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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
Processing time: 335 Days and 24 Hours
BACKGROUND
Temporal lobe epilepsy (TLE) is the most common focal epilepsy subtype in adults and is frequently accompanied by depression, anxiety and psychosis. Aberrations in total paraoxonase 1 (PON1) status may occur in TLE and these psychiatric conditions.
AIM
To examine PON1 status, namely Q192R PON1 genotypes and PON1 enzymatic activities, in TLE.
METHODS
We recruited 40 normal controls and 104 TLE patients, 27 without comorbidities and 77 with comorbidities including mood disorders (n = 25), anxiety disorders (n = 27) and psychosis (n = 25).
RESULTS
Four-(chloromethyl)phenyl acetate hydrolysis (CMPAase) and arylesterase activities were significantly lower in TLE and mesial temporal sclerosis (MTS) with and without psychiatric comorbidities than those in normal controls. The areas under the receiver operating characteristic curve of CMPAase were 0.893 (0.037) for TLE and 0.895 (± 0.037) for MTS. Partial least squares path analysis showed that there were specific indirect effects of PON1 genotype on TLE severity (P < 0.0001) and psychopathology (P < 0.0001), which were both mediated by lowered CMPAase activity, while arylesterase activity was not significant. The severity of TLE was significantly associated with psychopathology scores. Furthermore, PON1 CMPAase activity was inversely associated with Mini Mental State Examination score.
CONCLUSION
The severity of TLE and comorbidities are to a large extent explained by reduced PON1 enzyme activities and by effects of the Q192R genotype, which are mediated by reduced CMPAase activity. Total PON1 status plays a key role in the pathophysiology of TLE, MTS and psychiatric comorbidities by increasing the risk of oxidative toxicity. PON1 enzyme activities are new drug targets in TLE to treat seizure frequency and psychiatric comorbidities.
Core Tip: The severity of temporal lobe epilepsy (TLE) and mesial temporal sclerosis and their psychiatric comorbidities including depression, anxiety and psychosis are largely explained by lowered paraoxonase 1 (PON1) enzyme activities, which mediate the effects of the Q192R PON1 genotype on psychopathology and epilepsy severity. It is argued that PON1 status may play a key role in the pathophysiology of TLE, mesial temporal sclerosis and its psychiatric comorbidities by increasing the risk of neuro-oxidative toxicity. It is concluded that PON1 enzyme activities are new drug targets to treat seizure frequency and psychiatric comorbidities in patients with TLE.
