Neuropsychopharmacologia Hungarica : a Magyar Pszichofarmakologiai Egyesulet lapja = official journal of the Hungarian Association of Psychopharmacology, 2012
Depression can originate from changes in tryptophan availability, caused by activation of the kyn... more Depression can originate from changes in tryptophan availability, caused by activation of the kynurenine pathway (KP) as a result of inflammation. Alterations in the KP and the changing levels of its metabolites have recently been considered to be factors contributing to the pathogenesis of depression. The key molecular mediator which induces the conversion of tryptophan into kynurenine is indoleamine-2,3-dioxygenase. Following its activation, both the production of neurotoxic compounds and the diminished peripheral accessibility of tryptophan are regarded as essential steps in the pathophysiological processes. The aim of this review is to survey the role of the KP in depression and its relationships with cognitive functions.
Neuropsychopharmacologia Hungarica a Magyar Pszichofarmakologiai Egyesulet Lapja Official Journal of the Hungarian Association of Psychopharmacology, Dec 1, 2012
Depression can originate from changes in tryptophan availability, caused by activation of the kyn... more Depression can originate from changes in tryptophan availability, caused by activation of the kynurenine pathway (KP) as a result of inflammation. Alterations in the KP and the changing levels of its metabolites have recently been considered to be factors contributing to the pathogenesis of depression. The key molecular mediator which induces the conversion of tryptophan into kynurenine is indoleamine-2,3-dioxygenase. Following its activation, both the production of neurotoxic compounds and the diminished peripheral accessibility of tryptophan are regarded as essential steps in the pathophysiological processes. The aim of this review is to survey the role of the KP in depression and its relationships with cognitive functions.
Vitamin D receptor (VDR) gene encodes a transcription factor that influences calcium homeostasis ... more Vitamin D receptor (VDR) gene encodes a transcription factor that influences calcium homeostasis and immunoregulation, and may play a role in neurological disorders including Parkinson's disease (PD). The investigations of the association between VDR and PD in different populations revealed various results. In a present study 100 PD patients and 109 healthy controls from the Hungarian population were genotyped for four polymorphic sites (BsmI, ApaI, FokI and TaqI) in the VDR gene. The polymorphisms were determined by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Our results demonstrate an association between the FokI C allele and PD; the frequency of the C allele was significantly higher in PD patients than in controls, suggesting that this polymorphism may have a role in the development of PD in these patients.
Neuropsychopharmacologia Hungarica : a Magyar Pszichofarmakológiai Egyesület lapja = official journal of the Hungarian Association of Psychopharmacology, 2012
Depression can originate from changes in tryptophan availability, caused by activation of the kyn... more Depression can originate from changes in tryptophan availability, caused by activation of the kynurenine pathway (KP) as a result of inflammation. Alterations in the KP and the changing levels of its metabolites have recently been considered to be factors contributing to the pathogenesis of depression. The key molecular mediator which induces the conversion of tryptophan into kynurenine is indoleamine-2,3-dioxygenase. Following its activation, both the production of neurotoxic compounds and the diminished peripheral accessibility of tryptophan are regarded as essential steps in the pathophysiological processes. The aim of this review is to survey the role of the KP in depression and its relationships with cognitive functions.
Background and purpose of our study was to develop a precise dose delivery technique for partial ... more Background and purpose of our study was to develop a precise dose delivery technique for partial brain irradiation of two rats simultaneously. Using a self-developed frame stereotactic radiotherapy with single doses of 30-90 Gy was delivered to the frontal lobe of 22 animals. Tolerability and reproducibility of the method were evaluated and dosimetric measurements were conducted to verify the treatment plans. 2, 4 and 6 months after the irradiation magnetic resonance imaging (MRI) scans and histopathological examinations were performed to detect late radiation induced biological changes. Immobilization device provided excellent reproducibility and tolerability. Dosimetry revealed good correspondence with planned dose distribution, but the measured absorbed dose was 30% lower than the planned dose. During the 6 months follow-up period the procedure related death of subject animals after 30 Gy, 70 Gy and 90 Gy were 0%, 20% and 100% respectively. T2 signal and structural changes on MRI...
