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©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
Reduced paraoxonase 1 activities may explain the comorbidities between temporal lobe epilepsy and depression, anxiety and psychosis
Ana Paula Michelin, Michael H J Maes, Thitiporn Supasitthumrong, Chusak Limotai, Andressa Keiko Matsumoto, Laura de Oliveira Semeão, João Victor de Lima Pedrão, Estefânia Gastaldello Moreira, Buranee Kanchanatawan, Décio Sabbatini Barbosa
Ana Paula Michelin, Andressa Keiko Matsumoto, Laura de Oliveira Semeão, João Victor de Lima Pedrão, Estefânia Gastaldello Moreira, Décio Sabbatini Barbosa, Health Sciences Center, State University of Londrina, Londrina 86038-440, Brazil
Michael H J Maes, Thitiporn Supasitthumrong, Buranee Kanchanatawan, Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
Michael H J Maes, Department of Psychiatry, Medical University of Plovdiv, Plovdiv 4004, Bulgaria
Michael H J Maes, IMPACT Strategic Research Center, Deakin University, Geelong 3220, Australia
Chusak Limotai, Chulalongkorn Comprehensive Epilepsy Center of Excellence, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok 10330, Thailand
Chusak Limotai, Division of Neurology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
Author contributions: All the contributing authors have participated in the manuscript; Kanchanatawan B and Maes MHJ designed the study; Kanchanatawan B and Limothai C recruited patients and completed diagnostic interviews and rating scale measurements; Maes MHJ carried out the statistical analyses; all authors contributed to interpretation of the data and writing of the manuscript and approved the final version of the manuscript; Kanchanatawan B and Barbosa DS shared senior authorship.
Supported by Ratchadapisek Research Funds, Faculty of Medicine, Chulalongkorn University, No. RA60/042 (to BK), and No. RA61/050 (to MM).
Institutional review board statement: This study was approved by the Institutional Review Board of the Faculty of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand (IRB number 305/56), which is in accordance with the International Guideline for the Protection of Human Research, as established by the Declaration of Helsinki , The Belmont Report, International Conference on Harmonization of Good Clinical Practice and Council for International Organizations of Medical Sciences Guideline.
Informed consent statement: All participants in this study gave written informed consent form before participating in the study.
Conflict-of-interest statement: The authors have no conflict of interest with any commercial or other association in connection with the submitted article.
Data sharing statement: The dataset generated during and/or analyzed during the current study will be available from the corresponding author upon reasonable request and once the dataset has been fully exploited by the authors.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Michael H J Maes, MD, PhD, Professor, Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Patumwan 1873, Bangkok 10330, Thailand. dr.michaelmaes@hotmail.com
Received: March 18, 2021
Peer-review started: March 18, 2021
First decision: July 15, 2021
Revised: August 14, 2021
Accepted: January 10, 2022
Article in press: January 10, 2022
Published online: February 19, 2022
ARTICLE HIGHLIGHTS
Research background
Hippocampal sclerosis, also known as mesial temporal sclerosis (MTS), is the most common primary epileptic pathology, accounting for 36% of all focal epileptic pathologies. Depression, anxiety, and psychosis (PSY) affect between 30%–70% of temporal lobe epilepsy (TLE) patients. The pathophysiology of TLE, TLE progression, depression, anxiety and PSY is heavily influenced by oxidative pathways and decreased antioxidant defenses.
Research motivation
The enzyme paraoxonase 1 (PON1) protects against lipid peroxidation, and its activity is influenced in part by a single nucleotide polymorphism in PON1. There has been no research that examined the links between PON1 status and mental comorbidities in TLE.
Research objectives
The goal of this research was to look at PON1 status, namely 4-(chloromethyl) phenyl acetate CMPAase and arylesterase activities, as well as PON1 Q192R genotypes, in patients with TLE and MTS who had comorbid PSY, depression and anxiety.
Research methods
This is a case-control study that examined 104 patients with TLE and 40 normal controls. TLE patients were divided according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision criteria into: (1) Mood disorders due to TLE with depressive features (n = 25); (2) Anxiety disorders due to TLE (n = 25); (3) Psychotic disorder due to TLE (n = 25); and (4) "Pure TLE" when there were no psychiatric comorbidities. After an overnight fast, blood samples were obtained at 8:00 a.m., and serum was aliquoted and kept at -80 °C until thawed for total PON1 activity (PON1Q192R polymorphism, and arylesterase and CMPAase activities). Data were analyzed using partial least squares pathway analysis.
Research results
PON1 activities were significantly lower in TLE patients than those in controls. The area under the receiver operating characteristic curve using lower CMPAase activity as discriminatory variable was 0.893 (0.037) for TLE and 0.895 (± 0.037) for MTS. We found that 46.0% of the variance in the severity of depressive, anxiety and psychotic symptoms was explained by the severity of TLE features and PON1 CMPAse activity while 25.3% of the variance in TLE severity was explained by CMPAase activity. PON1 QQ and RR, but not QR, had significant effects on severity of TLE and comorbid psychopathology.
Research conclusions
In individuals with TLE, particularly MTS, the activity of CMPAse and arylesterase enzymes are much lower than in healthy controls. Reduced CMPAase mediates the negative effects of the PON1 genotype on TLE, depression, PSY and anxiety severity.
Research perspectives
Changes in PON1 status play a role in pathophysiology of TLE, MTS and mental comorbidities. PON1 enzymatic activity is a novel therapeutic target in TLE for the treatment of seizure frequency and mental comorbidities.
