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1

Early Parkinson ’s disease and mechanisms compensating for dopaminergic neurons loss-an energy metabolism point of view

100%
Kuter K.
Acta Neurobiologiae Experimentalis
|
2015
|
tom 75
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nr Supl.
Degeneration of dopaminergic neurons in substantia nigra (SN) is underlying cause of movement disorder observed in Parkinson’s disease.At its early stages motor deficits are masked by compensatory mechanisms. Our aim was to describe how prolonged metabolic dysfunction of astrocytes would influence processes of compensation for the dopaminergic neurons degeneration. Rat model of selective nigrostriatal dopaminergic system degeneration was induced by intracerebral injection of 6-OHDA into medial forebrain bundle. Astrocytes metabolic dysfunction was induced by 7-days infusion of fluorocitrate (FC) into SN. Dopaminergic neurons lesioning as well as astrocytes dysfunction induced motor deficits that were reversed with time, despite progressing neuronal degeneration after 6-OHDA. Inhibition of astrocytes metabolism by FC caused tendency to decrease performance of not-assembled complex I and IV. Double toxicity of 6-OHDA and FC also decreased performance in complex I and IV especially 4 weeks after operations and FC discontinuation, causing also significant decrease in specific activity of complex IV. Along with those changes, we observed decreased mitochondrial membranes viscosity. Results from aconitase activity showed that when neurons were devoid of astrocytes support, their aconitase activity increased drastically. Presented research shows that prolonged dysfunction of astrocytes influences dopaminergic cells metabolism and vulnerability. Surprisingly, changes in oxidative phosphorylation system were shown very small even after loss of 33% to 61% of dopaminergic neurons – what would suggest extensive adaptive possibilities, maybe in mitochondria volume. Supported by the Statutory Funds of the Institute of Pharmacology, PAS, Poland; Technische Universität Darmstadt, MOBILNOŚĆ PLUS MNiSW scholarship and NCN grant nr 2012/05/B/ NZ4/02599
2
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Astrocyty - gwiazdy pod sklepieniem czaszki. W czym są wyjątkowe i jak pomagają chronić mózg

63%
Kuter K., Kadluczka J.
Wszechświat
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2021
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tom 122
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nr 01-03
3

Ketogenic diet and neurodegeneration of dopaminergic neurons

51%
Kuter K., Olech L., Glowacka U.
Acta Neurobiologiae Experimentalis
|
2017
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tom 77
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nr Suppl.1
INTRODUCTION: Ketogenic diet (KD) changes energy metabolism by decreasing use of carbohydrates and substituting calories with fatty acids. Neuroprotection is attributed probably due to improved cellular energetics. It has been shown to be beneficial in epilepsy and recently also in neurodegenerative disorders as Parkinson’s Disease (PD). AIM(S): We studied effects of KD in an animal model representing early PD stages to see if KD would influence neuronal degeneration process. METHOD(S): We prepared early PD rat model of selective, medium size nigrostriatal dopaminergic system degeneration by stereotaxic injection of 3 µg /3 µl 6-OHDA into medial forebrain bundle. Ketogenic diet (1% carbohydrates, 70% fat, 8% protein) was started 3 weeks before operation and continued to the end of experiment. RESULTS: KD strongly increased ketone levels in plasma, striatum (STR) and substantia nigra (SN) and lesioning enhanced this effect in plasma 4 days and 2 weeks after operation. KD temporarily increased rats locomotor activity but didn’t rescue neurons from 6-OHDA toxicity, as showed stereological neurons counting and dopamine (DA) levels. Although at the time when locomotor activity was enhanced decrease in DA turnover was observed in SN but not in STR. After 4 weeks this effect was reversed, behaviour normalised and DA turnover in SN increased. Interestingly, lesioned animals kept on KD showed increased levels of succinate in SN at all studied time-points. CONCLUSIONS: We did not observe neuroprotective effect against 6-OHDA induced toxicity, although a modulatory effect in dopaminergic metabolism was detected along with some energetic changes. FINANCIAL SUPPORT: The study was supported by the NCN grant 2012/05/B/NZ4/02599 and statutory funds of the Institute of Pharmacology Polish Academy of Sciences, Krakow, Poland.
4

