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Updated: Oct 2, 2025
Experimental Models to Study the Neuroprotection of Acidic Postconditioning Against Cerebral Ischemia
Published on: July 31, 2017
An integrated chemo-informatics and in vitro experimental approach repurposes acarbose as a post-ischemic
Jyotirekha Das1, Fayaz Shaik Mahammad2, Rajanikant Golgodu Krishnamurthy1
1School of Biotechnology, National Institute of Technology Calicut, Calicut, Kerala 673601 India.
Abstract:
The increasing prevalence of ischemic stroke combined with limited therapeutic options highlights the compelling need for continued research into the development of future neuro-therapeutics. Death-Associated Protein Kinase 1 (DAPK1) and p53 protein-protein interaction serve as a signaling point for the convergence of apoptosis and necrosis in cerebral ischemia. In this study, we used an integrated chemo-informatics and in vitro experimental drug repurposing strategy to screen potential small-molecule inhibitors of DAPK1-p53 interaction from the United States of America Food and Drug Administration (FDA) approved drug database exhibiting post-ischemic neuroprotective and neuro-regenerative efficacy and mechanisms. The computational docking and molecular dynamics simulation of FDA-approved drugs followed by an in vitro experimental validation identified acarbose, an anti-diabetic medication and caloric restriction mimetic as a potential inhibitor of DAPK1-p53 interaction. The evaluation of post-ischemic neuroprotective and regenerative efficacy and mechanisms of action for acarbose was carried out using a set of experimental methods, including cell viability, proliferation and differentiation assays, fluorescence staining, and gene expression analysis. Post-ischemic administration of acarbose conferred significant neuroprotection against ischemia-reperfusion injury in vitro. The reduced fluorescence emission in cells stained with pS20 supported the potential of acarbose in inhibiting the DAPK1-p53 interaction. Acarbose prevented mitochondrial and lysosomal dysfunction, and favorably modulated gene expression related to cell survival, inflammation, and regeneration. BrdU staining and neurite outgrowth assay showed a significant increase in cell proliferation and differentiation in acarbose-treated group. This is the first study known to provide mechanistic insight into the post-ischemic neuroprotective and neuro-regenerative potential of acarbose. Our results provide a strong basis for preclinical studies to evaluate the safety and neuroprotective efficacy of acarbose against ischemic stroke.
Supplementary Information:
The online version contains supplementary material available at 10.1007/s13205-022-03130-5.
Insights
Acarbose, an anti-diabetic drug, shows neuroprotective and regenerative potential against ischemic stroke by inhibiting the Death-Associated Protein Kinase 1 (DAPK1)-p53 interaction. This study identifies acarbose as a promising candidate for future preclinical stroke research.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Ischemic stroke presents a growing health challenge with limited treatment options.
- The Death-Associated Protein Kinase 1 (DAPK1) and p53 interaction is a key signaling pathway in cerebral ischemia, involving both apoptosis and necrosis.
Purpose of the Study:
- To identify potential small-molecule inhibitors of the DAPK1-p53 interaction using a drug repurposing strategy.
- To evaluate the neuroprotective and neuro-regenerative efficacy of identified compounds in post-ischemic conditions.
Main Methods:
- Integrated chemo-informatics (computational docking, molecular dynamics) and in vitro experimental validation.
- Screening of Food and Drug Administration (FDA)-approved drugs.
- Assays for cell viability, proliferation, differentiation, mitochondrial/lysosomal function, gene expression, and immunofluorescence staining.
Main Results:
- Acarbose, an anti-diabetic medication, was identified as a potential inhibitor of the DAPK1-p53 interaction.
- Post-ischemic administration of acarbose demonstrated significant neuroprotection against ischemia-reperfusion injury in vitro.
- Acarbose treatment reduced DAPK1-p53 interaction, prevented cellular dysfunction, and promoted cell survival, regeneration, proliferation, and differentiation.
Conclusions:
- Acarbose exhibits significant post-ischemic neuroprotective and neuro-regenerative potential.
- This study provides the first mechanistic insight into acarbose's effects on DAPK1-p53 signaling in cerebral ischemia.
- Results support further preclinical investigation of acarbose for ischemic stroke treatment.
