Date of Award

12-20-2022

Degree Type

Thesis

Degree Name

MPhil in Biological and Biomedical Sciences

First Advisor

Dr Bushra Amin

Second Advisor

Dr Tashfeen Ahmad

Third Advisor

Dr Mati Ur Rehman

Department

Biological and Biomedical Sciences

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder, affecting approximately 55 M people globally. Disease symptoms appear decades later than its molecular onset, thus irreversible changes have occurred when treatment is initiated, so treatment remains mostly ineffective. To date, four FDA-approved drugs are available to provide symptomatic relief, however, none of these could restore, reverse, or prevent AD. Amid these environmental changes, stress, and unhealthy lifestyles dementia is rapidly increasing and posing a huge financial burden worldwide. Therefore, early, and cost-efficient drug treatment is essential. New effective therapeutic targets have to be tested. Calcium dysregulation in AD is reported regularly. Peptidyl arginine deiminase is a calcium-dependent enzyme that is hyperactivated with the rise in the Ca2+ level. It causes protein deamination/citrullination and may cause neuroinflammation and neurodegeneration. Cl-amidine is a synthetic organic molecule that binds with the PAD enzyme and inhibits it. Though deemed effective in other diseases, Cl-amidine’s efficacy in AD has not been tested yet. This current study aimed to test the efficacy of Cl-amidine for the reduction of neuronal loss and restoration of memory in the mice model of Alzheimer’s Disease. Balb/c mice aged between 6 -12 months old (N=10 for the pilot phase and N=22 for the study phase) were recruited. After random distribution into four groups, AD-like symptoms were induced by intraperitoneal administration of Dgalactose (150mg/kg) + AlCl3 (75mg/kg) for four weeks. The control group was injected intraperitoneally with saline instead. After successful disease induction of AD, confirmed by neurobehavioral analysis, neuronal sclerosis, and neuronal viability, Cl-amidine (15mg/kg) was given for 2 weeks to one treatment group and memantine (5mg/kg) was given to another treatment group as a positive control. The neurobehavioral tests for anxiety, depression, and memory alteration were performed in week 1, week 5, and week 7 to identify behavioural changes at each point. Histological changes in the hippocampus were studied after Nissl staining. Western blotting was used to monitor tau protein (hallmarks of AD). Data analysis was done via SPSS v.26. The study results revealed that Alzheimer’s disease model was successful in Balb/c mice where AD was induced via D-galactose and AlCl3 and our novel drug Cl-amidine was effective in treating AD-like symptoms i.e., memory alteration, and neuronal loss. Cl-amidine also reduced phosphorylated tau proteins. It also restored water and food consumption which had decreased in the AD mice. Thus, Cl-amidine may prove to be an effective novel drug to treat AD dementia, a condition with no effective treatment otherwise.

First Page

1

Last Page

40

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