الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
The Former Investigations Were Carried Out On Alzheimer Disease (AD) Concentrating In Induction Of The Disease And Amelioration Of Symptoms Of AD Using The Usual Treatment Strtaegies And Techniques Through Cholinergic And Amyloidogenic Classical Pathway. Recently Induction Of AD Was Performed Using Ovariectomy Coupled With Injection Of D-Galactose For Long Period About 2 Months For Induction And Presentation Of AD Features . Lately , Studying The Correlation Between Hypertension And AD Pathogenesis Is Of Great Interest As It Was Evidenced That Renin Angiotensin System Was Functionned And Located In Different Tissues In The Body Including The Brain. Moreover , Investigating The Interrelation Between Progression Of AD Pathogenic characters And Metabolic Abnormality Is Of Great Concern Specially Glucose Metabolic Disorder Resulting In Hyperglycemia. Interestingly , The Great Linkage Between Estrogen Deprivation And AD Is Currently Studied To Understand The Progression Of AD And Its Relation With Estrogen Dispossession.
In The Current Study We Evaluated The Probable Protective Effects Of Telmisartan And Metformin On The Pathogenic Features Of AD In A Rat Model Of Ovariectomized Female Rats Coupled With Injection Of D-Galactose For Only One Month And Animals Were Also Fed On High Fat High Fructose Diet During This Period In order O Induce An Accelerated Model Of AD After Only One Month. This Model Succeded To Induce Amyloidogenesis, Neuroinflammation, Oxidative Stress ,Apoptosis , Dirupted BBB Permeability And Finally Neurodegenration .
In Oder To Fullfil This Goal , We Conducted Two Sets Of Study, One Of Them Using Telmisartan As Treatment Agent And The Other Set Using Metformin As A Treatment Approach. All Animals Underwent Four Sets Of Experiments Including; Behavioral Test, Biochemical Analysis , Molecular Assays, Histopathological And Immunohistopathological Studies .
Female Rats Weighing 110-150 Gm Were Allocated Into Six Groups, 13 Rats In Each group In Two Sets Of Study And Each Study Consisted Of Three Groups ;
In Study I, Rats Were Allocated Into Three Groups, Normal Control group In Which Rats Were Injected Intraperitoneally With 0.9 Normal Saline , The Second group Was The Disease group In Which Ovariectomy Was Done Associated With Injection Of D-Galactose For One One Montha And High Fat High Fructose Diet ( OVX/D-Gal/HFFD). The Third group Is The Treatnent group Which Received Telmisartan At A Dose Of 0.1mg/Kg .
Additionally In Study II , Rats Were Categorized Into Three Groups, Normal Control group In Which Rate Were Administered 0.9 Normal Saline Intraperitoneally, The Second group Was The Disease group In Which Ovariectomy Was Done Accompanied With Injection Of D-Galactose For One One Montha And High Fat High Fructose Diet. The Third group Was The Treatnent group Which Received Metformin At A Dose Of 100 Mg/Kg .
During The Behavioral Tests, Rats Were Subjected To Morris Water Maze And Y-Maze Test ( For Assessment Of Spatial Working Memory) , Novel Object Recognition Test ( For Estimation Of Non Spatial Learning Memory ), Open Field Test ( For Ensurance Of That Locomotor Activity Didn’t Influence Any Other Behavioral Tests) And Forced Swimming Test ( For Evaluation Of Depressive Prodrome Or Like Activity . Data For Each Behavioral Test Was Recorded And Then Animals Were Collected For Biochemical Analysis Of Aβ1-42 , Ache, IDE, Albumin Level , Plasma Glucose Level , GSH, MDA, NOX-1, SOD, Tnfα, Inos, Nnos And Molecular Analysis Using Western Blotting And Real Time PCR Analysis For AT1R , AT2R , Erα, GLUT2 , Bax, Tubulin , BACE1 And IGF-1. In Addiotion , Other Remaining Brains Of Each group Were Collected For Histopathological Analysis Using Routine H&E Satin And Using Special Stain (Nissl Stain)For Intact Neuron Count And Immunohistochemical Analysis For Astrogliosis Biomarker Estimation.
