Background
Migraine is a debilitating neurological disorder where trigeminovascular activation plays a key role. We have previously reported that local application of Complete Freund’s Adjuvant (CFA) ...onto the dura mater caused activation in rat trigeminal ganglion (TG) which was abolished by a systemic administration of kynurenic acid (KYNA) derivate (SZR72). Here, we hypothesize that this activation may extend to the trigeminal complex in the brainstem and is attenuated by treatment with SZR72.
Methods
Activation in the trigeminal nucleus caudalis (TNC) and the trigeminal tract (Sp5) was achieved by application of CFA onto the dural parietal surface. SZR72 was given intraperitoneally (i.p.), one dose prior CFA deposition and repeatedly daily for 7 days. Immunohistochemical studies were performed for mapping glutamate, c-fos, PACAP, substance P, IL-6, IL-1β and TNFα in the TNC/Sp5 and other regions of the brainstem and at the C
1
-C
2
regions of the spinal cord.
Results
We found that CFA increased c-fos and glutamate immunoreactivity in TNC and C
1
-C
2
neurons. This effect was mitigated by SZR72. PACAP positive fibers were detected in the fasciculus cuneatus and gracilis. Substance P, TNFα, IL-6 and IL-1β immunopositivity were detected in fibers of Sp5 and neither of these molecules showed any change in immunoreactivity following CFA administration.
Conclusion
This is the first study demonstrating that dural application of CFA increases the expression of c-fos and glutamate in TNC neurons. Treatment with the KYNA analogue prevented this expression.
Background
Neurogenic inflammation has for decades been considered an important part of migraine pathophysiology. In the present study, we asked the question if administration of a novel kynurenic ...acid analogue (SZR72), precursor of an excitotoxin antagonist and anti-inflammatory substance, can modify the neurogenic inflammatory response in the trigeminal ganglion.
Methods
Inflammation in the trigeminal ganglion was induced by local dural application of Complete Freunds Adjuvant (CFA). Levels of phosphorylated MAP kinase pERK1/2 and IL-1β expression in V1 region of the trigeminal ganglion were investigated using immunohistochemistry and Western blot.
Findings
Pretreatment with one dose of SZR72 abolished the CFA-induced pERK1/2 and IL-1β activation in the trigeminal ganglion. No significant change was noted in case of repeated treatment with SZR72 as compared to a single dose.
Conclusions
This is the first study that demonstrates that one dose of KYNA analog before application of CFA can give anti-inflammatory response in a model of trigeminal activation, opening a new line for further investigations regarding possible effects of KYNA derivates.
During an ischemic event, the well-regulated glutamate (Glu) homeostasis is disturbed, which gives rise to extremely high levels of this excitatory neurotransmitter in the brain tissues. It was ...earlier reported that the administration of oxaloacetate (OxAc) as a Glu scavenger reduces the Glu level in the brain by enhancing the brain-to-blood Glu efflux. Here, we studied the neuroprotective effect of OxAc administration in a new focal ischemic model in rats. Occlusion of the middle cerebral artery resulted in immediate reduction of the somatosensory-evoked responses (SERs), and the amplitudes remained at the reduced level throughout the whole ischemic period. On reperfusion, the SERs started to increase, but never reached the control level. OxAc proved to be protective, since the amplitudes started to recover even during the ischemia, and finally fully regained the control level. The findings of the histological measurements were in accordance with the electrophysiological data. After Fluoro Jade C staining, significantly fewer labeled cells were detected in the OxAc-treated group relative to the control. These results provide new evidence of the neuroprotective effect of OxAc against ischemic injury, which strengthens the likelihood of its future applicability as a novel neuroprotective agent for the treatment of ischemic stroke patients.
Neurodegenerative disorders, e.g. Parkinson's, Huntington's and Alzheimer's diseases are distinct clinical and pathological entities sharing a number of leading features in their underlying ...processes. These common features involve the disturbances in the normal functioning of the mitochondria and the alterations in the delicate balance of tryptophan metabolism. The development of agents capable of halting the progression of these diseases is in the limelight of neuroscience research. This review highlights the role of mitochondria in the development of neurodegenerative processes with special focus on the involvement of neuroactive kynurenines both as pathological agents and potential targets and tools for future therapeutic approaches by providing a comprehensive summary of the main streams of rational drug design and giving an insight into present clinical achievements.
Background and purpose
The goal of this study was to determine the prevalence and incidence of neuromyelitis optica spectrum disorder (NMOSD) in Hungary based on the 2015 International Panel of NMO ...Diagnosis (IPND) criteria.
Methods
A retrospective population‐based cohort study was conducted of 6.4 million Hungarians (age ≥ 16 years) between 1 January 2006 and 31 December 2016. Possible NMOSD patients were selected via multistage re‐evaluation from multiple sources. Crude and sex‐ and serostatus‐specific prevalence (per 100 000 persons) and incidence rates (per 1 000 000 person‐years) from 2006 to 2015 were estimated and age‐adjusted rates were determined.
Results
Of 2262 study candidates, 154 NMOSD patients (age ≥ 16 years) with onset until 31 December 2016 were identified based on 2015 IPND criteria. The prevalence analysis on 1 January 2016 included 123 NMOSD living cases, resulting in a prevalence of 1.91 95% confidence interval (CI) 1.52–2.28 per 100 000 persons. The 101 incident cases emerging from the observed 76 394 288 person‐years provided an incidence rate of 1.32 (95% CI 1.08–1.61) per 1 000 000 person‐years. Age‐adjusted prevalence was 1.87 (95% CI 1.56–2.23) per 100 000 persons and incidence was 1.20 (95% CI 0.98–1.46) per 1 000 000 person‐years.
