MTA SZTE Neuroscience Research Group

Szeged, Hungary

MTA SZTE Neuroscience Research Group

Szeged, Hungary
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Varga N.,University of Szeged | Csapo E.,University of Szeged | Majlath Z.,University of Szeged | Ilisz I.,University of Szeged | And 7 more authors.
European Journal of Pharmaceutical Sciences | Year: 2016

Core-shell nanoparticles (CSNPs) were developed to get over therapeutic amount of kynurenic acid (KYNA) across the blood-brain barrier (BBB). Bovine serum albumin (BSA) was used as core for encapsulation of KYNA and the BSA/KYNA composite was finally encapsulated by poly(allylamine) hydrochloride (PAH) polymer as shell. In the interest of the optimization of the synthesis the BSA and KYNA interaction was studied by two-dimensional surface plasmon resonance (SPR) technique as well. The average size of d ~ 100 nm was proven by dynamic light scattering (DLS) and transmission electron microscopy (TEM), while the structure of the composites was characterized by fluorescence (FL) and circular dichroism (CD) spectroscopy. The in vitro release properties of KYNA were investigated by a vertical diffusion cell at 25.0 °C and 37.5 °C and the kinetic of the release were discussed. The penetration capacity of the NPs into the central nervous system (CNS) was tested by an in vitro BBB model. The results demonstrated that the encapsulated KYNA had significantly higher permeability compared to free KYNA molecules. In the neurobiological serial of in vivo experiments the effects of peripherally administered KYNA with CSNPs were studied in comparison with untreated KYNA. These results clearly proved that KYNA in the CSNPs, administrated peripherally is suitable to cross the BBB and to induce electrophysiological effects within the CNS. As the neuroprotective properties of KYNA nowadays are proven, the importance of the results is obvious. © 2016 Elsevier B.V. All rights reserved.

Dezsi L.,University of Szeged | Horvath Z.,University of Szeged | Vecsei L.,University of Szeged | Vecsei L.,MTA SZTE Neuroscience Research Group
Expert Opinion on Drug Metabolism and Toxicology | Year: 2016

Introduction: Intravenous immunoglobulin (IVIg) is increasingly used for the treatment of autoimmune and systemic inflammatory diseases with both licensed and off-label indications. The mechanism of action is complex and not fully understood, involving the neutralization of pathological antibodies, Fc receptor blockade, complement inhibition, immunoregulation of dendritic cells, B cells and T cells and the modulation of apoptosis. Areas covered: First, this review describes the pharmacological properties of IVIg, including the composition, mechanism of action, and adverse events. The second part gives an overview of some of the immune-mediated polyneuropathies, with special focus on the pathomechanism and clinical trials assessing the efficacy of IVIg. A literature search on PubMed was performed using the terms IVIg, IVIg preparations, side effects, mechanism of action, clinical trials, GBS, CIDP. Expert opinion: Challenges associated with IVIg therapy and the treatment possibilities for immune-mediated polyneuropathies are discussed. The availability of IVIg is limited, the expenses are high, and, in several diseases, a chronic therapy is necessary to maintain the immunomodulatory effect. The better understanding of the mechanism of action of IVIg could open the possibility of the development of disease-specific, targeted immune therapies. © 2016 Informa UK Limited, trading as Taylor & Francis Group.

Tuboly G.,University of Szeged | Tar L.,University of Szeged | Bohar Z.,University of Szeged | Safrany-Fark A.,University of Szeged | And 6 more authors.
Brain Research Bulletin | Year: 2015

Kynurenic acid (KYNA) is a neuroactive metabolite that interacts with NMDA, AMPA/kainate and alpha 7 nicotinic receptors. The goal of this study was to clarify the roles of these receptors in the action of KYNA at a spinal level by using highly specific receptor antagonists alone or in triple combinations.Chronic osteoarthritis-like joint pain was induced with monosodium-iodoacetate in male Wistar rats. Mechanical allodynia and motor function were quantified. In the first series we determined the dose-response and time course effects of intrathecally administered KYNA (10-100. μg), d-(-)-2-amino-5-phosphonopentanoic acid (AP5; an NMDA receptor antagonist; 10-200. μg), methyllycaconitine (MLA; an alpha 7 nicotinic receptor antagonist; 100-200. μg) and 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzoquinoxaline-7-sulfonamide (NBQX; an AMPA/kainate receptor antagonist; 1-20. μg). In the second series, four different triple combinations of MLA, AP5 and NBQX were investigated.Intrathecal administration of KYNA caused a dose-dependent motor impairment and antinociception. The highly specific NMDA receptor antagonist AP5 caused a motor impairment and antinociception with lower potency. High doses of NBQX resulted in significant antinociception with a slight motor impairment, while only the highest dose of MLA gave rise to significant antinociception with a slight motor impairment. After the coadministration of these ligands as combinations, no potentiation was observed. It may be supposed that the effects of KYNA are primarily due to the inhibition of NMDA receptors at both glycine and phencyclidine (PCP) binding sites, and not to the interactions at the different ionotropic receptors, but the mechanisms behind its high bio-efficiency are still unknown. © 2015 Elsevier Inc.

