Systemic L-Kynurenine sulfate administration disrupts object recognition memory, alters open field behavior and decreases c-Fos immunopositivity in C57Bl/6 mice

Abstract

L-Kynurenine (L-KYN) is a central metabolite of tryptophan degradation through the kynurenine pathway (KP). The systemic administration of L-KYN sulfate (L-KYNs) leads to a rapid elevation of the neuroactive KP metabolite kynurenic acid (KYNA). An elevated level of KYNA may have multiple effects on the synaptic transmission, resulting in complex behavioral changes, such as hypoactivity or spatial working memory deficits. These results emerged from studies that focused on rats, after low-dose L-KYNs treatment. However, in several studies neuroprotection was achieved through the administration of high-dose L-KYNs. In the present study, our aim was to investigate whether the systemic administration of a high dose of L-KYNs (300 mg/bwkg; i.p.) would produce alterations in behavioral tasks (open field or object recognition) in C57Bl/6j mice. To evaluate the changes in neuronal activity after L-KYNs treatment, in a separate group of animals we estimated c-Fos expression levels in the corresponding subcortical brain areas. The L-KYNs treatment did not affect the general ambulatory activity of C57Bl/6j mice, whereas it altered their moving patterns, elevating the movement velocity and resting time. Additionally, it seemed to increase anxiety-like behavior, as peripheral zone preference of the open field arena emerged and the rearing activity was attenuated. The treatment also completely abolished the formation of object recognition memory and resulted in decreases in the number of c-Fos-immunopositive-cells in the dorsal part of the striatum and in the CA1 pyramidal cell layer of the hippocampus. We conclude that a single exposure to L-KYNs leads to behavioral disturbances, which might be related to the altered basal c-Fos protein expression in C57Bl/6j mice.

The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington's disease

“…In this paper, we did not address any potential effects of CHDI-340246 on cognitive deficits associated with the HD mouse models, although studies in rats did not suggest any benefit of chronic KMO inhibition on a variety of tasks in wildtype animals (not shown). Of interest, previous reports have shown a potential detrimental effect of systemic administration of Kyn and of elevated KynA in various locomotor and cognitive tasks (Kozak et al, 2014;Varga et al, 2015). We did not observe any detrimental effects of CHDI-340246 in open field tests, rearing tests, rotarod, or in neurological scores, in spite of elevating KynA levels significantly in the brain.…”

Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

“…Accordingly, one of the KYNA amide compounds synthesized by our group, N-(2-N,N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride exerted protective effects both in the N171-82Q transgenic mouse model of Huntington's disease and the four-vessel occlusion model of cerebral ischemia in rats [310,311]. At the dose capable of exerting these neuroprotective effects, the KYNA analog did not demonstrate any significant systemic side effects, i.e., it did not alter locomotor activity, working memory performance, and long-lasting, consolidated reference memory in contrast to the observed indirect side-effects following KYN administration [312][313][314]. These results are supported by the findings that instead of decreasing LTP as it might be expected from its potential NMDAR antagonistic properties, it rather facilitated the potentiation of field excitatory postsynaptic potentials [315].…”

Role of Glia in Stress-Induced Enhancement and Impairment of Memory

“…In astrocytes, the KP increases production of the NMDA receptor agonist kynurenic acid; in microglia, the KP increases production of the NMDA receptor agonist quinolinic acid (Jo et al, 2015 ). Given the key role of NMDA receptors in hippocampal memory processing, it is not surprising that recent data suggests that activation of the KP can affect memory processes, and thus may be a novel pathway with importance for stress-related memory dysfunction (Heisler and O'Connor, 2015 ; Varga et al, 2015 ).…”