MTA SZTE Neuroscience Research Group

Szeged, Hungary

MTA SZTE Neuroscience Research Group

Szeged, Hungary

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Kocsis K.,University of Szeged | Kocsis K.,MTA SZTE Neuroscience Research Group | Knapp L.,University of Szeged | Gellert L.,University of Szeged | And 9 more authors.
Neuroscience | Year: 2014

As a consequence of an ischemic episode, energy production is disturbed, leading to neuronal cell death. Despite intensive research, the quest for promising neuroprotective drugs has largely failed, not only because of ineffectiveness, but also because of serious side-effects and dosing difficulties. Acetyl- l-carnitine (ALC) is an essential nutrient which plays a key role in energy metabolism by transporting fatty acids into mitochondria for β-oxidation. It is an endogenous compound and can be used at high dose without toxicity in research into ischemia. Its neuroprotective properties have been reported in many studies, but its potential action on long-term potentiation (LTP) and dendritic spine density has not been described to date. The aim of the present study was an evaluation of the possible protective effect of ALC after ischemic insults inflicted on hippocampal synaptic plasticity in a 2-vessel occlusion (2VO) model in rats. For electrophysiological measurements, LTP was tested on hippocampal slices. The Golgi-Cox staining technique was used to determine spine density. 2VO resulted in a decreased, unstable LTP and a significant loss of dendritic spines. ALC administered after 2VO was not protective, but as pretreatment prior to 2VO it restored LTP nearly to the control level. This finding paralleled the histological analysis: ALC pretreatment resulted in the reappearance of dendritic spines on the CA1 pyramidal cells. Our data demonstrate that ALC administration can restore hippocampal function and spine density. ALC probably acts by enhancing the aerobic metabolic pathway, which is inhibited during and following ischemic attacks. © 2014 IBRO.

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.

Rajda C.,University of Szeged | Majlath Z.,University of Szeged | Pukoli D.,University of Szeged | Pukoli D.,Markhot Ferenc County Hospital | And 2 more authors.
International Journal of Molecular Sciences | Year: 2015

Multiple sclerosis is an inflammatory disease of the central nervous system, in which axonal transection takes place in parallel with acute inflammation to various, individual extents. The importance of the kynurenine pathway in the physiological functions and pathological processes of the nervous system has been extensively investigated, but it has additionally been implicated as having a regulatory function in the immune system. Alterations in the kynurenine pathway have been described in both preclinical and clinical investigations of multiple sclerosis. These observations led to the identification of potential therapeutic targets in multiple sclerosis, such as synthetic tryptophan analogs, endogenous tryptophan metabolites (e.g., cinnabarinic acid), structural analogs (laquinimod, teriflunomid, leflunomid and tranilast), indoleamine-2,3-dioxygenase inhibitors (1MT and berberine) and kynurenine-3-monooxygenase inhibitors (nicotinylalanine and Ro 61-8048). The kynurenine pathway is a promising novel target via which to influence the immune system and to achieve neuroprotection, and further research is therefore needed with the aim of developing novel drugs for the treatment of multiple sclerosis and other autoimmune diseases. © 2015 by the authors; licensee MDPI, Basel, Switzerland.

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.

Torok R.,University of Szeged | Konya J.A.,University of Szeged | Zadori D.,University of Szeged | Veres G.,University of Szeged | And 4 more authors.
Cellular and Molecular Neurobiology | Year: 2015

Peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator-1 alpha (PGC-1α) is involved in the regulation of mitochondrial biogenesis, respiration, and adaptive thermogenesis. The full-length PGC-1α (FL-PGC-1α) comprises multiple functional domains interacting with several transcriptional regulatory factors such as nuclear respiratory factors, estrogen-related receptors, and PPARs; however, a number of PGC-1α splice variants have also been reported recently. In this study, we examined the expression levels of FL-PGC-1α and N-truncated PGC-1α (NT-PGC-1α), a shorter but functionally active splice variant of PGC-1α protein, in N171-82Q transgenic and 3-nitropropionic acid-induced murine model of Huntington’s disease (HD). The expression levels were determined by RT-PCR in three brain areas (striatum, cortex, and cerebellum) in three age groups (8, 12, and 16 weeks). Besides recapitulating prior findings that NT-PGC-1α is preferentially increased in 16 weeks of age in transgenic HD animals, we detected age-dependent alterations in both models, including a cerebellum-predominant upregulation of both PGC-1α variants in transgenic mice, and a striatum-predominant upregulation of both PGC-1α variants after acute 3-nitropropionic acid intoxication. The possible relevance of this expression pattern is discussed. Based on our results, we assume that increased expression of PGC-1α may serve as a compensatory mechanism in response to mitochondrial damage in transgenic and toxin models of HD, which may be of therapeutic relevance. © 2014, Springer Science+Business Media New York.

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