Endogenous QUIN synthesis was elevated
Our findings suggested increased expression and functional activity of
IDO enzyme in the hippocampal samples (Figure 6c and d). Reduction in
TRP/KYN ratio (Figure 2c) is suggestive of increased functional activity
of IDO in those samples. We observed that with increase in duration of
seizure, concentration of PLP was gradually decreases due to
downregulation of PNPO. Consequently, due to less availability of PLP
and downregulation of KAT II, concentration of KYNA gradually decreases
with increase in duration of seizure. As synthesis of KYNA decreases,
availability of substrate (KYN) increases with time. It is possible that
due to this reason, in spite of unaltered expression of KMO,
concentration of QUIN gradually increases with increase in duration of
seizure. This suggests that in patients with MTLE-HS, increase in
duration of seizures may redirect the kynurenine pathway towards reduced
KYNA synthesis and increased QUIN synthesis which could contribute to
enhanced glutamatergic synaptic transmission. An increase in QUIN/KYNA
ratio causes hyperexcitation, excitotoxicity, astrogliosis and decrease
in neuronal viability as evident from our histopathological findings
(Figure 1a, b, c). Under physiological condition, astrocytes contain
enzymes for degradation of QUIN, but during brain inflammation reactive
astrocytes produce KYN which translocate to resident activated microglia
or infiltrating macrophages to serve as substrate for QUIN synthesis
(Guillemin et al., 2001). It has been shown that infusion of KYN in the
pyriform cortex of chronic epileptic rats corresponds to progressive
decline in extracellular KYNA concentration after achieving peak
concentration, which is speculated to be due to downregulation of KAT in
reactive astrocytes (Wu et al., 1991). In the present study, it is
possible that reactive astrocytes/astrogliosis in the hippocampal
samples (Figure 1C) not only associate with downregulation of KAT II
enzyme (Figure 6a and b) but also facilitate synthesis of QUIN from
microglia/macrophages in lieu of KYNA which ultimately contribute to
glutamate receptor mediated hyperexcitability.