Stimulation of ACE2/ANG(1–7)/Mas Axis by Diminazene Ameliorates Alzheimer’s Disease in the D-Galactose-Ovariectomized Rat Model: Role of PI3K/Akt Pathway
Overactivation of angiotensin-converting enzyme/angiotensin 2/angiotensin receptor-1 (ACE/Ang2/AT1) axis provokes amyloid-β-induced apoptosis and neurodegeneration in Alzheimer’s disease (AD). Moreover, activation of AT1 impairs the survival pathway phosphoinositide 3-kinase/protein kinase B (PI3K/A...
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| Veröffentlicht in: | Molecular neurobiology 2018-10, Vol.55 (10), p.8188-8202 |
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| creator | Kamel, Ahmed S. Abdelkader, Noha F. Abd El-Rahman, Sahar S. Emara, Marwan Zaki, Hala F. Khattab, Mahmoud M. |
| description | Overactivation of angiotensin-converting enzyme/angiotensin 2/angiotensin receptor-1 (ACE/Ang2/AT1) axis provokes amyloid-β-induced apoptosis and neurodegeneration in Alzheimer’s disease (AD). Moreover, activation of AT1 impairs the survival pathway phosphoinositide 3-kinase/protein kinase B (PI3K/Akt). Interestingly, the coupling between ACE2/Ang(1–7)/Mas receptor (MasR) axis and PI3K/Akt activation opposes AT1-induced apoptosis. However, the effect of in vivo stimulation of MasR against AD and its correlation to PI3K/Akt is not yet elucidated. Thus, the present study aimed to investigate the relationship between PI3K/Akt pathway and the activation of ACE2/MasR in the AD model of D-galactose-ovariectomized rats. AD features were induced following 8-week injection of D-galactose (150 mg/kg, i.p.) in ovariectomized female rats. The ACE2 activator dimenazine (15 mg/kg, i.p.) was daily administered for 2 months. DIZE administration boosted the hippocampal expression of ACE2 and Mas receptors while suppressing AT1 receptor. Notably, dimenazine enhanced the expression of phosphorylated survival factors (PI3K, Akt, signal transducer, and activator of transcription-3) and neuroplasticity proteins such as cyclic adenosine monophosphate-responsive element-binding protein and brain-derived neurotrophic factor along with nicotinic and glutamatergic receptors. Such effects were accompanied by suppressing phosphorylated tau and glycogen synthase kinase3β along with caspase-3, cytochrome-c, nuclear factor kappa B, tumor necrosis factor alpha, and glial fibrillary acidic protein contents. Dimenazine ameliorated the histopathological damage observed in D-galactose-ovariectomized rats and improved their learning and recognition memory in Morris water maze and novel object recognition tests. In conclusion, dimenazine-induced stimulation of ACE2/Ang(1–7)/Mas axis subdues cognitive deficits in AD most probably through activation of PI3K/Akt pathway. |
| doi_str_mv | 10.1007/s12035-018-0966-3 |
| format | Article |
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Moreover, activation of AT1 impairs the survival pathway phosphoinositide 3-kinase/protein kinase B (PI3K/Akt). Interestingly, the coupling between ACE2/Ang(1–7)/Mas receptor (MasR) axis and PI3K/Akt activation opposes AT1-induced apoptosis. However, the effect of in vivo stimulation of MasR against AD and its correlation to PI3K/Akt is not yet elucidated. Thus, the present study aimed to investigate the relationship between PI3K/Akt pathway and the activation of ACE2/MasR in the AD model of D-galactose-ovariectomized rats. AD features were induced following 8-week injection of D-galactose (150 mg/kg, i.p.) in ovariectomized female rats. The ACE2 activator dimenazine (15 mg/kg, i.p.) was daily administered for 2 months. DIZE administration boosted the hippocampal expression of ACE2 and