Changes in metabolic substrates after prolonged astrocytes dysfunction and dopaminergic neurons degeneration in substantia nigra

51%
Kuter K., Olech L., Glowacka U.
Acta Neurobiologiae Experimentalis
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2015
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tom 75
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nr Supl.
BACKGROUND AND AIMS: Underlying cause of movement disorder in Parkinson’s disease is degeneration of dopaminergic neurons in substantia nigra (SN). Supportive role of astrocytes in neuronal energy metabolism was reported. Prolonged dysfunction of astrocytes could increase dopaminergic neurons vulnerability. Our aim was to investigate if prolonged metabolic inhibition of astrocytes influences dopaminergic neurons metabolic substrates utilization. METHODS: Rat model of selective nigrostriatal dopaminergic system degeneration was induced by injection of 6-hydroxydopamine (6-OHDA) into medial forebrain bundle. Astrocytes metabolic dysfunction was caused by 7-days infusion of fluorocitrate (FC) into SN. RESULTS: Densytometric analysis of astrocytes marker – GFAP showed decreased staining after FC treatment. After 4 weeks this effect was diminished suggesting regrowth of astrocytes. 6-OHDA injection caused smaller decreases. FC infusion for 7 days decreased tissue levels of succinate and lactate in SN. Lesioning of dopaminergic neurons increased succinate but decreased lactate levels. Combined treatment neutralized effect on succinate but aggravated lactate decrease. 4 weeks after operation and FC withdrawal lactate levels increased while lesion effect was normalized. At this timepoint profile of the changes on succinate was the same as after one week. Beta-hydroxybutyrate levels significantly increased after FC and dopaminergic lesion and combined effect was enhanced at 7th day. After 4 weeks all groups still showed slightly elevated levels. CONCLUSIONS: 7-day FC administration caused prolonged metabolic dysfunction of astrocytes and influenced dopaminergic neurons metabolism. We suggest that enhanced production of succinate and ketone bodies after dopaminergic neurons degeneration could be one of metabolic compensatory mechanisms. Study supported by the Statutory Funds of the Institute of Pharmacology, PAS, Poland and NCN grant nr 2012/05/B/NZ4/02599.
5

Influence of adenosine A2A receptor stimulation on proenkephalin (PENK) and prodynorphin (PDYN) mRNAs expression in rat brain

51%
Wardas J., Lenda T., Kuter K.
Acta Neurobiologiae Experimentalis
|
2005
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tom 65
|
nr 3
6

Brain energy metabolism in neurodegeneration of dopaminergic neurons in animal model of early Parkinson's disease: role of astrocytes

39%
Kuter K., Olech L., Glowacka U., Paleczna M., Kosmowska B., Jurga A.
Acta Neurobiologiae Experimentalis
|
2019
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tom 79
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nr Suppl.1
Glial pathology and energy metabolism changes in the brain precede symptoms of Parkinson’s disease (PD) and multiple other neurodegenerative diseases. Astrocytes govern and regulate a large part of the energy metabolism in the brain. Prolonged impairment of astrocytic functions could increase the vulnerability of dopaminergic neurons in the substantia nigra (SN). In this model, 40‑50% of dopaminergic neurons were selectively killed, causing transient locomotor disability compensated with time. We also induced death of astrocytes in the SN, simultaneously activating microglia but sparing the dopaminergic neurons. The astrocytes replenished after toxin withdrawal. We studied multiple markers of energy metabolism and mitochondrial oxidative phosphorylation (OxPhos) complex and supercomplex functioning during the early stages of neurodegeneration and compensation in the SN and striatum (STR). Death of astrocytes diminished the capability of the dopaminergic system to compensate for the degeneration of neurons. It caused a local energy deprivation, a shift in the usage of energy substrates, via increased glycogenolysis and glycolysis markers, ketone bodies availability, and fatty acid transport in remaining glial cells. Increased neuronal expression of CPT1c and astrocytic expression of CPT1a suggest adaptation in fatty acid use. On the other hand, lesion of dopaminergic neurons influenced OxPhos system and enhanced its functioning. Microglia activation also plays an important role in the processes of degeneration, compensation, and energy metabolism regulation. Modulation of its activation phenotypes might be beneficial towards the indicated processes. Astrocyte and microglia energetic influence is one of the factors in the neuronal compensatory mechanisms of dopaminergic system and might have a leading role in presymptomatic PD stages.
7

