met) and saxagliptin (Saxa), as insulin sensitizing agents, in a rat model of brain aging and AD using D-galactose (D-gal, 150 mg/kg/day, s.c. for 90 successive days). Six groups of adult male Wistar rats were used: normal, D-gal, Met (500 mg/kg/day, p.o), and Saxa (1 mg/kg/day, p.o) control groups, as well as D-gal/Met and D-gal/Sax treated groups. Impaired learning and memory function was observed in rats treated with D-gal using Morris water maze test. Biochemical and histopathological findings also revealed some characteristic changes of AD in the brain that include the increased content of acetylcholine, glutamate, and phosphorelated tau, as well as deposition of amyloid plaques and neurofibrillary tangles. Induction of insulin resistance in experimentally aged rats was evidenced by increased blood glycated hemoglobin, brain contents of insulin and receptors for advanced glycated end-products, as well as decreased brain insulin receptor level. Elevation of oxidative stress markers and TNF-α brain content was also demonstrated. Met and Saxa, with a preference to Met, restored the normal memory and learning functions in rats, improved D-gal-induced state of insulin resistance, oxidative stress and inflammation, and ameliorated the AD biochemical and histopathological alterations in brain tissues. Our findings suggest that D-gal model of aging results in a diminishing of learning and memory function by producing a state of impaired insulin signaling that causes a cascade of deleterious events like oxidative stress, inflammation, and tau hyper-phosphorylation. Reversing of these harmful effects by the use of insulin-sensitizing drugs like Met and Saxa suggests their involvement in alleviation insulin resistance as the underlying pathology of AD and hence their potential use as anti-dementia drugs.</description><subject>Acetylcholine</subject><subject>Adamantane - analogs & derivatives</subject><subject>Adamantane - toxicity</subject><subject>Aging</subject><subject>Aging (artificial)</subject><subject>Aging - pathology</subject><subject>Alzheimer's disease</subject><subject>Amyloid</subject><subject>Animal cognition</subject><subject>Animals</subject><subject>Antidiabetics</subject><subject>Biology and Life Sciences</subject><subject>Biomarkers - metabolism</subject><subject>Body Weight - drug effects</subject><subject>Brain</subject><subject>Brain - drug effects</subject><subject>Brain - metabolism</subject><subject>Brain - pathology</subject><subject>Brain research</subject><subject>D-Galactose</subject><subject>Dementia</subject><subject>Dementia - chemically induced</subject><subject>Dementia - pathology</subject><subject>Dementia - prevention & control</subject><subject>Dementia disorders</subject><subject>Diabetes</subject><subject>Dipeptides - toxicity</subject><subject>Drugs</subject><subject>Experiments</subject><subject>Galactose</subject><subject>Galactose - toxicity</subject><subject>Geriatrics</subject><subject>Glycated Hemoglobin A - metabolism</subject><subject>Hemoglobin</subject><subject>Hypoglycemic Agents - therapeutic use</subject><subject>Hypotheses</subject><subject>Insulin</subject><subject>Insulin Resistance</subject><subject>Kinases</subject><subject>Learning</subject><subject>Locomotion - drug effects</subject><subject>Male</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Memory</subject><subject>Metabolism</subject><subject>Metformin</subject><subject>Metformin - therapeutic use</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Neurodegeneration</subject><subject>Neurodegenerative diseases</subject><subject>Neurofibrillary tangles</subject><subject>Older people</subject><subject>Oxidation resistance</subject><subject>Oxidative Stress</subject><subject>Pathology</subject><subject>Pharmaceuticals</subject><subject>Pharmacology</subject><subject>Pharmacy</subject><subject>Phosphorylation</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Reaction Time - drug effects</subject><subject>Receptors</subject><subject>Research and Analysis Methods</subject><subject>Rodents</subject><subject>Senile plaques</subject><subject>Sensitizing</subject><subject>Tau protein</subject><subject>Tissues</subject><subject>Toxicology</subject><subject>Tumor necrosis factor</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNp1Uk1v1DAQjRCIlsI_QBCJcxY7iZ2YA1JVvlaqBAc4WxN7Erxy7MV2VnDmj-PtplV74OTR-L03M0-vKF5SsqFNR9_u_BIc2M3eO9wQ2jeMs0fFORVNXfGaNI_v1WfFsxh3hLCm5_xpcVb3fVNzxs-Lv1t38PaAM7pU-rE0Li7WuDJgNDGBU5hb5YdqAgsq-YiVcXpRqEuYsApoIeVa3_ANHLEBUnxXfgs-oUrmgGXwFo_SM6bRhzlDwOkywm-YrNkn454XT0awEV-s70Xx49PH71dfquuvn7dXl9eValvKKia00JSNHSqkfFCcqqERJJ-tB6h7nq9ThLTD0MPQ0Y6AIGM9YNMLDQIFNBfF65Pu3vooV_-izC5RLjihXUZsTwjtYSf3wcwQ_kgPRt40fJgkhGSURdkjB2CUjzXvWgoCss-803wch54IWmet9-u0ZZhRq2xQAPtA9OGPMz_l5A-SMd7ne7PAm1Ug-F8LxvSfldsTSgUfY8DxbgIl8hiUW5Y8BkWuQcm0V_e3uyPdJqP5By9-vuE</recordid><startdate>20170801</startdate><enddate>20170801</enddate><creator>Kenawy, Sara</creator><creator>Hegazy, Rehab</creator><creator>Hassan, Azza</creator><creator>El-Shenawy, Siham</creator><creator>Gomaa, Nawal</creator><creator>Zaki, Hala</creator><creator>Attia, Amina</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-2586-2104</orcidid></search><sort><creationdate>20170801</creationdate><title>Involvement