Background: Depression has most often been diagnosed in patients with temporal lobe epilepsy (TLE), but the mechanism underlying this association remains unclear. In this study, we report that indoleamine 2,3-dioxygenase 1 (IDO1), a rate-limiting enzyme in tryptophan metabolism, plays a key role in epilepsy-associated depressive-like behavior.
Methods: Rats which develop chronic epilepsy following pilocarpine status epilepticus exhibited a set of interictal disorders consistent with depressive-like behavior. Changes of depressive behavior were examined by taste preference test and forced swim test; brain IL-1β, IL-6 and IDO1 expression were quantified using real-time reverse transcriptase PCR; brain kynurenine/tryptophan and serotonin/tryptophan ratios were analyzed by liquid chromatography-mass spectrometry. Oral gavage of minocycline or subcutaneous injection of 1-methyltryptophan (1-MT) were used to inhibite IDO1 expression.
Results: We observed the induction of IL-1β and IL-6 expression in rats with chronic TLE, which further induced the upregulation of IDO1 expression in the hippocampus. The upregulation of IDO1 subsequently increased the kynurenine/tryptophan ratio and decreased the serotonin/tryptophan ratio in the hippocampus, which contributed to epilepsy-associated depressive-like behavior. The blockade of IDO1 activation prevented the development of depressive-like behavior but failed to influence spontaneous seizures. This effect was achieved either indirectly, through the anti-inflammatory tetracycline derivative minocycline, or directly, through the IDO antagonist 1-MT, which normalizes kynurenine/tryptophan and serotonin/tryptophan ratios.
Conclusion: Brain IDO1 activity plays a key role in epileptic rats with epilepsy-associated depressive-like behavior.