The Results Of Cuurent Investigation Can Be Summarized As Follows :
Effect Of OVX/D-Gal/HFFD:
• Spatial Memory Was Significantly Decreased When Compared With Normal Control Group. Moreover, Also Non- Spatial Memory Was Significantly Decreased By OVX/D-Gal/HFFD. Additionally, There Is No Significant Change In Latency Time , Ambulation Frequency, Grooming Frequency And Rearing Frequency. Furthermore, Swimming Time Till Immobility Was Significantly Decreased By OVX/D-Gal/HFFD.
• Deposition Of A Β 1-42 And P-Tau Protein In Hippocampus Was Significantly Increased By OVX/D-Gal/HFFD. In Addition, Significant Elevation Of BACE1 , Ache And Significant Suppression Of IDE And Neprilysin Were Observed .
• A Significant Increase Of Oxidative Stress Markers As : MDA And NOX-1 And Significant Inhibition Of GSH And SOD Was Reported. Likewise, A Significant Elevation Of Inflammtory Biomarkers As Tnfα, Inos And Nnos Was Recordered.
• A Significant Raise Of GLUT2 Expression And Plasma Glucose Level And A Significant Decrease Of IGF-1 Expression Were Observed.
• A Significant Increase Of AT1R Relative Expression And Significant Inhibition Of AT2R Expression Were Noticed.
• A Significant Elevation Of Apoptotic Biomarkers As Bax And Tubulin Expression Wa Reported.
• A Significant Increase Of Albumin Level And Infilteration Was Recordered.
• Estrogen Receptors Were Greatly Declined Due To Estrogen Deprivation Occurred By Ovariectomy.
Effects Of Telmisartan And Metformin On OVX/D-Gal/HFFD Induced AD Include The Following:
• Spatial Memory Was Significantly Increased When Compared With OVX/D-Gal/HFFD Group. Also, Non- Spatial Memory Was Significantly Increased When Compared With OVX/D-Gal/HFFD Group. Additionally, There Is No Significant Change In Latency Time , Ambulation Frequency, Grooming Frequency And Rearing Frequency. Moreover, Swimming Time Till Immobility Was Significantly Elevated When Compared With By OVX/D-Gal/HFFD.
• Deposition Of A Β 1-42 And P-Tau Protein In Hippocampus Was Significantly Decreased When Compared With OVX/D-Gal/HFFD Group. Likewise, A Significant Decline Of BACE1 , Ache Was Observed . Moreover, A Significant Elevation Of IDE And Neprilysin Was Confirmed .
• A Significant Decrease Of Oxidative Stress Markers As : MDA And NOX-1 And A Significant Raise Of GSH And SOD Were Recordered . Furthermore, A Significant Suppression Of Inflammtory Biomarkers As Tnfα, Inos And Nnos Was Noticed.
• A Significant Decrease Of GLUT2 Expression And Plasma Glucose Level And A Significant Increase Of IGF-1 Expression Were Reported .
• A Significant Inhibition Of AT1R Relative Expression And A Significant Elevation Of AT2R Expression Were Recordered.
• A Significant Decline Of Apoptotic Biomarkers As Bax And Tubulin Expression Was Registered.
• A Significant Prohibtion Of Albumin Level And Infilteration Was Observed.
• Interestingly , Declined Estrogen Receptors Was Ameliorated Due To Estrogen Deprivation Occurred By Ovariectomy.
7. Conclusion
from The Previous Findings It Could Be Concluded That AD Pathogenesis Was Affected Critically By Imbalance Between Survival And Pathogenic Pathways. Telmisartan And Metformin Switched The Balance Towards Anti-Amyloidogenic, Anti-Inflammatory, Anti-Oxidative And Anti-Apoptotic Pathways Which In Turn Affected Learning And Cognitive Function Through AT1R/GLUT2/Erα Axis Regulation And So Exhibited New Potential Strategy For Management Of AD Via Slowing Down Of The Progression And Reduction Of The Symptoms Of AD In A Better Way Rather Than Olde Strategies And Techniques .
Further Clinical Studies Should Be Conducted On These Drugs.