An influence of compounds acting on glutamatergic and noradrenergic receptors on the tremor induced by harmaline; automatic measurements by force plate actimeters

39%
Glowacka U., Wardas J., Kuter K., Berghauzen K., Pilc A., Ossowska K., Acher F.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr 1
Harmaline, a derivative of beta-carboline is a well-known tremorgenic compound which induces the action and postural tremor in animals. Oscillation frequency of this symptom is equal to 10–12 Hz in rats. A synchronous activation of the olivo-cerebellar pathway and release of glutamate in the cerebellum has been suggested to be a primary cause of the harmaline-induced tremor. Subtype 4 of metabotropic glutamate receptors (mGluR4) is mainly an autoreceptor and its stimulation decreases glutamate release. MGluR4 receptors are abundant in the cerebellum and therefore their influence on the harmaline-induced tremor might be expected. However, mechanisms underlying this symptom are more complex and seem to involve also other neurotransmitter systems, especially the noradrenergic neurotransmission in the cerebellum. The aim of the present study was to examine an influence of an orthosteric agonist of mGluR4 – AF22898:8 on the tremor induced by harmaline in rats. An antagonist of beta-adrenoceptors – propranolol was used as a reference compound. Tremor of animals was measured automatically by actimeters where four force tranducers measured the force exerted by an animal on the floor. The Power Spectra analysis which uses a Fourier transform generated power spectra for examination of the tremor. The average power over three specific frequency bands AP1 (0–8 Hz), AP2 (9–15 Hz), AP3 (16–25 Hz), and tremor indices, which quantified the differences in power between the AP2 and AP1 (T1) and AP3 and AP1 (T2) were used to quantify the tremor intensity. Harmaline in doses of 7.5–25 mg/kg i.p. induced the generalized tremor which was dose-dependent and lasted longer than 2 h. Propranolol in a dose of 20 mg/kg i.p. diminished the tremor (decreased T1 and AP2) induced by harmaline (15 mg/ kg i.p.). In contrast, AF22898:8 administered in doses of 2.5–20 mg/kg i.p. was ineffective. The present results indicate that the harmaline-induced tremor measured in the force plate actimeters consititute a good model for screening antitremorgenic compounds. However, in contrast to earlier expectations the agonist of mGluR4 had no influence on this symptom.The study was supported by the grant of the National Science Centre nr N N401 570638, and partly by Statutory Funds of the Department of Neuro-Psychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, Cracow, Poland.
8

The influence of imipramine and pramipexole on depressivelike behaviour in an animal model of a pre-clinical stage of Parkinson’s disease

