Effects of Dasatinib with Resveratrol in Toxin-Based Cell Models of Neurodegeneration

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Vadivelan Ramachandran, Arun Thulaseedharan Nair, Gaurav Tiwari, Stuti Verma

Abstract

Background: Neurodegenerative disorders like Parkinson’s disease are characterized by dysfunction of motor control and cognition due to the gradual loss of dopamine-generating brain cells. Recent research linked kinase activities, its phosphorylation pathways and α-synuclein with mitochondrial dysfunction and neuroinflammation to neurodegeneration. Current treatments provide only symptomatic relief. In the present study, we have demonstrated that a combination of dasatinib and resveratrol has potential to treat neurodegeneration more efficiently.


Methods: SH-SY5Y (α-synuclein proteinopathy and mitochondrial dysfunction model) cell lines were used to study (i) α-synuclein level and autophagy intensity (ii) mitochondrial dysfunction parameters like ROS, complex-1, calcium level, PGC-1α activity (iii) dopamine level estimation (iv) mRNA expression of beclin1, parkin and SIRT-1. IMR-32 (neuroinflammation model) cell lines were used to study NFkB, TNF α, IL1B mRNA expressions and protein levels.


Results: The drug combination significantly attenuates α-synuclein level, shows 38% increase (P<0.001) in mean autophagy intensity (11.53 ± 0.06) compared to rotenone group and an increment of 11% and 19% (P<0.001) compared to individual dasatinib and resveratrol treatment groups respectively. ROS fluorescence intensity for drug combination shows a reduction of 52% (P< 0.001) compared to rotenone group and further 12% (P<0.01) and 25% (P<0.001) reductions compared to dasatinib and resveratrol groups, respectively. mRNA expression and protein levels for neuroinflammation show reductions in the levels of IL1B, NFkB, TNF a (P<0.001) for the drug combination compared to LPS group.


Conclusion: The mechanism of action of the drug combination may possibly be due to its activity in multiple targets such as α-synucleinopathy, mitochondrial dysfunction and neuroinflammation. The drug combination has, therefore, a better efficacy to treat neurodegeneration.

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