Worldwide, 50 million people suffer from dementia, a group of symptoms affecting cognitive and social functions, progressing severely enough to interfere with daily life. Alzheimer’s disease (AD) accounts for most of the dementia cases. Pathological and clinical findings have led to proposing several hypotheses of AD pathogenesis, finding a presence of positive feedback loops and additionally observing the disturbance of a branch of tryptophan metabolism, the kynurenine (KYN) pathway. Either causative or resultant of dementia, elevated levels of neurotoxic KYN metabolites are observed, potentially upregulating multiple feedback loops of AD pathogenesis. Memantine is an N-methyl-D-aspartate glutamatergic receptor (NMDAR) antagonist, which belongs to one of only two classes of medications approved for clinical use, but other NMDAR modulators have been explored so far in vain. An endogenous KYN pathway metabolite, kynurenic acid (KYNA), likewise inhibits the excitotoxic NMDAR. Besides its anti-excitotoxicity, KYNA is a multitarget compound that triggers anti-inflammatory and antioxidant activities. Modifying the KYNA level is a potential multitarget strategy to normalize the disturbed KYN pathway and thus to alleviate juxtaposing AD pathogeneses. In this review, the maintenance of KYN metabolism by modifying the level of KYNA is proposed and discussed in search for a novel lead compound against the progression of dementia.

/pdf/are-kynurenines-accomplices-or-principal-villains-in-3nmsvdzx70.pdf

Are Kynurenines Accomplices or Principal Villains in Dementia? Maintenance of Kynurenine Metabolism.

The kynurenine pathway is the main pathway of tryptophan metabolism. L-kynurenine is a central compound of this pathway since it can change to the neuroprotective agent kynurenic acid or to the neurotoxic agent quinolinic acid. The break-up of these endogenous compounds’ balance can be observable in many disorders. It can be occur in neurodegenerative disorders, such as Parkinson’s disease, Huntington’s and Alzheimer’s disease, in stroke, in epilepsy, in multiple sclerosis, in amyotrophic lateral sclerosis, and in mental failures, such as schizophrenia and depression. The increase of QUIN concentration or decrease of KYNA concentration could enhance the symptoms of several diseases. According to numerous studies, lowered KYNA level was found in patients with Parkinson’s disease. It can be also noticeable that KYNA-treatment prevents against the QUIN-induced lesion of rat striatum in animal experiments. Administrating of KYNA can be appear a promising therapeutic approach, but its use is limited because of its poorly transport across the blood-brain barrier. The solution may be the development of KYNA analogues (e.g. glucoseamine-kynurenic acid) which can pass across this barrier and disengaging in the brain, then KYNA can exert its neuroprotective effects binding at the excitatory glutamate receptors, in particular the NMDA receptors. Furthermore, it seems hopeful to use kynurenine derivatives (e.g. 4-chloro-kynurenine) or enzyme inhibitors (e.g. Ro-61-8048) to ensure an increased kynurenic acid concentration in the central nervous system.

Kynurenines, Parkinson's disease and other neurodegenerative disorders: preclinical and clinical studies.

Neuroprotective effect of L-kynurenine sulfate administered before focal cerebral ischemia in mice and global cerebral ischemia in gerbils

Context: Temporal lobe epilepsy (TLE) is an intractable neurological disorder. Curcumin is the bioactive component of turmeric with anti-epileptic and neuroprotective potential.Objective: The beneficial effect of curcumin on the intrahippocampal kainate-induced model of TLE was investigated.Materials and methods: Rats were divided into sham, curcumin-pretreated sham, kainate and curcumin-pretreated kainate groups. The rat model of TLE was induced by unilateral intrahippocampal injection of 4 μg of kainate. Rats received curcumin p.o. at a dose of 100 mg/kg/d starting 1 week before the surgery. Seizure activity (SE) and oxidative stress-related markers were measured. Furthermore, the Timm index for evaluation of mossy fiber sprouting (MFS) and number of Nissl-stained neurons were quantified.Results: All rats in the kainate group had SE, while 28.5% of rats showed seizures in the curcumin-pretreated kainate group. Malondialdehyde and nitrite and nitrate levels significantly increased in the kainate ...

https://www.tandfonline.com/doi/pdf/10.3109/13880209.2013.803128

Antiepileptogenic effect of curcumin on kainate-induced model of temporal lobe epilepsy.

Aims

Synaptic vesicle proteins 2 (SV2) are neuronal vesicles membrane glycoproteins that appear as important targets in the treatment of partial and generalized epilepsies. Therefore, we analysed the expression of SV2 isoforms in the hippocampus of patients with temporal lobe epilepsy (TLE).



Methods

SV2A, SV2B and SV2C immunostaining and QuantiGene branched DNA assay were performed on biopsies from 31 consecutive TLE patients with mesial temporal sclerosis (MTS) and compared with 10 autopsy controls. SV2 expression was further compared with Timm's staining, and synaptophysin, Zinc transporter 3 (ZnT3), dynorphin, vesicular glutamate transporter 1 (VGLUT1) and vesicular GABA transporter (VGAT) expression.



