Investigation of Low Dose Cabazitaxel Potential as Microtubule Stabilizer in Experimental Model of Alzheimer's Disease: Restoring Neuronal Cytoskeleton

Author(s): Pallavi Duggal, Kuldeep S. Jadaun, Ehraz M. Siqqiqui, Sidharth Mehan*

Journal Name: Current Alzheimer Research

Volume 17 , Issue 7 , 2020


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Abstract:

Background: Neuronal Microtubule (MT) tau protein, providing cytoskeleton to neuronal cells, plays a vital role, including maintenance of cell shape, intracellular transport, and cell division. Tau hyperphosphorylation mediated MT destabilization results in axonopathy, additionally neurotransmitter deficit and ultimately causing Alzheimer's disease. Pre-clinically, streptozotocin (3mg/kg, 10μl/ unilateral, ICV) stereotaxically mimics the behavioral and neurochemical alterations similar to Alzheimer's tau pathology resulting in MT assembly defects further lead to neuropathological cascades.

Objective: Clinically approved medications such as Donepezil (DNP), rivastigmine, and Memantine (MEM) are responsible for symptomatic care only, but there is no specific pharmacological intervention that directly interacts with the neuronal microtubule destabilization.

Methods: The current study focused on the involvement of anti-cancer agent microtubule stabilizer cabazitaxel at a low dose (0.5 and 2 mg/kg) alone and in combination with standard drugs DNP (5 mg/kg), MEM (10 mg/kg) and microtubule stabilizer Epothilone D (EpoD) (3 mg/kg) in the prevention of intracerebroventricular streptozotocin (ICV-STZ) intoxicated microtubule-associated tau protein hyperphosphorylation.

Results: Chronic treatment of CBZ at a low dose alone and in combination with standard drugs showing no side effect and significantly improve the cognitive impairment, neurochemical alterations along with reducing the level of hyperphosphorylated tau by preventing the breakdown of the neuronal cytoskeleton, respectively.

Conclusion: The above findings suggested that CBZ at low dose show neuroprotective effects against ICV-STZ induced microtubule-associated tau protein hyperphosphorylation in rats and may be an effective agent for the preventive treatment of AD.

Keywords: Alzheimer's disease, tau hyperphosphorylation, microtubule destabilization, Cabazitaxel, Donepezil, Epothilone D.

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VOLUME: 17
ISSUE: 7
Year: 2020
Published on: 07 October, 2020
Page: [601 - 615]
Pages: 15
DOI: 10.2174/1567205017666201007120112
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