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.