Mas receptors while suppressing AT1 receptor. Notably, dimenazine enhanced the expression of phosphorylated survival factors (PI3K, Akt, signal transducer, and activator of transcription-3) and neuroplasticity proteins such as cyclic adenosine monophosphate-responsive element-binding protein and brain-derived neurotrophic factor along with nicotinic and glutamatergic receptors. Such effects were accompanied by suppressing phosphorylated tau and glycogen synthase kinase3β along with caspase-3, cytochrome-c, nuclear factor kappa B, tumor necrosis factor alpha, and glial fibrillary acidic protein contents. Dimenazine ameliorated the histopathological damage observed in D-galactose-ovariectomized rats and improved their learning and recognition memory in Morris water maze and novel object recognition tests. In conclusion, dimenazine-induced stimulation of ACE2/Ang(1–7)/Mas axis subdues cognitive deficits in AD most probably through activation of PI3K/Akt pathway.</description><identifier>ISSN: 0893-7648</identifier><identifier>EISSN: 1559-1182</identifier><identifier>DOI: 10.1007/s12035-018-0966-3</identifier><identifier>PMID: 29516284</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>1-Phosphatidylinositol 3-kinase ; ACE2 ; AKT protein ; Alzheimer Disease - drug therapy ; Alzheimer Disease - genetics ; Alzheimer Disease - pathology ; Alzheimer Disease - physiopathology ; Alzheimer's disease ; Amyloid ; Angiotensin AT1 receptors ; Angiotensin I - metabolism ; Angiotensin-converting enzyme 2 ; Animals ; Apoptosis ; Apoptosis - drug effects ; Biomedical and Life Sciences ; Biomedicine ; Brain-derived neurotrophic factor ; Caspase-3 ; Cell Biology ; Cell Survival - drug effects ; Cognition - drug effects ; Cognitive ability ; Cyclic AMP ; Cytochrome c ; D-Galactose ; Diminazene - pharmacology ; Diminazene - therapeutic use ; Female ; Galactose ; Gene Expression Regulation - drug effects ; Glial fibrillary acidic protein ; Glial Fibrillary Acidic Protein - metabolism ; Glutamatergic transmission ; Glycogen ; Glycogen synthase ; Hippocampus ; Inflammation - pathology ; Kinases ; Learning ; Maze Learning - drug effects ; Memory ; Nerve Growth Factors - metabolism ; Neurobiology ; Neurodegeneration ; Neurology ; Neuronal Plasticity - drug effects ; Neuroplasticity ; Neurosciences ; Organelle Biogenesis ; Ovariectomy ; Peptide Fragments - metabolism ; Peptidyl-dipeptidase A ; Peptidyl-Dipeptidase A - metabolism ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphorylation - drug effects ; Proteins ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-akt - metabolism ; Rats ; Rats, Wistar ; Receptors, G-Protein-Coupled - metabolism ; Receptors, Glutamate - metabolism ; Receptors, Nicotinic - metabolism ; Rodents ; Signal Transduction - drug effects ; Survival ; tau Proteins - metabolism ; Transcription</subject><ispartof>Molecular neurobiology, 2018-10, Vol.55 (10), p.8188-8202</ispartof><rights>Springer Science+Business Media, LLC, part of Springer Nature 2018</rights><rights>Molecular Neurobiology is a copyright of Springer, (2018). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c438t-4103dd44fb067099f4986f7ccd1057bb46987af4a25797232a1c3dd4ee4b35ec3</citedby><cites>FETCH-LOGICAL-c438t-4103dd44fb067099f4986f7ccd1057bb46987af4a25797232a1c3dd4ee4b35ec3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s12035-018-0966-3$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s12035-018-0966-3$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29516284$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kamel, Ahmed S.</creatorcontrib><creatorcontrib>Abdelkader, Noha F.