39%
Berghauzen K., Wardas J., Kuter K., Kolasiewicz W., Glowacka U., Ossowska K.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr 1
Motor disturbances in Parkinson’s disease (PD) results from the massive degeneration of dopaminergic neurons and terminals of the nigrostriatal pathway and a decrease in the dopamine (DA) level in the caudate nucleus and putamen. The clinical phase of PD is preceded by a preclinical period where depression is a frequent comorbid disturbance.Dysfunctions of monoaminergic systems could underlie depression in PD. Clinical trials suggest that a treatment with tricyclic antidepressant drugs can be effective in ameliorating depression in PD. Moreover, recent studies have suggested that the administration of pramipexole (the mixed dopamine D2/D3 receptor agonist) may reduce not only motor symptoms (akinesia, rigidity and tremor at rest) but also depression in PD. The aim of the study was to examine the influence of classic tricyclic antidepressant -imipramine and pramipexole on the ‘depressivelike’ behaviour of rats with moderate lesion of the nigrostriatal system. Male Wistar rats were injected bilaterally with 6-OHDA (3.75–15 µg/2.5 µl) into the ventral striatum (vSTR). Imipramine was injected i.p. at a dose of 10 mg/kg once a day and pramipexole s.c. at a dose of 1 mg/kg twice a day for 14 days. The locomotor activity in actometers and behaviour of rats in the forced swimming test (FS) were measured on the 15th day after the surgery. The lesion extent was analysed by HPLC and immunohistochemically. The lesion increased immobility and swimming and decreased climbing in FS, however, it did not influence the locomotor activity of rats. All the lesion-induced disturbances observed in FS were decreased by pramipexole. Imipramine increased only climbing, but had no influence on immobility in lesioned rats. Moreover, imipramine but not pramipexole reduced the locomotor activity in lesioned animals. After the administration of 6-OHDA levels of DA decreased (ca. 45%) in the dorsal striatum (dSTR), vSTR and frontal cortex (FCX). Pramipexole and imipramine injections had no influence on DA levels in lesioned rats. Levels of DA metabolites (DOPAC, HVA) were markedly increased in dSTR and vSTR after injections of pramipexole. Moreover, pramipexole significantly increased the turnover of DOPAC/DA and HVA/DA in dSTR and vSTR in sham-operated and lesioned rats. These results indicate that a relatively moderate dopaminergic lesion which does not produce any motor disturbances, may induce “depressive-like” symptoms which are reversed by dopamine agonist but not by a classic antidepressant. Acknowledgments Study supported by the Project “Depression-Mechanisms-Therapy” (POIG.01.01.02-12-004/09-00), co-financed by EU from the European Regional Development Fund as a part of the Operational Programme “Innovative Economy 2007-2013”
9

Chronic intraventricular infusion of MPP+ with alzet osmotic minipumps in rats as a model of parkinson's disease

39%
Kuter K., Kolasiewicz W., Zapala M., Kowalska M., Golembiowska K., Morelli M., Wardas J.
Acta Neurobiologiae Experimentalis
|
2009
|
tom 69
|
nr 3
An underlying mechanism of degeneration in Parkinson’s disease (PD) is unknown. The animal models of PD, developed so far have certain disadvantages; hence a search for a new model of PD seems necessary. Chronic, unilateral, intraventricular delivery of MPP+ (0.284 and 0.428 mg/kg/day for 28 days) using an ALZET osmotic minipump, implanted s.c., produced a marked, dose-dependent loss of DA and its metabolites DOPAC and HVA (50–90%) in the striatum, ipsilateral to the infusion site. DA concentration was normal in the non-infused, right striatum. Also no changes in the 5-HT level were observed. The stereological counting of the number of dopaminergic neurons in the substantia nigra pars compacta (SNc), stained with the antibody against tyrosine hydroxylase, showed their 30–50% loss on the lesioned side. Those changes were accompanied with a diminished expression of mRNA for the dopamine transporter in the SNc (by ca. 30%). Additionally, in situ hybridization studies indicated an enhanced expression of mRNA for both adenosine A2A and dopamine D2 receptors in the striatum and diminished expression of mRNA for BDNF in the hippocampus. The obtained results showed that this chronic model of continuous, intracerebral infusion of MPP+ , produced a selective nigrostriatal DA cell loss and number of other neurochemical changes resembling PD. Study supported by the grant No. NN401 1137 33 (MS&HE) and by a statutory fund from the Institute of Pharmacology, PAS, Poland.
10

The influence of acute and chronic paraquat administration on catecholaminergic systems in rat frontal cortex

33%
Kuter K., Nowak P., Wieronska J. M., Zieba R., Dabrowska J., Bortel A., Kwiecinski A., Smialowska M.
Acta Neurobiologiae Experimentalis
|
2005
|
tom 65
|
nr 3
11

6-OHDA-induced lesion of a8-a9 dopaminergic neurons increases the harmaline-induced tremor in rats