of insulin resistance in D-galactose-induced age-related dementia in rats: Protective role of metformin and saxagliptin</title><author>Kenawy, Sara ; Hegazy, Rehab ; Hassan, Azza ; El-Shenawy, Siham ; Gomaa, Nawal ; Zaki, Hala ; Attia, Amina</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4415-59d9d15f7ece16bc61cb390565dba286053c004bb8ab7170a90f2be389da9e9a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Acetylcholine</topic><topic>Adamantane - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kenawy, Sara</au><au>Hegazy, Rehab</au><au>Hassan, Azza</au><au>El-Shenawy, Siham</au><au>Gomaa, Nawal</au><au>Zaki, Hala</au><au>Attia, Amina</au><au>Ginsberg, Stephen D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Involvement of insulin resistance in D-galactose-induced age-related dementia in rats: Protective role of metformin and saxagliptin</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-08-01</date><risdate>2017</risdate><volume>12</volume><issue>8</issue><spage>e0183565</spage><pages>e0183565-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Age-related dementia is one of the most devastating disorders affecting the elderly. Recently, emerging data suggest that impaired insulin signaling is the major contributor in the development of Alzheimer's dementia (AD), which is the most common type of senile dementia. In the present study, we investigated the potential therapeutic effects of metformin (Met) and saxagliptin (Saxa), as insulin sensitizing agents, in a rat model of brain aging and AD using D-galactose (D-gal, 150 mg/kg/day, s.c. for 90 successive days). Six groups of adult male Wistar rats were used: normal, D-gal, Met (500 mg/kg/day, p.o), and Saxa (1 mg/kg/day, p.o) control groups, as well as D-gal/Met and D-gal/Sax treated groups. Impaired learning and memory function was observed in rats treated with D-gal using Morris water maze test. Biochemical and histopathological findings also revealed some characteristic changes of AD in the brain that include the increased content of acetylcholine, glutamate, and phosphorelated tau, as well as deposition of amyloid plaques and neurofibrillary tangles. Induction of insulin resistance in experimentally aged rats was evidenced by increased blood glycated hemoglobin, brain contents of insulin and receptors for advanced glycated end-products, as well as decreased brain insulin receptor level. Elevation of oxidative stress markers and TNF-α brain content was also demonstrated. Met and Saxa, with a preference to Met, restored the normal memory and learning functions in rats, improved D-gal-induced state of insulin resistance, oxidative stress and inflammation, and ameliorated the AD biochemical and histopathological alterations in brain tissues. Our findings suggest that D-gal model of aging results in a diminishing of learning and memory function by producing a state of impaired insulin signaling that causes a cascade of deleterious events like oxidative stress, inflammation, and tau hyper-phosphorylation. Reversing of these harmful effects by the use of insulin-sensitizing drugs like Met and Saxa suggests their involvement in alleviation insulin resistance as the underlying pathology of AD and hence their potential use as anti-dementia drugs.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28832656</pmid><doi>10.1371/journal.pone.0183565</doi><orcidid>https://orcid.org/0000-0002-2586-2104</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2017-08, Vol.12 (8), p.e0183565 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1931696017 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Acetylcholine Adamantane - analogs & derivatives Adamantane - toxicity Aging Aging (artificial) Aging - pathology Alzheimer's disease Amyloid Animal cognition Animals Antidiabetics Biology and Life Sciences Biomarkers - metabolism Body Weight - drug effects Brain Brain - drug effects Brain - metabolism Brain - pathology Brain research D-Galactose Dementia Dementia - chemically induced Dementia - pathology Dementia - prevention & control Dementia disorders Diabetes Dipeptides - toxicity Drugs Experiments Galactose Galactose - toxicity Geriatrics Glycated Hemoglobin A - metabolism Hemoglobin Hypoglycemic Agents - therapeutic use Hypotheses Insulin Insulin Resistance Kinases Learning Locomotion - drug effects Male Medical research Medicine Medicine and Health Sciences Memory Metabolism Metformin Metformin - therapeutic use Nerve Tissue Proteins - metabolism Neurodegeneration Neurodegenerative diseases Neurofibrillary tangles Older people Oxidation resistance Oxidative Stress Pathology Pharmaceuticals Pharmacology Pharmacy Phosphorylation Rats Rats, Wistar Reaction Time - drug effects Receptors Research and Analysis Methods Rodents Senile plaques Sensitizing Tau protein Tissues Toxicology Tumor necrosis factor |
| title | Involvement of insulin resistance in D-galactose-induced age-related dementia in rats: Protective role of metformin and saxagliptin |
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