Antidepressant-like Effects of Kynurenic Acid Analogues

Kynurenic acid (KYNA) is a metabolite of the L-tryptophan (TRP)-kynurenine (KYN) pathway which has been shown to possess neuroprotective and antidepressant-like properties. The intracerebroventricular (i.c.v.) administration of kynurenic acid (KYNA) triggered antidepressant-like effects at least in part through the serotonin 5-hydroxytryptamine (5-HT) type 2 receptors, D₂, D₃, D₄ dopamine receptors, and gamma-aminobutyric acid subunit A (GABA_A) receptors in modified forced swimming test (FST) of mouse. However, KYNA is impermeable to the blood-brain-barrier (BBB) and thus it is probably a cause that the peripheral administration of KYNA did not exhibit an antidepressant-like effect.

New KYNA analogues were designed to overcome the BBB in attempt to deliver neuroprotective KYNA molecules to the central nervous system (CNS). The antidepressant-like effects of KYNA analogues SZR-72, SZR-81, and SZR-104 were studied i.c.v. and intraperitoneally (i.p.) with a modified FST.

The FST revealed that i.c.v. administration of SZR-81 significantly decreased immobility and significantly increased swimming time, which suggested that its antidepressant-like effects were triggered through the serotonin 5-HT nervous system. SZR-72 and SZR-104 did not significantly change either immobility, climbing, or swimming time, suggesting SZR-72and SZR-104 did not have antidepressant-like effects. Furthermore, i.p. administration of SZR-81 did not change either immobility, climbing, or swimming time like i.c.v. administration.

Two of the KYNA analogues SZR-72and SZR-104 may not have the antidepressant-like properties and SZR-81 may not cross the BBB or be modified on the way to the CNS. Novel KYNA analogues are expected to be designed in search of potent antidepressants which reserve antidepressant properties, cross the BBB, and target in the CNS.