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.