Papaverine, a phosphodiesterase 10A inhibitor, ameliorates quinolinic acid-induced synaptotoxicity in human cortical neurons

Abid Bhat, Vanessa Tan, Benjamin Heng, Sharron Chow, Salundi Basappa, Musthafa M. Essa, Saravana B. Chidambaram, Gilles J. Guillemin

Research output: Contribution to journalArticlepeer-review

Abstract

Phosphodiesterase-10A (PDE10A) hydrolyse the secondary messengers cGMP and cAMP, two molecules playing important roles in neurodevelopment and brain functions. PDE10A is associated to progression of neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's diseases, 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), a PDE10A isoenzyme inhibitor, 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 were measured using ELISA kits. Effect of PAP on the CREB, BNDF and synaptic proteins such as SAP-97, synaptophysin, synapsin-I, and PSD-95 expression was analysed by Western blot. Pre-treatment with PAP increased intracellular cAMP and nicotinamide adenine dinucleotide (NAD+) levels, restored mitochondrial membrane potential (ΔΨm), and decreased ROS and caspase 3/7 content in QUIN exposed neurons. PAP up-regulated CREB and BDNF, and synaptic protein expression. In summary, these data indicate that PDE10A is involved in QUIN-mediated synaptotoxicity and its inhibition elicit neuroprotection by reducing the oxidative stress and protecting synaptic proteins via up-regulation of cAMP signalling cascade.

Original languageEnglish
Pages (from-to)1238-1250
Number of pages13
JournalNeurotoxicity Research
Volume39
Issue number4
Early online date29 Apr 2021
DOIs
Publication statusPublished - Aug 2021

Keywords

  • CAMP
  • Oxidative stress
  • Papaverine
  • Phosphodiesterase-10A
  • Quinolinic acid
  • Synaptic proteins

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