The aim of the present study was to determine which isoform of the cyclooxygenase (COX) enzyme pl... more The aim of the present study was to determine which isoform of the cyclooxygenase (COX) enzyme plays a role in the neuronal nitric oxide synthase (nNOS) activation caused by nitroglycerin (NTG), in the most caudal part of the trigeminal caudal nucleus (TNC) of the rat. Nitric oxide donor, NTG, can trigger migraine attack in migraineurs, but not in healthy persons. In rats, subcutaneous administration of NTG (10 mg/kg) increases significantly the number of nNOS-immunoreactive neurons in the TNC after 4 hours, which could be attenuated by acetyl-salicylate (Aspirin), a nonselective COX-inhibitor. SPRD rats were divided into 3 groups: (1) control group (no drug administration), (2) NS398 (selective COX-2 inhibitor) administration (1, 3, or 5 mg/kg), and (3) SC560 (selective COX-1 inhibitor) administration (1, 5, or 10 mg/kg). Thirty minutes after drug administration, the animals received NTG (10 mg/kg) or placebo injection. Four hours later the animals were transcardially perfused and the cervical part of the TNC was removed for immunohistochemistry. Results.-The selective COX-2 inhibitor NS398 in contrast to the selective COX-1 inhibitor SC560 attenuates the NTG-induced nNOS expression dose-dependently. These findings suggest that metabolites deriving from COX-2 (but not COX-1) may be the most important factors in the NTG-induced nNOS expression. These data could help to better understand the pathogenesis of headaches and the action of antimigraine drugs.
Translational research in radiation oncology is important for the detection of adverse radiation ... more Translational research in radiation oncology is important for the detection of adverse radiation effects, cellular responses, and radiation modifications, and may help to improve the outcome of radiation therapy in patients with cancer. The present study aimed to optimize and validate a real‑time label‑free assay for the dynamic monitoring of cellular responses to ionizing radiation. The xCELLigence system is an impedance‑based platform that provides continuous information on alterations in cell size, shape, adhesion, proliferation, and survival. In the present study, various malignant human primary fibroblast cells (U251, GBM2, MCF7, A549, HT‑29) were exposed to 0, 5 and 10 Gy of Cobalt60 radiation. As well as the xCELLigence system, cell survival and proliferation was evaluated using the following conventional end‑point cell‑based methods: Clonogenic, MTS, and lactate dehydrogenase assays, and apoptosis was detected by fluorescence‑activated cell sorting. The effects of ionizing radiation were detected for each cell line using impedance monitoring. The real‑time data correlated with the colony forming assay results. At low cell densities (1,000‑2,000 cells/well) the impedance‑based method was more accurate at monitoring dose‑dependent changes in the malignant human primary fibroblast cell lines, as compared with the end‑point assays. The results of the present study demonstrated that the xCELLigence system may be a reliable and rapid diagnostic method for the monitoring of dynamic cell behavior following radiation. In addition, the xCELLigence system may be used to investigate the cellular mechanisms underlying the radiation response, as well as the time‑dependent effects of radiation on cell proliferation and viability.
The available scientific data indicate that the pathomechanism of Parkinson's disease (PD) in... more The available scientific data indicate that the pathomechanism of Parkinson's disease (PD) involves the accumulation of endogenous and exogenous toxic substances. The disruption of the proper functioning of certain transporters in the blood-brain barrier and in the blood-cerebrospinal fluid barrier in PD would accompany to that accumulation. Although there is an emerging role of the dysfunction of multidrug resistance-associated proteins (MRPs), members of ATP-b nding cassette (ABC) transporter superfamily, in neurodegenerative disorders, there is only a few available data as regards PD. So the aim of our study was the assessment of the role of certain MRPs (1 ,2, 4 and 5) in neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Following the intraperitoneal administration of silymarin (with MRP1, 2, 4 and 5 inhibitory effects), naringenin (with MRP1, 2 and 4 stimulatory effects), sulfinpyrazone (with MRP1, 4 and 5 inhibitory and MRP2 stimulatory effects) and all...
Alzheimer's disease (AD) is a chronic neurodegenerative disorder associated with dementia as ... more Alzheimer's disease (AD) is a chronic neurodegenerative disorder associated with dementia as a main feature. Despite decades of thorough research in the field of AD, the pathomechanism is still not fully understood. The development of novel experimental models can help us in the discovery of both genetic and non-genetic components of disease pathogenesis. As currently available therapies in AD can provide merely moderate or only temporary symptomatic relief, there is a great demand for the development of new drugs with higher therapeutic potential. Some of the candidates would be those targeting the kynurenine pathway, the neuroactive metabolites of which are surely involved in both neurodegeneration and neuroprotection, mainly in relation with glutamate excitotoxicity and oxidative stress. Both analogs of the neuroprotective kynurenic acid and small molecule enzyme inhibitors preventing the formation of neurotoxic compounds may have potential therapeutic significance. However, ...