</creatorcontrib><creatorcontrib>Abd El-Rahman, Sahar S.</creatorcontrib><creatorcontrib>Emara, Marwan</creatorcontrib><creatorcontrib>Zaki, Hala F.</creatorcontrib><creatorcontrib>Khattab, Mahmoud M.</creatorcontrib><title>Stimulation of ACE2/ANG(1–7)/Mas Axis by Diminazene Ameliorates Alzheimer’s Disease in the D-Galactose-Ovariectomized Rat Model: Role of PI3K/Akt Pathway</title><title>Molecular neurobiology</title><addtitle>Mol Neurobiol</addtitle><addtitle>Mol Neurobiol</addtitle><description>Overactivation of angiotensin-converting enzyme/angiotensin 2/angiotensin receptor-1 (ACE/Ang2/AT1) axis provokes amyloid-β-induced apoptosis and neurodegeneration in Alzheimer’s disease (AD). Moreover, activation of AT1 impairs the survival pathway phosphoinositide 3-kinase/protein kinase B (PI3K/Akt). Interestingly, the coupling between ACE2/Ang(1–7)/Mas receptor (MasR) axis and PI3K/Akt activation opposes AT1-induced apoptosis. However, the effect of in vivo stimulation of MasR against AD and its correlation to PI3K/Akt is not yet elucidated. Thus, the present study aimed to investigate the relationship between PI3K/Akt pathway and the activation of ACE2/MasR in the AD model of D-galactose-ovariectomized rats. AD features were induced following 8-week injection of D-galactose (150 mg/kg, i.p.) in ovariectomized female rats. The ACE2 activator dimenazine (15 mg/kg, i.p.) was daily administered for 2 months. DIZE administration boosted the hippocampal expression of ACE2 and Mas receptors while suppressing AT1 receptor. Notably, dimenazine enhanced the expression of phosphorylated survival factors (PI3K, Akt, signal transducer, and activator of transcription-3) and neuroplasticity proteins such as cyclic adenosine monophosphate-responsive element-binding protein and brain-derived neurotrophic factor along with nicotinic and glutamatergic receptors. Such effects were accompanied by suppressing phosphorylated tau and glycogen synthase kinase3β along with caspase-3, cytochrome-c, nuclear factor kappa B, tumor necrosis factor alpha, and glial fibrillary acidic protein contents. Dimenazine ameliorated the histopathological damage observed in D-galactose-ovariectomized rats and improved their learning and recognition memory in Morris water maze and novel object recognition tests. In conclusion, dimenazine-induced stimulation of ACE2/Ang(1–7)/Mas axis subdues cognitive deficits in AD most probably through activation of PI3K/Akt pathway.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>ACE2</subject><subject>AKT protein</subject><subject>Alzheimer Disease - drug therapy</subject><subject>Alzheimer Disease - genetics</subject><subject>Alzheimer Disease - pathology</subject><subject>Alzheimer Disease - physiopathology</subject><subject>Alzheimer's disease</subject><subject>Amyloid</subject><subject>Angiotensin AT1 receptors</subject><subject>Angiotensin I - metabolism</subject><subject>Angiotensin-converting enzyme 2</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Brain-derived neurotrophic factor</subject><subject>Caspase-3</subject><subject>Cell Biology</subject><subject>Cell Survival - drug effects</subject><subject>Cognition - drug effects</subject><subject>Cognitive ability</subject><subject>Cyclic AMP</subject><subject>Cytochrome c</subject><subject>D-Galactose</subject><subject>Diminazene - pharmacology</subject><subject>Diminazene - therapeutic use</subject><subject>Female</subject><subject>Galactose</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Glial fibrillary acidic protein</subject><subject>Glial Fibrillary Acidic Protein - metabolism</subject><subject>Glutamatergic transmission</subject><subject>Glycogen</subject><subject>Glycogen