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bioRxiv · 10.1101/2020.12.04.411868

Inhibition of phosphodiesterase - 10A by Papaverine protects human cortical neurons from quinolinic acid-induced oxidative stress and synaptic proteins alterations

Bhat, A.·Tan, V.·Heng, B.·M. Essa, M.·Babu, S.·Guillemin, G. J.
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Abstract

Phosphodi esterase-10A (PDE10A) hydrolyse the secondary messengers cGMP and cAMP which play critical role in neurodevelopment and brain functions. PDE10A is linked to progression of neurodegenerative diseases like Alzheimers, Parkinsons, Huntingtons diseases etc and a critical role in cognitive functions. The present study was undertaken to determine the possible neuroprotective effects and the associated mechanism of papaverine (PAP) against quinolinic acid (QUIN) induced excitotoxicity using human primary cortical neurons. Cytotoxicity potential of PAP was analysed using MTS assay. Reactive oxygen species (ROS) and mitochondrial membrane potential were measured by DCF-DA and JC10 staining, respectively. Caspase 3/7 and cAMP levels using ELISA kits. Effect of PAP on the CREB, BNDF and synaptic proteins such as SAP-97, synaptophysin, synapsin-I, PSD-95 expression was analysed by Western blotting technique. Pre-treatment with PAP increased intracellular cAMP and nicotinamide adenine dinucleotide (NAD+) levels, restored mitochondrial membrane potential ({Delta}{Psi}m), and decreased ROS and caspase3/7 content in QUIN exposed neurons. PAP up-regulated CREB and BDNF, and synaptic proteins expression. In summary, these data indicate that PDE10A involves in QUIN mediated neurotoxicity and its inhibition can elicit neuroprotection by reducing the oxidative stress and protecting synaptic proteins via upregulation of cAMP signalling cascade.

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Bhat, A., Tan, V., Heng, B., M. Essa, M., Babu, S., Guillemin, G. J.. 2020-12-04. Inhibition of phosphodiesterase - 10A by Papaverine protects human cortical neurons from quinolinic acid-induced oxidative stress and synaptic proteins alterations. https://doi.org/10.1101/2020.12.04.411868

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