Soumil Dey1, Aparna Banerjee Dixit2, Manjari Tripathi3, Ramesh S Doddamani1, Meher C Sharma4, Sanjeev Lalwani5, P Sarat Chandra1, Jyotirmoy Banerjee6. 1. Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India. 2. Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi, India. 3. Department of Neurology, All India Institute of Medical Sciences, New Delhi, India. 4. Department of Pathology, All India Institute of Medical Sciences, New Delhi, India. 5. Department of Forensic Medicine and Toxicology, All India Institute of Medical Sciences, New Delhi, India. 6. Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India.
Abstract
BACKGROUND AND PURPOSE: Glutamate receptor mediated enhanced excitatory neurotransmission is typically associated with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Kynurenic acid (KYNA) and quinolinic acid (QUIN) are two important tryptophan-kynurenine pathway (KP) metabolites that modulate glutamate receptor activity. This study was designed to test the hypothesis that alteration in metabolism of KP metabolites in the hippocampus of patients with MTLE-HS contributes to abnormal glutamatergic transmission. EXPERIMENTAL APPROACH: KP metabolites level were determined using HPLC and LC-MS/MS in the hippocampal samples of patients with MTLE-HS compared to autopsy and non-seizure control samples. mRNA and protein expression of KP enzymes were determined by qPCR and western blot. Spontaneous glutamatergic activities were recorded from pyramidal neurons in presence of kynurenine (KYN) and KYNA using whole cell patch clamp. KEY RESULTS: We observed significantly reduced KYNA and elevated QUIN levels in the hippocampal samples, while KYN level remains unaltered. Spontaneous glutamatergic activity in the hippocampal samples was higher compared to that in non-seizure controls. Treatment with kynurenine inhibited the glutamatergic activity in non-seizure control samples but not in case of the hippocampal samples. However, exogenously applied KYNA inhibited glutamatergic activity in both non-seizure control and hippocampal samples. We also observed reduced levels of enzyme kynurenine aminotransferase II and its co-factor pyridoxal phosphate in the hippocampal samples. CONCLUSION: Our findings indicate that altered metabolism of KP metabolites in hippocampus could contribute to hyperglutamatergic tone in patients with MTLE-HS. This article is protected by copyright. All rights reserved.
BACKGROUND AND PURPOSE: Glutamate receptor mediated enhanced excitatory neurotransmission is typically associated with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Kynurenic acid (KYNA) and quinolinic acid (QUIN) are two important tryptophan-kynurenine pathway (KP) metabolites that modulate glutamate receptor activity. This study was designed to test the hypothesis that alteration in metabolism of KP metabolites in the hippocampus of patients with MTLE-HS contributes to abnormal glutamatergic transmission. EXPERIMENTAL APPROACH: KP metabolites level were determined using HPLC and LC-MS/MS in the hippocampal samples of patients with MTLE-HS compared to autopsy and non-seizure control samples. mRNA and protein expression of KP enzymes were determined by qPCR and western blot. Spontaneous glutamatergic activities were recorded from pyramidal neurons in presence of kynurenine (KYN) and KYNA using whole cell patch clamp. KEY RESULTS: We observed significantly reduced KYNA and elevated QUIN levels in the hippocampal samples, while KYN level remains unaltered. Spontaneous glutamatergic activity in the hippocampal samples was higher compared to that in non-seizure controls. Treatment with kynurenine inhibited the glutamatergic activity in non-seizure control samples but not in case of the hippocampal samples. However, exogenously applied KYNA inhibited glutamatergic activity in both non-seizure control and hippocampal samples. We also observed reduced levels of enzyme kynurenine aminotransferase II and its co-factor pyridoxal phosphate in the hippocampal samples. CONCLUSION: Our findings indicate that altered metabolism of KP metabolites in hippocampus could contribute to hyperglutamatergic tone in patients with MTLE-HS. This article is protected by copyright. All rights reserved.
Authors: Korrapati V Sathyasaikumar; Verónica Pérez de la Cruz; Benjamín Pineda; Gustavo Ignacio Vázquez Cervantes; Daniela Ramírez Ortega; David W Donley; Paul L Severson; Brian L West; Flaviano Giorgini; Jonathan H Fox; Robert Schwarcz Journal: Antioxidants (Basel) Date: 2022-02-04