Behavioural studies with a newly developed neuroprotective KYNA-amide

Abstract

The neuroactive properties and neuroprotective potential of endogenous L: -kynurenine, kynurenic acid (KYNA) and its derivatives are well established. KYNA acts as an antagonist on the obligatory co-agonist glycine site, and has long been at the focus of neuroprotective trials. Unfortunately, KYNA is barely able to cross the blood-brain barrier. Accordingly, the development and synthesis of KYNA analogs which can readily cross the BBB have been at the focus of research interest with the aim of neuroprotection. Earlier we reported a new KYNA-amide crosses the BBB and proved neuroprotective in several experiments. In the present study, we investigated the locomotor activity, working memory performance, and also the long-lasting, consolidated reference memory of animals treated intraperitoneally (i.p.) with the novel analog. The effects of the novel analog on the spatial orientation and learning ability of rats were assessed in the Morris water maze (MWM) paradigm. The effects on locomotor activity of mice was assessed in the open field (OF) paradigm, and those on the spatial orientation and learning ability of mice were investigated in the radial arm maze (RAM) paradigm. It emerged that there is a dose of this KYNA-amide which is neuroprotective, but does not worsen the cognitive function of the brain. This result is significant in that a putative neuroprotectant without adverse cognitive side-effects is of great benefit.

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].…”

A comparative assessment of two kynurenic acid analogs in the formalin model of trigeminal activation: a behavioral, immunohistochemical and pharmacokinetic study

“…Following this comparative study, KA-1 was tested in several experimental setups and proved to have beneficial effects (Gellért et al, 2012Knyihar-Csillik et al, 2008;Marosi et al, 2010;Vámos et al, 2010Vámos et al, , 2009Zádori et al, 2011c). In contrast with the electrophysiological findings with KA-1, N-(2-N-pyrrolidinylethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride (KA-2, Figure 1b) did not decrease, but rather slightly increased the amplitudes of field excitatory postsynaptic potentials (fEPSPs) (Nagy et al, 2011).…”

Paradox effects of kynurenines on LTP induction in the Wistar rat. An in vivo study

“…Interestingly, neither KYNA nor SZR72 in a dose that results in effective neuroprotection induced a significant decrease in the cognitive function of behaving animals [10] or in the LTP function, as revealed by the present electrophysiological study. It might have been expected that KYNA (as an NMDA receptor antagonist) or SZR72 in a dose of 283.5 mg/kg and 295 mg/kg, respectively, would result in a decrease in LTP function.…”

“…Although KYNA displays a marked neuroprotective effect, the potential risks of interfering with cognitive functions when dealing with molecules capable of impairing glutamatergic and cholinergic transmission should always be borne in mind. That was the reason why we earlier tested the effects of SZR72 on behaving animals [8,10], and now on the LTP function of the hippocampus. Hippocampal LTP is an activity-dependent increase in the synaptic response, first demonstrated by Bliss and Lomo in 1973 [2].…”