Vecsei L.,Hungarian Academy of Sciences | Vecsei L.,University of Szeged | Vecsei L.,MTA SZTE Neuroscience Research Group | Majlath Z.,University of Szeged | And 3 more authors.
Expert Opinion on Drug Safety | Year: 2015

Introduction: Migraine is a frequent, disabling primary headache disorder, whose pathomechanism is not yet fully understood. Prophylactic treatment is advisable for migraineurs with severe or highly frequent attacks, which impair the quality of life.Areas covered: The different types of prophylactic migraine drugs are discussed, with particular regard to potential adverse effects and safety issues. β-Adrenergic blockers, antiepileptic drugs and calcium-channel blockers are drugs widely used for migraine prevention, whereas complementary medicine and onabotulinumtoxin A can be used in selected cases.Expert opinion: The background of the recurrence and chronification of migraine attacks has not been fully clarified, and causative preventive therapy is therefore not currently available. The tolerability and adverse effects of the currently used medications often limit their use. β-Adrenergic receptor blockers may induce adverse cardiovascular events, whereas flunarizine is frequently associated with a weight gain and depression. As most migraine sufferers are young women of child-bearing age, the use of valproate is limited. Topiramate is associated with central nervous system-related side effects. There is a need for future development of pathomechanism-based preventive drugs, and personalized therapy tailored to the patient. © 2015 Informa UK, Ltd.

Dezsi L.,University of Szeged | Tuka B.,MTA SZTE Neuroscience Research Group | Martos D.,University of Szeged | Vecsei L.,University of Szeged | Vecsei L.,MTA SZTE Neuroscience Research Group
Current Alzheimer Research | Year: 2015

Alzheimer’s disease (AD) is an age-related neurodegenerative disease and the most common cause of dementia. The etiology of AD is not entirely clear and despite the increasing knowledge regarding the pathomechanism, no effective disease-modifying therapy is yet available. Astrocytes earlier presumed to serve merely supportive roles for the neuronal network, have recently been shown to play an active role in the synaptic dysfunction, impairment of homeostasis, inflammation as well as excitotoxicity in relation to AD pathology. This review focuses on the pathomechanism of AD with special attention to the role of the astrocytes, excitotoxicity and the alterations in the kynurenine metabolism in the development of the disease. The correction of the neuroprotective/neurotoxic imbalance in the kynurenine pathway may represent a novel target for pharmaceutical interventions in dementia related to neurodegenerative disorders. © 2015 Bentham Science Publishers.

Dezsi L.,University of Szeged | Vecsei L.,University of Szeged | Vecsei L.,MTA SZTE Neuroscience Research Group
Expert Opinion on Investigational Drugs | Year: 2014

Introduction: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. Non-dopaminergic neurotransmitter systems are also involved in its pathomechanism. The aim of the treatment is to improve the dopamine-deficient state and to alleviate the motor and the non-motor symptoms. Safinamide is an α-aminoamide derivative with a combined, dopaminergic and non-dopaminergic mode of action. Phase III clinical trials with safinamide, as add-on therapy to a dopamine agonist (DAA) and to levodopa (LD) in early and advanced stage PD, respectively, demonstrated an improvement of the motor symptoms. Areas covered: The review discusses the pharmacokinetic and pharmacodynamic properties of safinamide and provides an overview of the clinical trials conducted with safinamide in PD. A literature search was made in PubMed for safinamide, safinamide pharmacokinetics, PD treatment and monoamine oxidase-B inhibitors, and in PubMed and on the site for clinical trials with safinamide in PD. Expert opinion: The place of safinamide in the therapy of PD is yet to be determined. However, the authors believe that safinamide is a valuable drug in the treatment of PD treatment with favorable pharmacokinetic and side-effect profiles. Data so far suggest that it can be used beneficially as add-on therapy both to DAAs in early PD and to LD in the later stages of the disease. © 2014 Informa UK, Ltd.

Torok R.,University of Szeged | Zadori D.,University of Szeged | Torok N.,University of Szeged | Csility E.,University of Szeged | And 3 more authors.
Neuroscience Letters | Year: 2016

Parkinson's disease (PD) is the second most common neurodegenerative disorder, with cases of either familial or sporadic origin. Several polymorphisms in a number of genes have been proved to have an important role in the development of PD. Particular attention has recently been paid to genes of the glucocerebrosidase (GBA) and the vacuolar protein sorting-associated protein 35 (VPS35).In this study, the three most common mutations (L444P, N370S and R120W) of the GBA gene and the D620N mutation of the VPS35 gene were examined in 124 Hungarian patients diagnosed with sporadic PD (SPD) and 122 control subjects.The frequency of the L444P mutation of the GBA gene proved to be higher in the PD patients (2.4%) than in the controls (0%), although the difference was not statistically significant. All the patients who carried the mutant allele were in the early-onset PD (EOPD) group. However, neither the R120W nor the N370S variant of the GBA gene nor D620N mutation of the VPS35 gene were detected among the PD cases or the controls.Even though these results suggest that the studied mutations are quite rare in SPD patients, the most frequent L444P mutation of the GBA gene may be associated with the development of EOPD in the Hungarian population. © 2015 Elsevier Ireland Ltd.