Deficient peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) function is one co... more Deficient peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) function is one component of mitochondrial dysfunction in neurodegenerative diseases. Current molecular classification of such diseases is based on the predominant protein accumulating as intra- or extracellular aggregates. Experimental evidence suggests that mitochondrial dysfunction and impaired protein processing are closely interrelated. In vitro findings further indicate that PGC-1α dysfunction may contribute to protein misfolding in neurodegeneration. To systematically evaluate the neuropathological alterations of mice lacking the expression of the full-length PGC-1α protein (FL-PGC-1α) but expressing an N-truncated fragment. To assess the pattern of neurodegeneration-related proteins, we performed immunostaining for Tau, pTau, α-synuclein, amyloid-β, amyloid precursor protein, prion protein, FUS, TDP-43 and ubiquitin. Using hematoxylin and eosin, Klüver-Barrera and Bielschowsky silver stainings and...
Ionizing radiation plays a major role in the treatment of brain tumors, but side-effects may rest... more Ionizing radiation plays a major role in the treatment of brain tumors, but side-effects may restrict the efficacy of therapy. In the present study, our goals were to establish whether the administration of L-alpha-glycerylphosphorylcholine (GPC) can moderate or prevent any of the irradiation-induced functional and morphological changes in a rodent model of hippocampus irradiation. Anesthetized adult (6-weeks-old) male Sprague-Dawley rats were subjected to 40 Gy irradiation of one hemisphere of the brain, without or with GPC treatment (50 mg/kg bw by gavage), the GPC treatment continuing for 4 months. The effects of this partial rat brain irradiation on the spatial orientation and learning ability of the rats were assessed with the repeated Morris water maze (MWM) test. Histopathologic (HP) evaluation based on hematoxylin-eosin and Luxol blue staining was performed 4 months after irradiation. The 40 Gy irradiation resulted in a moderate neurological deficit at the levels of both cognitive function and morphology 4 months after the irradiation. The MWM test proved to be a highly sensitive tool for the detection of neurofunctional impairment. The site navigation of the rats was impaired by the irradiation, but the GPC treatment markedly decreased the cognitive impairment. HP examination revealed lesser amounts of macrophage density, reactive gliosis, calcification and extent of demyelination in the GPC-treated group. GPC treatment led to significant protection against the cognitive decline and cellular damage, evoked by focal brain irradiation at 40 Gy dose level. Our study warrants further research on the protective or mitigating effects of GPC on radiation injuries.
Neuropsychopharmacologia Hungarica : a Magyar Pszichofarmakologiai Egyesulet lapja = official journal of the Hungarian Association of Psychopharmacology, 2012
Depression can originate from changes in tryptophan availability, caused by activation of the kyn... more Depression can originate from changes in tryptophan availability, caused by activation of the kynurenine pathway (KP) as a result of inflammation. Alterations in the KP and the changing levels of its metabolites have recently been considered to be factors contributing to the pathogenesis of depression. The key molecular mediator which induces the conversion of tryptophan into kynurenine is indoleamine-2,3-dioxygenase. Following its activation, both the production of neurotoxic compounds and the diminished peripheral accessibility of tryptophan are regarded as essential steps in the pathophysiological processes. The aim of this review is to survey the role of the KP in depression and its relationships with cognitive functions.
Neuropsychopharmacologia Hungarica a Magyar Pszichofarmakologiai Egyesulet Lapja Official Journal of the Hungarian Association of Psychopharmacology, Dec 1, 2012
Depression can originate from changes in tryptophan availability, caused by activation of the kyn... more Depression can originate from changes in tryptophan availability, caused by activation of the kynurenine pathway (KP) as a result of inflammation. Alterations in the KP and the changing levels of its metabolites have recently been considered to be factors contributing to the pathogenesis of depression. The key molecular mediator which induces the conversion of tryptophan into kynurenine is indoleamine-2,3-dioxygenase. Following its activation, both the production of neurotoxic compounds and the diminished peripheral accessibility of tryptophan are regarded as essential steps in the pathophysiological processes. The aim of this review is to survey the role of the KP in depression and its relationships with cognitive functions.
Vitamin D receptor (VDR) gene encodes a transcription factor that influences calcium homeostasis ... more Vitamin D receptor (VDR) gene encodes a transcription factor that influences calcium homeostasis and immunoregulation, and may play a role in neurological disorders including Parkinson's disease (PD). The investigations of the association between VDR and PD in different populations revealed various results. In a present study 100 PD patients and 109 healthy controls from the Hungarian population were genotyped for four polymorphic sites (BsmI, ApaI, FokI and TaqI) in the VDR gene. The polymorphisms were determined by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Our results demonstrate an association between the FokI C allele and PD; the frequency of the C allele was significantly higher in PD patients than in controls, suggesting that this polymorphism may have a role in the development of PD in these patients.
