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1

Ketogenic diet and neurodegeneration of dopaminergic neurons

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Kuter K., Olech L., Glowacka U.
Acta Neurobiologiae Experimentalis
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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.
2

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

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Kuter K., Olech L., Glowacka U.
Acta Neurobiologiae Experimentalis
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2015
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tom 75
|
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.
3

Usuwanie anionowych srodkow powierzchniowo czynnych metoda sorpcji na weglu aktywnym

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Glowacka U., Smolko M., Swislocka R., Samsonowicz R.
Zeszyty Naukowe. Politechnika Białostocka. Nauki Techniczne. Inżynieria Środowiska
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2001
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tom 15
124-127
4

Pramipexole at a low dose induces beneficial effects in the harmaline-induced model of essential tremor in rats

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Kosmowska B., Wardas J., Glowacka U., Ananthan S.
Acta Neurobiologiae Experimentalis
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2015
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tom 75
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nr Supl.
BACKGROUND AND AIMS: Harmaline-induced tremor is a model of essential tremor (ET). Tremor induced by harmaline has been suggested to result from activation of the olivo-cerebellar projection. Recent studies have indicated that cerebellum functions may be modulated by dopamine. METHODS: We examined the effects of preferential agonists of dopamine D3 receptors: pramipexole and 7-OH-DPAT on the harmaline-induced tremor in rats. In order to study receptor mechanisms of these drugs rats were pretreated with dopamine D3 receptor antagonists [SB-277011-A (10 mg/kg ip) and SR-21502 (15 mg/ kg ip)], an antagonist of presynaptic D2/D3 receptors [amisulpride (1 mg/kg ip)], or a non-selective antagonist of postsynaptic dopamine receptors [haloperidol (0.5 mg/kg ip)]. RESULTS: The tremor was measured using fully automated Force Plate Actimeters. The following parameters were calculated: power within 0–8 Hz band (AP1) and 9–15 Hz band (AP2), and tremor index (a difference in power between AP2 and AP1). Harmalinetriggered (15 mg/kg ip) tremor was manifested by an increase in AP2 and tremor index. Pramipexole at a low (0.1 mg/kg sc), but not higher doses (0.3 and 1 mg/kg sc) lowered the harmaline-increased AP2. 7-OH-DPAT (0.1 mg/kg sc) reduced AP2 in the harmalinetreated rats. None of the examined dopamine antagonists influenced the above effect of dopamine agonists. In contrast, SB-277011-A administered alone lowered the harmaline-increased AP2. CONCLUSIONS: The present study indicates that pramipexole reduces the harmaline-induced tremor. However, mechanisms underlying its action are still unclear and require further examination. Financial support: Statutory Funds of the Department of NeuroPsychopharmacology, Institute of Pharmacology, PAS; National Science Center (grant OPUS 6, 2013/11/B/NZ4/04565); Southern Research Institute, Birmingham, AL, USA (S. Ananthan) - SR21502 donation. Barbara Kosmowska is a holder of scholarship from the KNOW sponsored by Ministry of Science and Higher Education, Poland.
5

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

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Kuter K., Olech L., Glowacka U., Paleczna M., Kosmowska B., Jurga A.
Acta Neurobiologiae Experimentalis
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2019
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tom 79
|
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.
6

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

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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.
7

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

76%
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”
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