Background Kynurenic acid (KYNA) is an l-tryptophan metabolite with neuromodulatory activities, regulating the release of neurotransmitters such as glutamate, dopamine (DA), and acetylcholine (Ach). Dysregulation of the kynurenine pathway has been associated with neurodegenerative, neurological, and psychological disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, major depressive disorder, and schizophrenia. Methods The antidepressant-like effects of KYNA were studied with a modified mouse forced swimming test (FST), and the potential involvement of the serotonin (SER), norepinephrine, DA, Ach, N-methyl-d-aspartate, or gamma-aminobutyric acid subunit A (GABA A) receptors in its antidepressant-like effect was assayed by modified combination mouse FST. In combination studies, the mice were pretreated with the respective receptor antagonist, cyproheptadine (CPH), phenoxybenzamine, yohimbine, propranolol, haloperidol (HPD), atropine, MK-801, or bicuculline (BCL). Results The FST revealed that KYNA reversed immobility, climbing, and swimming times, suggesting the antidepressant-like effects of KYNA. Furthermore, the combination studies showed that CPH prevented the antidepressant-like effects of KYNA on immobility, climbing, and swimming times, whereas HPD reduced climbing time and BCL influenced immobility and climbing times and prevented the effects of KYNA on swimming time. Conclusions The results demonstrated, for the first time, the presence of antidepressant-like effects of KYNA in a modified mouse FST. Furthermore, modified combination FST showed that the antidepressant-like actions of KYNA strongly interacted with 5-hydroxytryptamine type 2 SER-ergic receptors, weakly interacted with D 2 , D 3 , D 4 DA-ergic receptors, and interacted moderately with GABA A receptors.
Kynurenic acid (KYNA) is an endogenous tryptophan (Trp) metabolite known to possess neuroprotective property. KYNA plays critical roles in nociception, neurodegeneration, and neuroinflammation. A lower level of KYNA is observed in patients with neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases or psychiatric disorders such as depression and autism spectrum disorders, whereas a higher level of KYNA is associated with the pathogenesis of schizophrenia. Little is known about the optimal concentration for neuroprotection and the threshold for neurotoxicity. In this study the effects of KYNA on memory functions were investigated by passive avoidance test in mice. Six different doses of KYNA were administered intracerebroventricularly to previously trained CFLP mice and they were observed for 24 h. High doses of KYNA (i.e., 20–40 μg/2 μL) significantly decreased the avoidance latency, whereas a low dose of KYNA (0.5 μg/2 μL) significantly elevated it compared with controls, suggesting that the low dose of KYNA enhanced memory function. Furthermore, six different receptor blockers were applied to reveal the mechanisms underlying the memory enhancement induced by KYNA. The series of tests revealed the possible involvement of the serotonergic, dopaminergic, α and β adrenergic, and opiate systems in the nootropic effect. This study confirmed that a low dose of KYNA improved a memory component of cognitive domain, which was mediated by, at least in part, four systems of neurotransmission in an animal model of learning and memory.
Alzheimer's disease (AD) is an age-related neurodegenerative disease and the most common cause of dementia. The etiology of AD is not entirely clear and despite the increasing knowledge regarding the pathomechanism, no effective disease-modifying therapy is yet available. Astrocytes earlier presumed to serve merely supportive roles for the neuronal network, have recently been shown to play an active role in the synaptic dysfunction, impairment of homeostasis, inflammation as well as excitotoxicity in relation to AD pathology. This review focuses on the pathomechanism of AD with special attention to the role of the astrocytes, excitotoxicity and the alterations in the kynurenine metabolism in the development of the disease. The correction of the neuroprotective/neurotoxic imbalance in the kynurenine pathway may represent a novel target for pharmaceutical interventions in dementia related to neurodegenerative disorders.
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