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Abstract
Background:
Alzheimer’s disease (AD) is a progressive neurodegenerative condition marked by the accumulation of amyloid-beta plaques, a process largely influenced by the activity of β-site amyloid precursor protein cleaving enzyme 1 (BACE-1). Current therapeutic options are mainly symptomatic and do not alter the course of the disease, highlighting the need for treatments that can target its underlying pathology. Protease inhibitors have therefore emerged as promising candidates for modulating this key pathological mechanism.
Objective: This study aimed to investigate the influence of the protease inhibitor Ritonavir on BACE-1 gene expression, cognitive performance, and depression-like behaviours in a mouse model of Alzheimer’s disease induced by aluminium chloride (AlCl₃). Methods: Fifty-six Swiss albino mice were allocated into seven groups: a control group, three groups treated with Ritonavir at doses of 100, 200, and 400 mg/kg, an AlCl₃-induced Alzheimer’s model group, and two positive control groups administered Donepezil (5 mg/kg) and Ascorbic Acid (100 mg/kg). After 28 days of treatment, molecular analysis was carried out to quantify BACE-1 gene expression. Cognitive function and depression-related behaviours were assessed using the Novel Object Recognition (NOR) test and the Tail Suspension Test (TST), respectively.
Results: The high dose of Ritonavir (400 mg/kg) significantly suppressed AlCl₃-induced BACE-1 gene overexpression, demonstrating efficacy comparable to the positive controls. However, this robust molecular effect did not translate into significant improvements in the behavioural assays. No significant differences were observed in the NOR test discrimination index or in the immobility duration during the TST across all treatment groups. Conclusion: The findings suggest that Ritonavir is effective in normalizing BACE-1 gene expression at a high dose, indicating potential disease-modifying properties at the molecular level. However, its inability to reverse cognitive deficits or depression-like behaviour in this model suggests that BACE-1 inhibition alone may be insufficient for comprehensive functional recovery. Further investigation in chronic models and exploration of combination therapies is warranted.
Alzheimer’s disease (AD) is a progressive neurodegenerative condition marked by the accumulation of amyloid-beta plaques, a process largely influenced by the activity of β-site amyloid precursor protein cleaving enzyme 1 (BACE-1). Current therapeutic options are mainly symptomatic and do not alter the course of the disease, highlighting the need for treatments that can target its underlying pathology. Protease inhibitors have therefore emerged as promising candidates for modulating this key pathological mechanism.
Objective: This study aimed to investigate the influence of the protease inhibitor Ritonavir on BACE-1 gene expression, cognitive performance, and depression-like behaviours in a mouse model of Alzheimer’s disease induced by aluminium chloride (AlCl₃). Methods: Fifty-six Swiss albino mice were allocated into seven groups: a control group, three groups treated with Ritonavir at doses of 100, 200, and 400 mg/kg, an AlCl₃-induced Alzheimer’s model group, and two positive control groups administered Donepezil (5 mg/kg) and Ascorbic Acid (100 mg/kg). After 28 days of treatment, molecular analysis was carried out to quantify BACE-1 gene expression. Cognitive function and depression-related behaviours were assessed using the Novel Object Recognition (NOR) test and the Tail Suspension Test (TST), respectively.
Results: The high dose of Ritonavir (400 mg/kg) significantly suppressed AlCl₃-induced BACE-1 gene overexpression, demonstrating efficacy comparable to the positive controls. However, this robust molecular effect did not translate into significant improvements in the behavioural assays. No significant differences were observed in the NOR test discrimination index or in the immobility duration during the TST across all treatment groups. Conclusion: The findings suggest that Ritonavir is effective in normalizing BACE-1 gene expression at a high dose, indicating potential disease-modifying properties at the molecular level. However, its inability to reverse cognitive deficits or depression-like behaviour in this model suggests that BACE-1 inhibition alone may be insufficient for comprehensive functional recovery. Further investigation in chronic models and exploration of combination therapies is warranted.
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