This will require lots of human testing. Low levels of KYNA lead to Alzheimer’s and Parkinson’s while high levels lead to schizophrenia. I wouldn't want to be in this clinical trial if the range is that delicate.
Memory Enhancement with Kynurenic Acid and its Mechanisms in Neurotransmission
Diána Martos 1, Bernadett Tuka 1, Masaru Tanaka 1, László Vécsei 1,2,*, and Gyula Telegdy 3
1 MTA-SZTE Neuroscience Research Group, Hungarian Academy of Sciences-University of Szeged (MTASZTE), Semmelweis u. 6, Szeged, H-6725 Hungary
2 Department of Neurology, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis u. 6, H6725 Szeged, Hungary
3 Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis
u. 5, H-6725 Szeged, Hungary
* Correspondence: vecsei.laszlo@med.u-szeged.hu; Tel.: +36 62 342 361
Abstract:
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 following 24 hours. 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. The 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.
Keywords: tryptophan; kynurenine; kynurenic acid; passive avoidance; cognitive domain; memory;
cognitive enhancer; neurotransmission; receptor blockers; translational
1. Introduction
Worldwide, around 50 million people suffer from major neurocognitive disorders.
Alzheimer’s disease (AD) represents 60-70 percent of cases, imposing a physical, psychological, social, and economic burden on the elderly, their families, caregivers as well as
society [1]. Patients who develop AD first demonstrate a subtle decline in memory and
learning, followed by changes in executive cognitive function and in language and
visuospatial processing; indeed, recent evidence suggests that impairments in the ability
to process contextual information and in the regulation of responses to threat are related
to structural and physiological alterations in the prefrontal cortex (PFC) and medial temporal lobe, addressing how this progressive brain deterioration can eventually cause patterns of cognitive dysfunctions observed in patients with AD [2]. The cause of major neurocognitive disorders remains unknow, but it is considered to be caused by convergence
of multifactorial factors including genetic, environmental, infectious, and nutritional components, and lifestyle, among others [3,4]. There is no remedy for neurodegenerative diseases. Disease-modifying and symptom-relieving measures are mainstays of treatment.
Thus, a tremendous effort has been made to identify pathomechanisms, discover interventional targets, and design novel pharmaceutical agents [5].
KYNA is a metabolite of the Trp-kynurenine (KYN) metabolic system, known to possess neuroprotective property [6Encyclopedia]. The neuroprotective activities are considered to be attributed to the antagonism of the excitatory amino acid receptors (EAARs)
such as the N-methyl-D-aspartate (NMDA) receptor, the α-amino-3-hydroxy-5-methyl-4-
isoxazole propionic acid (AMPA) receptor, and the kainic acid receptor [7-10]. Furthermore, KYNA acts as an agonist of the G-protein-coupled receptor 35 (GPR35) and the aryl
hydrocarbon receptor (AHR) [11-14]. In addition, opioid receptors are presumed to be
interacting partners of KYNA [15,16].
It was previously postulated that the main component of KYNA-induced inhibition
in glutamatergic neurotransmission may attribute to non-competitive inhibition of α7-
nicotinic acetylcholine receptors at glutamatergic presynaptic axon terminals [17], thereby
regulating the release of glutamate. However, these results could not be reproduced by
four different, independent groups subsequently. Thus, it is still questionable that KYNA
may affect glutamate release via the mechanism [18-22]. KYNA plays crucial roles in the
regulation of the intracellular Ca2+ and mitochondrial dysfunction-induced neuronal cell
death in conditions associated with excitotoxicity (Fig. 1).
Figure 1. KYNA influences the neuronal and glial glutamatergic neurotransmission.
Recently, KYNA and its novel pharmacokinetically favorable analogues demonstrated beneficial effects in animal models of neurologic diseases including pathologic
pain sensation, migraine, ischemic stroke, and epilepsy, neurodegenerative diseases, and
psychiatric disorder including depression, anxiety, and addiction [23-39]. Accordingly,
neuroprotective KYN metabolites, their analogues, the inhibition of Trp-KYN enzymes
which are responsible for production of toxic metabolites, their use for biomarkers, and
its interaction with adjacent biosystems are under extensive research [40-48].