33%
Kuter K., Berghauzen K., Wardas J., Kolasiewicz W., Nowak P., Zapala M., Mikolajun U., Ossowska K.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr 1
Degeneration of dopaminergic nigrostriatal pathway is generally accepted to be a cause of Parkinson’s disease (PD) motor symptoms such as akinesia, bradykinesia and tremor. Unfortunately the extent of the degeneration does not correlate with tremor occurrence and intensity, therefore cannot explain sufficiently its appearance. Mechanisms leading to induction of tremor are still not explained. Interestingly, image analysis studies have suggested contribution of an increased activity of the cerebellum to the PD tremor. The aim of the present study was to examine whether a selective, partial lesion of dopaminergic structures – the substantia nigra pars compacta (SNc, A9) and retrorubral field (RRF, A8) would influence the tremor behaviour induced by harmaline. Harmaline model of tremor induces an abnormal synchronous activation of the climbing glutamatergic olivo-cerebellar pathway and cerebellar Purkinje cells. 6-OHDA (8 mg /2 ml) was injected unilaterally into the region of the posterior part of the SNc and RRF to induce moderate size of degeneration, similar to early PD. Harmaline was administered in a dose of 7.5 mg/kg i.p. on the 8th day after the operation and tremor of forelimbs, head and trunk was measured. In precise behavioural studies we have found that the lesion of dopaminergic system increased intensity of the tremor induced by harmaline but did not influence its character. Stereological examination of the lesion extent revealed losses of dopaminergic (tyrosine hydroxylase-immunoreactive) neurons in the anterior (30%) and posterior (72%) SNc, as well as in RRF (72% on the average). Levels of dopamine and all its metabolites, as well as noradrenaline concentrations on ipsilateral to lesioned side were moderately decreased in the caudate-putamen, while, dopamine and DOPAC in the anterior cerebellum were increased. In the caudate-putamen, the ipsi/contra ratio of dopamine level correlated negatively, while that of dopamine turnover positively with the tremor intensity. However, in the anterior cerebellum an inverse relationship was found. Moreover, this symptom correlated positively with serotonin level and negatively with the 5-HIAA/serotonin ratio on the contralateral side of the posterior cerebellum. The presented results indicate that modulation of dopaminergic and serotonergic transmissions by the dopaminergic system lesion, modelling early stages of PD, may influence cerebellar mechanisms triggering tremor. The study was supported by the grant of the Ministry of Science and Higher Education No N_N401_570638 and by Statutory Funds of the Department of Neuropsychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, Cracow, Poland
12

An influence of lesions of the catecholaminergic cerebellar innervation on the harmaline-induced tremor in rats

33%
Wardas J., Kolasiewicz W., Kuter K., Berghauzen K., Nowak P., Mikolajun U., Zapala M., Ossowska K.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr 1
Recent studies have suggested a crucial role of the cerebellum in different forms of tremor. Abnormal synchronous activation of the glutamatergic olivo-cerebellar pathway and Purkinje cells results in the essential tremor in humans and the harmaline-induced tremor in animals. Moreover, an increased neuronal activity of the cerebellum has been found to contribute to the tremor in Parkinson’s disease (PD). Since the cerebellum receives dopaminergic and noradrenergic pathways arising from regions affected in PD, the aim of the present study was to examine a contribution of the cerebellar catecholaminergic innervation to the harmaline-induced tremor in rats. Rats were bilaterally injected into the cerebellar vermis (lobules 8–10) with 6-hydroxydopamine (6-OHDA) (8 μg/0.5 μl) either alone or this treatment was preceded by desipramine (15 mg/kg i.p.). Harmaline was administered at a dose of 7.5 mg/kg i.p. on the 9th post-operative day. Tremor of forelimbs was measured as a number of episodes. After completion of behavioural experiments rats were killed by decapitation and the levels of monoamines and their metabolites were measured by HPLC in lobules 1–3, 4–7 and 8–10 of the cerebellum. 6-OHDA injected alone decreased the noradrenaline level by ca. 40–80% in the cerebellum and enhanced the harmaline-induced tremor. When 6-OHDA administration was preceded by desipramine, it decreased dopaminergic transmission in some regions of the cerebellum but induced its compensatory activation in others. Finally no influence of the latter treatment on the tremor induced by harmaline was observed. The present study indicates that the noradrenergic innervation of the cerebellum plays an inhibitory role in the harmaline-induced tremor. The study was supported by the grant of the Ministry of Science and Higher Education No N N401 570638, and partly by Statutory Funds of the Department of Neuro-Psychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, Cracow, Poland.
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