Conclusions
In this first report of a large population‐based epidemiological study from an Eastern European Caucasian population using robust case validation, a greater prevalence and incidence of NMOSD was found compared to previous large studies in Caucasian populations.
Background
Amyotrophic lateral sclerosis (ALS) patients manifest aberrations in the vitamin D endocrine system, with a vitamin D deficiency. Genetic investigations have identified those proteins ...which link vitamin D to ALS pathology: major histocompatibility complex class II molecules, toll‐like receptors, poly(ADP ribose) polymerase‐1, haeme oxygenase‐1, the reduced form of nicotinamide adenine dinucleotide phosphate and calcium‐binding proteins. Vitamin D additionally impacts ALS through cell‐signalling mechanisms: glutamate, matrix metalloproteinases, the Wnt/β‐catenin signalling pathway, mitogen‐activated protein kinase pathways, prostaglandins, reactive oxygen species and nitric oxide synthase, but its role has been only poorly investigated.
Objective
Our aim was to investigate vitamin D receptor (VDR) gene single nucleotide polymorphisms (SNPs) in an ALS population. This gene encodes the nuclear hormone receptor for vitamin D3.
Materials and Methods
A total of 75 consecutive sporadic ALS patients (~20% of the Hungarian ALS population) and 97 healthy controls were enrolled to investigate the possible effects of the different VDR alleles. A restriction fragment length polymorphism technique was utilized for allele discrimination.
Results
One of the four investigated SNPs was associated with the disease, but none of the alleles of these SNPs influenced the age at disease onset. The ApaI A allele was more frequent in the ALS group than in the control group and may be an ALS risk factor.
Conclusions
This is the first verification of the genetic link between ALS and VDR. However, further studies are needed to confirm these findings.
Parkinson’s, Alzheimer’s and Huntington’s diseases are chronic neurodegenerative disorders of a progressive nature which lead to a considerable deterioration of the quality of life. Their ...pathomechanisms display some common features, including an imbalance of the tryptophan metabolism. Alterations in the concentrations of neuroactive kynurenines can be accompanied by devastating excitotoxic injuries and metabolic disturbances. From therapeutic considerations, possibilities that come into account include increasing the neuroprotective effect of kynurenic acid, or decreasing the levels of neurotoxic 3-hydroxy-
l
-kynurenine and quinolinic acid. The experimental data indicate that neuroprotection can be achieved by both alternatives, suggesting opportunities for further drug development in this field.
Highlights • We confirmed the changes in cortical activity in a new model of focal ischemia with EEG recordings. • We characterized the neural and glial responses after brief focal ischemia. • We ...tested the neuroprotective potential of systemically administered L-kynurenine sulfate. • We postulated that L-kynurenine sulfate treatment after brief focal ischemia may be harmful.
This paper reports the synthesis of 10 new KYNA amides (KYNA-1–KYNA10) and on the effectiveness of this molecule as an inhibitor of excitatory synaptic transmission in the CA1 region of the ...hippocampus. The most effected molecule is newly synthetized KYNA-analogue (KYNA-1).
The overactivation of excitatory amino acid receptors plays a key role in the pathomechanism of several neurodegenerative disorders and in ischemic and post-ischemic events. Kynurenic acid (KYNA) is an endogenous product of the tryptophan metabolism and, as a broad-spectrum antagonist of excitatory amino acid receptors, may serve as a protective agent in neurological disorders. The use of KYNA is excluded, however, because it hardly crosses the blood–brain barrier. Accordingly, new KYNA analogs which can readily cross this barrier and exert their complex anti-excitatory activity are generally needed. During the past 6years, we have developed several KYNA derivatives, among others KYNA amides. These new analogs included one, N-(2-N,N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride (KYNA-1), that has proved to be neuroprotective in several models.
This paper reports on the synthesis of 10 new KYNA amides (KYNA-1–KYNA-10) and on the effectiveness of these molecules as inhibitors of excitatory synaptic transmission in the CA1 region of the hippocampus. The molecular structure and functional effects of KYNA-1 are compared with those of other KYNA amides. Behavioral studies with these KYNA amides demonstrated that they do not exert significant nonspecific general side-effects. KYNA-1 may therefore be considered a promising candidate for clinical studies.
Introduction: Little is known about neurological training curricula in Europe. A joint approach by the European Federation of Neurological Societies (EFNS), the Union of European Medical ...Specialists/European Board of Neurology and the European Association of Young Neurologist and Trainees was established to explore the spectrum of neurology training in Europe.
Methods: In 2006, a questionnaire‐based survey on neurology curricula as well as demographic data was designed by WS and WG and distributed by the EFNS to the national delegates of the EFNS, which comprises all European countries and Israel.
Results: By 2009, delegates from 31 of 41 countries (representing 76% of 505 million) had returned the questionnaire. A total of 24 165 specialists (46% women) were registered in the 31 countries. This corresponds to an average of 6.6 neurologists per 100 000 inhabitants (range 0.9–17.4/100 000 inhabitants). Duration of training in Europe was on average 4.9 years, ranging from 3 to 6 years. The number of residents interested in neurological training exceeded the amount of available training positions. Performance of neurological trainees was regularly assessed in 26 countries (84%), usually by recurrent clinical evaluation. Board examinations were held in 23 countries (74%). Interim examinations were performed in three countries, exit examinations in 14 and both interim and exit examination in 6. Considerable differences were also found in manpower (0.9–17.4 neurologists/100 000 inhabitants) and working conditions (e.g. average weekly working hours ranging from 30–80 h/month). We found a significant positive correlation between manpower and theoretical training hours.
Conclusion: Considerable differences exist in training curricula of European countries. These data might provide the basis for European training and quality assurance initiatives.
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