The beneficial effects were detected when these molecules were peripherally administered in an acute or semi-chronic manner with relatively high (millimolar) concentrations. Lower levels of KYNA were observed in patients with neurodegenerative diseases
and psychiatric disorders [3,6,32,49]. Those illnesses are generally characterized by alterations in inflammatory mediators and mu-opioid receptor, and increased levels in neurotoxic Try-KYN metabolites, which, furthermore, lead to changes in the amygdala [50].
However, Manipulations to elevate KYNA levels have a potential risk of interfering with
cognitive functions. Indeed, elevated levels of KYNA in the brain or its chronic application
in higher doses are known to evoke cognitive impairment by inhibiting predominantly
the glutamatergic system, a phenomenon having been linked to the pathophysiology of AD [51]. Furthermore, prenatal exposure of high levels of KYNA has also been experimentally shown to be associated with sustained cognitive deficits, with implications to
schizophrenia [52,53]. Therefore, it is essential to identify the doses of KYNA and KYNArelated molecules to provide neuroprotection without any associated cognitive side effects.
In humans, KYNA is robustly synthesized in the endothelium and its serum levels
correlate with homocysteine, a risk factor for cognitive decline: recent studies have suggested that a selective hippocampal increase of the KYNA level may be an important factor contributing to KYNA-related cognitive impairment. Identifying the mechanisms by
which high KYNA levels in the hippocampal area may contribute to the deterioration of
cognition would provide insight that might be used to manage inflammation-associated
mental health disorders, including the discovery of new diagnostic and treatment therapies for depression: recently, several studies have suggested the effectiveness of non-invasive brain simulation (NIBS) to interfere and modulate the abnormal activity of neural
circuits including the amygdala-mPFC-hippocampus, involved in the acquisition and
consolidation of memories, which are altered in psychiatric disorders, such as fear-related
disorder including anxiety disorder, phobias, posttraumatic stress disorder, or depression
[54,55].
Our previous studies did not detect any behavior impairment of animals when they
were treated intraperitoneally (i.p.) with millimolar doses of KYNA or its analogues
[23,56]. The administration of KYNA and its analogues increased inducibility of long-term
potentiation (LTP) in the CA1 region in rats, indicating better hippocampal function [57].
However, few data are available on the effects of a low dose KYNA. It was reported that
KYNA has a dose-dependent dual action on AMPA receptors: the nanomolar and micromolar concentrations of KYNA could facilitate the responses of AMPA receptors via
modulating their desensitization, whereas the millimolar doses of this compound antagonized these receptors [58].
It was demonstrated that KYNA was able to reduce the amplitudes of the field excitatory postsynaptic potentials (EPSPs) in hippocampal slices of young rats at micromolar
concentrations, whereas the nanomolar concentrations evoked stimulation. Therefore,
KYNA as a 'Janus-faced' molecule may display different effects according to its concentration by acting on different receptors and through mechanisms [59]. A lower endogenous formation of KYNA induce positive effects in the cognition. Indeed, the role of the
kynurenine aminotransferase II (KAT II), an enzyme responsible for the endogenous
KYNA synthesis in the human brain, has been recently emphasized in the mechanisms of
memory; activities of KAT I and II showed age-dependent increase with an exception for
KAT II in the frontal cortex, which could be related to functional alterations in the PFC
reported in psychiatric and brain-damaged patients’ memory and learning abilities. Furthermore, recent studies revealed that naturally occurring bilateral lesions in the human
ventromedial PFC compromise the capacity of associative learning [60,61], suggesting that
PFC dysfunctions cause impairment of aversive learning and emotional memory circuits,
which might be transversal across many psychiatric disorders in humans. Pharmacological inhibition or genetic ablation of KAT II reduced KYNA levels in the brain and improved the performance in working/spatial memory and sustained attention tasks in different animal models [62-64]. The inhibition of KAT II, with a subsequent reduction of an
endogenous KYNA level restores normal cognitive function and thus, a manipulation of
KYNA levels may be a promising therapeutic target in cognitive impairment associated
with elevated concentrations of KYNA in the brain.
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