Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Aug;39(4):1238-1250.
doi: 10.1007/s12640-021-00368-4. Epub 2021 Apr 29.

Papaverine, a Phosphodiesterase 10A Inhibitor, Ameliorates Quinolinic Acid-Induced Synaptotoxicity in Human Cortical Neurons

Abid Bhat  1   2   3 , Vanessa Tan  3 , Benjamin Heng  3 , Sharron Chow  3 , Salundi Basappa  4 , Musthafa M Essa  5   6 , Saravana B Chidambaram  7   8   9 , Gilles J Guillemin  3
Affiliations

Papaverine, a Phosphodiesterase 10A Inhibitor, Ameliorates Quinolinic Acid-Induced Synaptotoxicity in Human Cortical Neurons

Abid Bhat et al. Neurotox Res. 2021 Aug.

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.

Keywords: CAMP; Oxidative stress; Papaverine; Phosphodiesterase-10A; Quinolinic acid; Synaptic proteins.

PubMed Disclaimer

References

    1. Abraham WC, Jones OD, Glanzman DL (2019) Is plasticity of synapses the mechanism of long-term memory storage? Npj Sci. Learn 4:1–10. https://doi.org/10.1038/s41539-019-0048-y - DOI
    1. Ansari MA, Roberts KN, Scheff SW (2008a) A time course of contusion-induced oxidative stress and synaptic proteins in cortex in a rat model of TBI. J Neurotrauma 25:513–526. https://doi.org/10.1089/neu.2007.0451 - DOI - PubMed
    1. Ansari MA, Roberts KN, Scheff SW (2008b) Oxidative stress and modification of synaptic proteins in hippocampus after traumatic brain injury. Free Radic Biol Med 45:443–452. https://doi.org/10.1016/j.freeradbiomed.2008.04.038 - DOI - PubMed - PMC
    1. Bading H (2017) Therapeutic targeting of the pathological triad of extrasynaptic NMDA receptor signaling in neurodegenerations. J Exp Med 214:569–578. https://doi.org/10.1084/jem.20161673 - DOI - PubMed - PMC
    1. Benej M et al (2018) Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism. Proc Natl Acad Sci U S A 115:10756–10761. https://doi.org/10.1073/pnas.1808945115 - DOI - PubMed - PMC

MeSH terms

LinkOut - more resources