synthase</subject><subject>Hippocampus</subject><subject>Inflammation - pathology</subject><subject>Kinases</subject><subject>Learning</subject><subject>Maze Learning - drug effects</subject><subject>Memory</subject><subject>Nerve Growth Factors - metabolism</subject><subject>Neurobiology</subject><subject>Neurodegeneration</subject><subject>Neurology</subject><subject>Neuronal Plasticity - drug effects</subject><subject>Neuroplasticity</subject><subject>Neurosciences</subject><subject>Organelle Biogenesis</subject><subject>Ovariectomy</subject><subject>Peptide Fragments - metabolism</subject><subject>Peptidyl-dipeptidase A</subject><subject>Peptidyl-Dipeptidase A - metabolism</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphorylation - drug effects</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Receptors, Glutamate - metabolism</subject><subject>Receptors, Nicotinic - metabolism</subject><subject>Rodents</subject><subject>Signal Transduction - drug effects</subject><subject>Survival</subject><subject>tau Proteins - metabolism</subject><subject>Transcription</subject><issn>0893-7648</issn><issn>1559-1182</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kc1u1DAURi0EokPhAdggS2zKwh3_JU7YRdMyVLS0KrCOnOSGcUni1naAmVXfgVUXvFyfBEdTQKrUlS3d8333Sgehl4zuM0rV3DNORUIoywjN05SIR2jGkiQnjGX8MZrRLBdEpTLbQc-8v6CUc0bVU7TD84SlPJMz9PtTMP3Y6WDsgG2Li8Uhnxcfl3vs9vqXejM_0R4XP43H1RofmN4MegMD4KKHzlinA8Rxt1mB6cHdXt_4CHnQHrAZcFgBPiBL3ek6WA_k9Lt2BuK_Nxto8LkO-MQ20L3F57aDafvZkfgwL74FfKbD6odeP0dPWt15eHH37qIv7w4_L96T49Pl0aI4JrUUWSCSUdE0UrYVTRXN81bmWdqqum4YTVRVyTTPlG6l5onKFRdcs3oKAMhKJFCLXbS37b109moEH8re-Bq6Tg9gR19yyjhjMkYj-voeemFHN8TrJiqRqUgzFSm2pWpnvXfQlpfO9NqtS0bLyV25dVdGd-XkrpyaX901j1UPzb_EX1kR4FvAx9HwFdz_1Q-3_gEI3qQL</recordid><startdate>20181001</startdate><enddate>20181001</enddate><creator>Kamel, Ahmed S.</creator><creator>Abdelkader, Noha F.</creator><creator>Abd El-Rahman, Sahar S.</creator><creator>Emara, Marwan</creator><creator>Zaki, Hala F.</creator><creator>Khattab, Mahmoud M.</creator><general>Springer US</general><general>Springer Nature B.V</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>7QR</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88G</scope><scope>88I</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>M2P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>7X8</scope></search><sort><creationdate>20181001</creationdate><title>Stimulation of ACE2/ANG(1–7)/Mas Axis by Diminazene Ameliorates Alzheimer’s Disease in the D-Galactose-Ovariectomized Rat Model: Role of PI3K/Akt Pathway</title><author>Kamel, Ahmed S. ; Abdelkader, Noha F. ; Abd El-Rahman, Sahar S. ; Emara, Marwan ; Zaki, Hala F. ; Khattab, Mahmoud M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c438t-4103dd44fb067099f4986f7ccd1057bb46987af4a25797232a1c3dd4ee4b35ec3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>ACE2</topic><topic>AKT protein</topic><topic>Alzheimer Disease - drug therapy</topic><topic>Alzheimer Disease - genetics</topic><topic>Alzheimer Disease - pathology</topic><topic>Alzheimer Disease - physiopathology</topic><topic>Alzheimer's disease</topic><topic>Amyloid</topic><topic>Angiotensin AT1 receptors</topic><topic>Angiotensin I - metabolism</topic><topic>Angiotensin-converting enzyme 2</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Brain-derived neurotrophic factor</topic><topic>Caspase-3</topic><topic>Cell Biology</topic><topic>Cell Survival - drug effects</topic><topic>Cognition - drug effects</topic><topic>Cognitive ability</topic><topic>Cyclic AMP</topic><topic>Cytochrome c</topic><topic>D-Galactose</topic><topic>Diminazene - pharmacology</topic><topic>Diminazene - therapeutic use</topic><topic>Female</topic><topic>Galactose</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Glial fibrillary acidic protein</topic><topic>Glial Fibrillary Acidic Protein - metabolism</topic><topic>Glutamatergic transmission</topic><topic>Glycogen</topic><topic>Glycogen synthase</topic><topic>Hippocampus</topic><topic>Inflammation - pathology</topic><topic>Kinases</topic><topic>Learning</topic><topic>Maze Learning - drug effects</topic><topic>Memory</topic><topic>Nerve Growth Factors - metabolism</topic><topic>Neurobiology</topic><topic>Neurodegeneration</topic><topic>Neurology</topic><topic>Neuronal Plasticity - drug effects</topic><topic>Neuroplasticity</topic><topic>Neurosciences</topic><topic>Organelle Biogenesis</topic><topic>Ovariectomy</topic><topic>Peptide Fragments - metabolism</topic><topic>Peptidyl-dipeptidase A</topic><topic>Peptidyl-Dipeptidase A - metabolism</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphorylation - drug effects</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>Receptors, Glutamate - metabolism</topic><topic>Receptors, Nicotinic - metabolism</topic><topic>Rodents</topic><topic>Signal Transduction - drug effects</topic><topic>Survival</topic><topic>tau Proteins - metabolism</topic><topic>Transcription</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kamel, Ahmed S.</creatorcontrib><creatorcontrib>Abdelkader, Noha F.</creatorcontrib><creatorcontrib>Abd El-Rahman, Sahar S.</creatorcontrib><creatorcontrib>Emara, Marwan</creatorcontrib><creatorcontrib>Zaki, Hala F.</creatorcontrib><creatorcontrib>Khattab, Mahmoud M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Psychology Database (Alumni)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest Psychology</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</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>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular neurobiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kamel, Ahmed S.</au><au>Abdelkader, Noha F.</au><au>Abd El-Rahman, Sahar S.</au><au>Emara, Marwan</au><au>Zaki, Hala F.</au><au>Khattab, Mahmoud M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Stimulation of ACE2/ANG(1–7)/Mas Axis by Diminazene Ameliorates Alzheimer’s Disease in the D-Galactose-Ovariectomized Rat Model: Role of PI3K/Akt Pathway</atitle><jtitle>Molecular neurobiology</jtitle><stitle>Mol Neurobiol</stitle><addtitle>Mol Neurobiol</addtitle><date>2018-10-01</date><risdate>2018</risdate><volume>55</volume><issue>10</issue><spage>8188</spage><epage>8202</epage><pages>8188-8202</pages><issn>0893-7648</issn><eissn>1559-1182</eissn><abstract>Overactivation of angiotensin-converting enzyme/angiotensin 2/angiotensin receptor-1 (ACE/Ang2/AT1) axis provokes amyloid-β-induced apoptosis and neurodegeneration in Alzheimer’s disease (AD). Moreover, activation of AT1 impairs the survival pathway phosphoinositide 3-kinase/protein kinase B (PI3K/Akt). Interestingly, the coupling between ACE2/Ang(1–7)/Mas receptor (MasR) axis and PI3K/Akt activation opposes AT1-induced apoptosis. However, the effect of in vivo stimulation of MasR against AD and its correlation to PI3K/Akt is not yet elucidated. Thus, the present study aimed to investigate the relationship between PI3K/Akt pathway and the activation of ACE2/MasR in the AD model of D-galactose-ovariectomized rats. AD features were induced following 8-week injection of D-galactose (150 mg/kg, i.p.) in ovariectomized female rats. The ACE2 activator dimenazine (15 mg/kg, i.p.) was daily administered for 2 months. DIZE administration boosted the hippocampal expression of ACE2 and Mas