Introduction
Tryptophan-kynurenine pathway (KP) is the principal route for tryptophan (TRP) metabolism. Almost 95% of TRP is directed to KP, catabolised through several “kynurenines”, and generates NAD+ as end product (Schwarcz et al., 2012; Vécsei et al., 2013). Kynurenic acid is one of the most important neuroactive “kynurenines” which selectively inhibits glycine co-agonist site of NMDA receptors at low concentration and a broad-spectrum antagonist of all excitatory amino receptors at high micromolecular concentration (Perkins & Stone, 1982; Kessler et al., 1989). KYNA is known to interact directly with NMDA receptors, which is shown to contribute to the maintenance of glutamatergic synaptic activity in pyramidal neurons of the hippocampus (Cull-Candy et al., 2001). The inhibition of glutamatergic activity by KYNA could also be attributed to its effect on presynaptic nicotinic acetylcholine receptors which may reduce glutamate release (Carpenedo et al., 2001). Upon entering into TKP, TRP converts into L-kynurenine (KYN) by indoleamine2,3‑dioxygenase (IDO) (Moroni et al., 2012). From KYN, the pathway divided into two branches. One leads to irreversible transamination of KYN to KYNA by kynurenine aminotransferase II (KAT II) and its co-factor pyridoxal phosphate (PLP) which is synthesized from dietary vitamin B6 by Pyridoxamine 5’-Phosphate Oxidase (PNPO) (Moroni et al., 2012; Musayev et al., 2009). Through another branch, KYN is converted into quinolinic acid (QUIN) which is an agonist of NMDA receptor and kynurnine-3-monooxygenase (KMO) is the rate-limiting enzyme for QUIN synthesis (Schwarcz et al., 2012). Under physiological condition QUIN/KYNA ratio is critically maintained, as any fluctuation may lead to severe neuropathological conditions (Schwarcz et al., 2012). Fluctuation in KYNA concentration within the brain is associated with changes in neurotransmitters concentration (Carpenedo et al., 2001; Rassoulpour et al., 2005), and electrophysiological manifestation of epilepsy in animal models (Kamiński et al., 2003; Szyndler et al., 2012; Maciejak et al., 2009). Reduction in the cerebrospinal fluid (CSF) KYNA level has been reported in pediatric epilepsy patients (Yamamoto et al., 1994, 1995). However, increase in the level of KYNA in mammalian brain or CSF is associated with reduction of excitatory neurotransmission (Schwarcz et al., 2012). Alteration of KYNA and QUIN in central nervous system may constitute a common occurrence of abnormal synaptic transmission which has a pivotal role in generation of epileptogenesis.
Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is the most common substrate for drug resistant epilepsy (DRE) (Jallon et al., 2001; Jin et al., 2015). Although origin of seizure generation are diversified, one prevailing hypothesis for hyperexcitation is the imbalance between excitatory and inhibitory synaptic transmissions mediated by glutamate (NMDA, AMPA/kainate) and GABA receptors. Under resting state, augmented synaptic endogenous NMDA receptor tone (Banerjee et al., 2015), differential upregulation of NR1 (de Moura et al. 2012), NR2A and NR2B subunits of this receptor, glutamatergic network reorganisation and synchronised excitatory interconnections within hippocampus contribute towards hyperexcitation (Banerjee et al., 2017). α7 nicotinic receptors (nAChR) also contributes to enhanced hippocampal glutamatergic activity in MTLE-HS (Banerjee et al., 2020). Presently, surgical intervention which includes anterior temporal lobectomy and amygdalo-hippocampectomy is the only available therapeutic option to achieve seizure freedom (Josephson et al., 2013; Engel, 2001). This study was designed to test the central hypothesis that alteration in metabolism of KP pathway metabolites in the hippocampus of patients with MTLE-HS contributes to abnormal glutamatergic transmission.