Majlath Z.,University of Szeged | Torok N.,University of Szeged | Toldi J.,MTA SZTE Neuroscience Research Group | Toldi J.,University of Szeged | And 2 more authors.
Current Neuropharmacology | Year: 2016

Glutamatergic neurotransmission, of special importance in the human brain, is implicated in key brain functions such as synaptic plasticity and memory. The excessive activation of N-methyl-D-aspartate (NMDA) receptors may result in excitotoxic neuronal damage; this process has been implicated in the pathomechanism of different neurodegenerative disorders, such as Alzheimer’s disease (AD). Memantine is an uncompetitive antagonist of NMDA receptors with a favorable pharmacokinetic profile, and is therefore clinically well tolerated. Memantine is approved for the treatment of AD, but may additionally be beneficial for other dementia forms and pain conditions. Kynurenic acid (KYNA) is an endogenous antagonist of NMDA receptors which has been demonstrated under experimental conditions to be neuroprotective. The development of a well-tolerated NMDA antagonist may offer a novel therapeutic option for the treatment of neurodegenerative disease and pain syndromes. KYNA may be a valuable candidate for future drug development. © 2016, Bentham Science Publishers.

Tajti J.,University of Szeged | Tuka B.,MTA SZTE Neuroscience Research Group | Botz B.,University of Pécs | Helyes Z.,University of Pécs | And 3 more authors.
CNS and Neurological Disorders - Drug Targets | Year: 2015

Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors are widely distributed at different levels of the pain-processing pathway. Its action at the peripheral sensory nerve terminals has been found to be divergent; it can exert both pro- and anti-nociceptive effects, depending on the mode of administration (local or systemic) and the mechanism of the pain process (acute or chronic, inflammatory or neuropathic). In the central nervous system it exerts mainly neuronal excitation, leading to increased nociceptive signalling. Since the clinical data strongly suggest the involvement of PACAP in the pathophysiology of migraine, special emphasis is placed on examinations of its role and the mechanisms of activation of the trigeminovascular system. The intravenous administration of PACAP to migraineurs induces migraine-like headache and extracranial arterial dilatation. Furthermore, an increased PACAP concentration has been detected in the peripheral blood of patients during a migraine attack. Animal experiments have also revealed that PACAP elicits peripheral and central sensitization of the neuronal elements of the trigeminovascular system and evokes meningeal vasodilatation. This review summarizes data relating to the expression of PACAP and its receptors, and the main effects and mechanisms in the nociceptive pathways, with special emphasis on migraine. It is clear that PACAP plays an excitatory role in migraine, but its target and signalling pathways have not yet been elucidated due to the lack of non-peptide, selective agonists and antagonists. Identification of its up- and downstream regulations and receptorial molecular mechanisms might open up future perspectives for the development of novel analgesic drugs. © 2015 Bentham Science Publishers.

PubMed | MTA SZTE Neuroscience Research Group, University of Szeged and Semmelweis University
Type: | Journal: Brain topography | Year: 2016

The pathomechanism of cluster headache (CH) is not entirely understood, but central and peripheral components were suggested. A recent report showed that transcranial magnetic stimulation measured cortical excitability was increased in the hemisphere ipsilalteral to the pain. In the current study we set out to investigate the amplitude of resting brain fMRI activity to find signatures of the increased excitability. High resolution T1 weighted and resting state functional MRI images were acquired from seventeen patients with CH in pain free period and from twenty-six healthy volunteers. Patients data were normalized (e.g. inverted along the midsagittal axis) according to the headache side. Independent component analysis and a modified dual regression approach were used to reveal the differences between the resting state networks. Furthermore, the timecourses were decomposed into five frequency bands by discrete wavelet decomposition and were also re-regressed to the original data to reveal frequency specific resting activity maps. Two of the identified resting state networks showed alterations in CH. When the data were inverted to have patients headaches on the left, the ipsilateral attention network showed increased connectivity in 0.08-0.04Hz frequency band in the in CH group. In the same dataset, cerebellar network showed higher functional connectivity in 0.02-0.01Hz range in the ipsilateral cerebellum. When the data of patients having headache on the left were inverted to the right, similar increased signal was found in the ipsilateral attention network in 0.08-0.04Hz band. The cerebellar network showed increased connectivity in the cerebellum in 0.02-0.01Hz band in patients. The Fourier analysis of these area revealed increased power in CH at all cases. Our results showed alterations of brain functional networks in CH. The alterations of resting state activity were found in the hemisphere ipsilateral to the pain, signifying the altered cortical processing in the pathomechanism of CH.

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