2. Academic Validation
  3. Roflumilast, a cAMP-Specific Phosphodiesterase-4 Inhibitor, Reduces Oxidative Stress and Improves Synapse Functions in Human Cortical Neurons Exposed to the Excitotoxin Quinolinic Acid

Roflumilast, a cAMP-Specific Phosphodiesterase-4 Inhibitor, Reduces Oxidative Stress and Improves Synapse Functions in Human Cortical Neurons Exposed to the Excitotoxin Quinolinic Acid

  • ACS Chem Neurosci. 2020 Dec 16;11(24):4405-4415. doi: 10.1021/acschemneuro.0c00636.
Abid Bhat 1 2,  Vanessa Tan 2,  Benjamin Heng 2,  David B Lovejoy 2,  Meena Kishore Sakharkar 3,  Musthafa Mohamed Essa 4 5,  Saravana Babu Chidambaram 1 6,  Gilles J Guillemin 2
Affiliations

Affiliations

  • 1 Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagar, Mysuru, Karnataka 570015, India.
  • 2 Neuroinflammation Group, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
  • 3 College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5A2, Canada.
  • 4 Department of Food Science and Nutrition, CAMS, Sultan Qaboos University, Muscat, Oman.
  • 5 Ageing and Dementia Research Group, Sultan Qaboos University, Muscat, Oman.
  • 6 Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru, Karnataka 570015, India.
PMID: 33261317 DOI: 10.1021/acschemneuro.0c00636
Abstract

The overexpression of phosphodiesterase 4 (PDE4) Enzymes is reported in several neurodegenerative diseases. PDE4 depletes cyclic 3'-5' adenosine monophosphate (cAMP) and, in turn, cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), the key players in cognitive function. The present study was undertaken to investigate the mechanism behind the protective effects of roflumilast (ROF), a cAMP-specific PDE4 Inhibitor, against quinolinic acid (QUIN)-induced neurotoxicity using human primary cortical neurons. Cytotoxicity was analyzed using an MTS assay. Reactive Oxygen Species (ROS) and mitochondrial membrane potential were measured by DCF-DA and JC-10 staining, respectively. Caspase 3/7 activity was measured using an ApoTox-Glo Triplex assay kit. cAMP was measured using an ELISA kit. The protein expression of CREB, BDNF, SAP-97, synaptophysin, synapsin-I, and PSD-95 was analyzed by the Western blotting technique. QUIN exposure down-regulated CREB, BDNF, and synaptic protein expression in neurons. Pretreatment with ROF increased the intracellular cAMP, mitochondrial membrane potential, and nicotinamide adenine dinucleotide (NAD+) content and decreased the ROS and Caspase 3/7 levels in QUIN-exposed neurons. ROF up-regulated the expression of synapse proteins SAP-97, synaptophysin, synapsin-I, PSD-95, and CREB and BDNF, which indicates its potential role in memory. This study suggests for the first time that QUIN causes pre- and postsynaptic protein damage. We further demonstrate the restorative effects of ROF on the mitochondrial membrane potential and antiapoptotic properties in human neurons. These data encourage further investigations to reposition ROF in neurodegenerative diseases and their associated cognitive deficits.

Keywords

Phosphodiesterase; cAMP; mitochondrial membrane potential; quinolinic acid; roflumilast; synaptic proteins.

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