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

被引：16

作者：

Bhat, Abid ^{[1
,2
]}

Tan, Vanessa ^{[2
]}

Heng, Benjamin ^{[2
]}

Lovejoy, David B. ^{[2
]}

Sakharkar, Meena Kishore ^{[3
]}

Essa, Musthafa Mohamed ^{[4
]}

Chidambaram, Saravana Babu ^{[1
,5
]}

Guillemin, Gilles J. ^{[2
]}

机构：

[1] JSS Acad Higher Educ & Res, JSS Coll Pharm, Dept Pharmacol, Mysuru 570015, Karnataka, India

[2] Macquarie Univ, Fac Med Hlth & Human Sci, Neuroinflammat Grp, Sydney, NSW 2109, Australia

[3] Univ Saskatchewan, Coll Pharm & Nutr, Saskatoon, SK S7N 5A2, Canada

[4] Sultan Qaboos Univ, Dept Food Sci & Nutr, CAMS & Ageing & Dementia Res Grp, Muscat, Oman

[5] JSS Acad Higher Educ & Res, Ctr Expt Pharmacol & Toxicol, Cent Anim Facil, Mysuru 570015, Karnataka, India

来源：

ACS CHEMICAL NEUROSCIENCE | 2020年 / 11卷 / 24期

基金：

英国医学研究理事会; 澳大利亚研究理事会;

关键词：

Phosphodiesterase; cAMP; roflumilast; quinolinic acid; mitochondrial membrane potential; synaptic proteins; KYNURENINE PATHWAY; MOUSE MODEL; DEFICITS; MEMORY; ROLIPRAM; METABOLISM; EXPRESSION; BDNF; RATS; DYSFUNCTION;

D O I：

10.1021/acschemneuro.0c00636

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The overexpression of phosphodiesterase 4 (PDE4) enzymes is reported in several neurodegenerative diseases. PDE4 depletes cyclic 3'-S' 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, synapsinI, and PSD-9S 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.

引用

页码：4405 / 4415

页数：11