Neuropsychopharmacologia Hungarica : a Magyar Pszichofarmakológiai Egyesület lapja = official journal of the Hungarian Association of Psychopharmacology, 2012
Depression can originate from changes in tryptophan availability, caused by activation of the kyn... more Depression can originate from changes in tryptophan availability, caused by activation of the kynurenine pathway (KP) as a result of inflammation. Alterations in the KP and the changing levels of its metabolites have recently been considered to be factors contributing to the pathogenesis of depression. The key molecular mediator which induces the conversion of tryptophan into kynurenine is indoleamine-2,3-dioxygenase. Following its activation, both the production of neurotoxic compounds and the diminished peripheral accessibility of tryptophan are regarded as essential steps in the pathophysiological processes. The aim of this review is to survey the role of the KP in depression and its relationships with cognitive functions.
Background and purpose of our study was to develop a precise dose delivery technique for partial ... more Background and purpose of our study was to develop a precise dose delivery technique for partial brain irradiation of two rats simultaneously. Using a self-developed frame stereotactic radiotherapy with single doses of 30-90 Gy was delivered to the frontal lobe of 22 animals. Tolerability and reproducibility of the method were evaluated and dosimetric measurements were conducted to verify the treatment plans. 2, 4 and 6 months after the irradiation magnetic resonance imaging (MRI) scans and histopathological examinations were performed to detect late radiation induced biological changes. Immobilization device provided excellent reproducibility and tolerability. Dosimetry revealed good correspondence with planned dose distribution, but the measured absorbed dose was 30% lower than the planned dose. During the 6 months follow-up period the procedure related death of subject animals after 30 Gy, 70 Gy and 90 Gy were 0%, 20% and 100% respectively. T2 signal and structural changes on MRI...
The aim of the present study was to determine which isoform of the cyclooxygenase (COX) enzyme pl... more The aim of the present study was to determine which isoform of the cyclooxygenase (COX) enzyme plays a role in the neuronal nitric oxide synthase (nNOS) activation caused by nitroglycerin (NTG), in the most caudal part of the trigeminal caudal nucleus (TNC) of the rat. Nitric oxide donor, NTG, can trigger migraine attack in migraineurs, but not in healthy persons. In rats, subcutaneous administration of NTG (10 mg/kg) increases significantly the number of nNOS-immunoreactive neurons in the TNC after 4 hours, which could be attenuated by acetyl-salicylate (Aspirin), a nonselective COX-inhibitor. SPRD rats were divided into 3 groups: (1) control group (no drug administration), (2) NS398 (selective COX-2 inhibitor) administration (1, 3, or 5 mg/kg), and (3) SC560 (selective COX-1 inhibitor) administration (1, 5, or 10 mg/kg). Thirty minutes after drug administration, the animals received NTG (10 mg/kg) or placebo injection. Four hours later the animals were transcardially perfused and the cervical part of the TNC was removed for immunohistochemistry. Results.-The selective COX-2 inhibitor NS398 in contrast to the selective COX-1 inhibitor SC560 attenuates the NTG-induced nNOS expression dose-dependently. These findings suggest that metabolites deriving from COX-2 (but not COX-1) may be the most important factors in the NTG-induced nNOS expression. These data could help to better understand the pathogenesis of headaches and the action of antimigraine drugs.
Translational research in radiation oncology is important for the detection of adverse radiation ... more Translational research in radiation oncology is important for the detection of adverse radiation effects, cellular responses, and radiation modifications, and may help to improve the outcome of radiation therapy in patients with cancer. The present study aimed to optimize and validate a real‑time label‑free assay for the dynamic monitoring of cellular responses to ionizing radiation. The xCELLigence system is an impedance‑based platform that provides continuous information on alterations in cell size, shape, adhesion, proliferation, and survival. In the present study, various malignant human primary fibroblast cells (U251, GBM2, MCF7, A549, HT‑29) were exposed to 0, 5 and 10 Gy of Cobalt60 radiation. As well as the xCELLigence system, cell survival and proliferation was evaluated using the following conventional end‑point cell‑based methods: Clonogenic, MTS, and lactate dehydrogenase assays, and apoptosis was detected by fluorescence‑activated cell sorting. The effects of ionizing radiation were detected for each cell line using impedance monitoring. The real‑time data correlated with the colony forming assay results. At low cell densities (1,000‑2,000 cells/well) the impedance‑based method was more accurate at monitoring dose‑dependent changes in the malignant human primary fibroblast cell lines, as compared with the end‑point assays. The results of the present study demonstrated that the xCELLigence system may be a reliable and rapid diagnostic method for the monitoring of dynamic cell behavior following radiation. In addition, the xCELLigence system may be used to investigate the cellular mechanisms underlying the radiation response, as well as the time‑dependent effects of radiation on cell proliferation and viability.