Results

In TLE patients, SV2A and SV2B expression was decreased in areas of synaptic loss. SV2C, which is weakly expressed or absent in the hippocampus of controls, was overexpressed in 10/11 cases with classical MTS1A and mossy fibre sprouting but not in cases with other types of MTS. SV2C staining was located in the inner molecular layer of the dentate gyrus and colocalized with dynorphin, ZnT3 and VGLUT1, suggesting selective expression in presynaptic glutamatergic Zn2+-rich terminals of abnormal sprouting fibres. SV2 expression patterns correlated with histological subtypes of MTS, but not with clinical features or therapeutic regimens in this patient cohort.



Conclusion

In classical MTS1A, the expression of SV2 isoforms is altered with a marked decrease of SV2A and SV2B paralleling synaptic loss and a selective increase of SV2C in sprouting mossy fibres. These findings suggest a different physiology of sprouting synapses and the possibility to target them with SV2C-specific strategies.

Expression pattern of synaptic vesicle protein 2 (SV2) isoforms in patients with temporal lobe epilepsy and hippocampal sclerosis

Kynurenic acid (KYNA) is the only known endogenous N-methyl-d-aspartate (NMDA) receptor inhibitor and might therefore come into consideration as a therapeutic agent in certain neurobiological disorders. However, its use as a neuroprotective compound is practically excluded because KYNA does not readily cross the blood-brain barrier (BBB). We recently synthetized a new compound, glucosamine–kynurenic acid (KYNA-NH-GLUC), which is presumed to cross the BBB more easily. In this study, the effects of KYNA and KYNA-NH-GLUC on behavior and cortical activity were investigated in adult rats. The results show that (1) on intracerebroventricular application, the behavioral changes induced by KYNA and by KYNA-NH-GLUC are quite similar; (2) on intravenous administration, KYNA (25 mg/kg) has no effect on the somatosensory-evoked cortical potentials, whereas KYNA-NH-GLUC (25 mg/kg) causes transient but appreciable reductions in the amplitudes of the evoked responses within 5 min after application; and (3) the results of in vitro studies demonstrated that both KYNA and KYNA-NH-GLUC reduced the amplitudes of the field excitatory postsynaptic potentials (fEPSPs). These observations suggest that the two compounds have similar effects, but that KYNA-NH-GLUC passes the BBB much more readily than does KYNA. These results imply that the conjugated NH-GLUC is of importance in the passage across the BBB.

Comparative study on the effects of kynurenic acid and glucosamine–kynurenic acid

http://anatomy.szote.u-szeged.hu/neuroplast/cikk/actahistochem.pdf

Comparative immunohistochemistry of synaptic markers in the rodent hippocampus in pilocarpine epilepsy

Treatment with pilocarpine (PILO) induces variable degrees of loss of mossy cells (MCs) and mossy fibre (MF) sprouting in rodents, the relationships of which have not been examined in individual animals. Our aim was to test whether the loss of MCs and MF sprouting are coupled processes in PILO-treated rodents. Animals which exhibited intense PILO-induced convulsions for at least 30 min were used in this study. After a 2-month survival period, the incidence of epileptic seizures was checked individually by neuropeptide-Y (NPY) immunohistochemistry, and the numbers of MCs were counted by means of immunohistochemistry, for calretinin (CR) in mice and calcitonin gene-related peptide (CGRP) in rats. MF sprouting was checked by using Timm's silver-sulphide method for zinc. In our comparative studies, NPY immunohistochemistry resulted in more positive animals than on zinc staining. The CR immunoreactivity remained unchanged even in those mice that displayed MF sprouting and greatly increased NPY immunoreactivity. CR immunoreactivity was also verified after transection of the fornix to exclude the extrahippocampal source of this peptide. However, the CGRP immunoreactivity was severely reduced in those rats that exhibited simultaneous increases in zinc content and NPY immunoreactivity in the supragranular layer and stratum lucidum. Our findings suggest that the MCs survive PILO treatment in mice, but not in rats. There is direct evidence of a close relationship between the loss of MCs and MF sprouting in rats, but not in mice. Thus, similar PILO seizures may result from different changes in the neuronal circuits of rodents.

Comparative immunohistochemical study of the effects of pilocarpine on the mossy cells, mossy fibres and inhibitory neurones in murine dentate gyrus.

Interstrain differences of ionotropic glutamate receptor subunits in the hippocampus and induction of hippocampal sclerosis with pilocarpine in mice.

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Comparative study on the effects of kynurenic acid and glucosamine–kynurenic acid

Comparative immunohistochemistry of synaptic markers in the rodent hippocampus in pilocarpine epilepsy

Comparative immunohistochemical study of the effects of pilocarpine on the mossy cells, mossy fibres and inhibitory neurones in murine dentate gyrus.

Interstrain differences of ionotropic glutamate receptor subunits in the hippocampus and induction of hippocampal sclerosis with pilocarpine in mice.