receptors while suppressing AT1 receptor. Notably, dimenazine enhanced the expression of phosphorylated survival factors (PI3K, Akt, signal transducer, and activator of transcription-3) and neuroplasticity proteins such as cyclic adenosine monophosphate-responsive element-binding protein and brain-derived neurotrophic factor along with nicotinic and glutamatergic receptors. Such effects were accompanied by suppressing phosphorylated tau and glycogen synthase kinase3β along with caspase-3, cytochrome-c, nuclear factor kappa B, tumor necrosis factor alpha, and glial fibrillary acidic protein contents. Dimenazine ameliorated the histopathological damage observed in D-galactose-ovariectomized rats and improved their learning and recognition memory in Morris water maze and novel object recognition tests. In conclusion, dimenazine-induced stimulation of ACE2/Ang(1–7)/Mas axis subdues cognitive deficits in AD most probably through activation of PI3K/Akt pathway.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>29516284</pmid><doi>10.1007/s12035-018-0966-3</doi><tpages>15</tpages></addata></record> |
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| recordid | cdi_proquest_miscellaneous_2012114723 |
| source | MEDLINE; SpringerLink Journals |
| subjects | 1-Phosphatidylinositol 3-kinase ACE2 AKT protein Alzheimer Disease - drug therapy Alzheimer Disease - genetics Alzheimer Disease - pathology Alzheimer Disease - physiopathology Alzheimer's disease Amyloid Angiotensin AT1 receptors Angiotensin I - metabolism Angiotensin-converting enzyme 2 Animals Apoptosis Apoptosis - drug effects Biomedical and Life Sciences Biomedicine Brain-derived neurotrophic factor Caspase-3 Cell Biology Cell Survival - drug effects Cognition - drug effects Cognitive ability Cyclic AMP Cytochrome c D-Galactose Diminazene - pharmacology Diminazene - therapeutic use Female Galactose Gene Expression Regulation - drug effects Glial fibrillary acidic protein Glial Fibrillary Acidic Protein - metabolism Glutamatergic transmission Glycogen Glycogen synthase Hippocampus Inflammation - pathology Kinases Learning Maze Learning - drug effects Memory Nerve Growth Factors - metabolism Neurobiology Neurodegeneration Neurology Neuronal Plasticity - drug effects Neuroplasticity Neurosciences Organelle Biogenesis Ovariectomy Peptide Fragments - metabolism Peptidyl-dipeptidase A Peptidyl-Dipeptidase A - metabolism Phosphatidylinositol 3-Kinases - metabolism Phosphorylation - drug effects Proteins Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-akt - metabolism Rats Rats, Wistar Receptors, G-Protein-Coupled - metabolism Receptors, Glutamate - metabolism Receptors, Nicotinic - metabolism Rodents Signal Transduction - drug effects Survival tau Proteins - metabolism Transcription |
| title | Stimulation of ACE2/ANG(1–7)/Mas Axis by Diminazene Ameliorates Alzheimer’s Disease in the D-Galactose-Ovariectomized Rat Model: Role of PI3K/Akt Pathway |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T05%3A24%3A25IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Stimulation%20of%20ACE2/ANG(1%E2%80%937)/Mas%20Axis%20by%20Diminazene%20Ameliorates%20Alzheimer%E2%80%99s%20Disease%20in%20the%20D-Galactose-Ovariectomized%20Rat%20Model:%20Role%20of%20PI3K/Akt%20Pathway&rft.jtitle=Molecular%20neurobiology&rft.au=Kamel,%20Ahmed%20S.&rft.date=2018-10-01&rft.volume=55&rft.issue=10&rft.spage=8188&rft.epage=8202&rft.pages=8188-8202&rft.issn=0893-7648&rft.eissn=1559-1182&rft_id=info:doi/10.1007/s12035-018-0966-3&rft_dat=%3Cproquest_cross%3E2012114723%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2015463687&rft_id=info:pmid/29516284&rfr_iscdi=true |