The available scientific data indicate that the pathomechanism of Parkinson's disease (PD) in... more The available scientific data indicate that the pathomechanism of Parkinson's disease (PD) involves the accumulation of endogenous and exogenous toxic substances. The disruption of the proper functioning of certain transporters in the blood-brain barrier and in the blood-cerebrospinal fluid barrier in PD would accompany to that accumulation. Although there is an emerging role of the dysfunction of multidrug resistance-associated proteins (MRPs), members of ATP-b nding cassette (ABC) transporter superfamily, in neurodegenerative disorders, there is only a few available data as regards PD. So the aim of our study was the assessment of the role of certain MRPs (1 ,2, 4 and 5) in neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Following the intraperitoneal administration of silymarin (with MRP1, 2, 4 and 5 inhibitory effects), naringenin (with MRP1, 2 and 4 stimulatory effects), sulfinpyrazone (with MRP1, 4 and 5 inhibitory and MRP2 stimulatory effects) and all...
Alzheimer's disease (AD) is a chronic neurodegenerative disorder associated with dementia as ... more Alzheimer's disease (AD) is a chronic neurodegenerative disorder associated with dementia as a main feature. Despite decades of thorough research in the field of AD, the pathomechanism is still not fully understood. The development of novel experimental models can help us in the discovery of both genetic and non-genetic components of disease pathogenesis. As currently available therapies in AD can provide merely moderate or only temporary symptomatic relief, there is a great demand for the development of new drugs with higher therapeutic potential. Some of the candidates would be those targeting the kynurenine pathway, the neuroactive metabolites of which are surely involved in both neurodegeneration and neuroprotection, mainly in relation with glutamate excitotoxicity and oxidative stress. Both analogs of the neuroprotective kynurenic acid and small molecule enzyme inhibitors preventing the formation of neurotoxic compounds may have potential therapeutic significance. However, ...
Deficient peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) function is one co... more Deficient peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) function is one component of mitochondrial dysfunction in neurodegenerative diseases. Current molecular classification of such diseases is based on the predominant protein accumulating as intra- or extracellular aggregates. Experimental evidence suggests that mitochondrial dysfunction and impaired protein processing are closely interrelated. In vitro findings further indicate that PGC-1α dysfunction may contribute to protein misfolding in neurodegeneration. To systematically evaluate the neuropathological alterations of mice lacking the expression of the full-length PGC-1α protein (FL-PGC-1α) but expressing an N-truncated fragment. To assess the pattern of neurodegeneration-related proteins, we performed immunostaining for Tau, pTau, α-synuclein, amyloid-β, amyloid precursor protein, prion protein, FUS, TDP-43 and ubiquitin. Using hematoxylin and eosin, Klüver-Barrera and Bielschowsky silver stainings and...
Ionizing radiation plays a major role in the treatment of brain tumors, but side-effects may rest... more Ionizing radiation plays a major role in the treatment of brain tumors, but side-effects may restrict the efficacy of therapy. In the present study, our goals were to establish whether the administration of L-alpha-glycerylphosphorylcholine (GPC) can moderate or prevent any of the irradiation-induced functional and morphological changes in a rodent model of hippocampus irradiation. Anesthetized adult (6-weeks-old) male Sprague-Dawley rats were subjected to 40 Gy irradiation of one hemisphere of the brain, without or with GPC treatment (50 mg/kg bw by gavage), the GPC treatment continuing for 4 months. The effects of this partial rat brain irradiation on the spatial orientation and learning ability of the rats were assessed with the repeated Morris water maze (MWM) test. Histopathologic (HP) evaluation based on hematoxylin-eosin and Luxol blue staining was performed 4 months after irradiation. The 40 Gy irradiation resulted in a moderate neurological deficit at the levels of both cognitive function and morphology 4 months after the irradiation. The MWM test proved to be a highly sensitive tool for the detection of neurofunctional impairment. The site navigation of the rats was impaired by the irradiation, but the GPC treatment markedly decreased the cognitive impairment. HP examination revealed lesser amounts of macrophage density, reactive gliosis, calcification and extent of demyelination in the GPC-treated group. GPC treatment led to significant protection against the cognitive decline and cellular damage, evoked by focal brain irradiation at 40 Gy dose level. Our study warrants further research on the protective or mitigating effects of GPC on radiation injuries.
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