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The potential relevaceof neuropeptide Y (NPY) and NPY receptors in neuroprotection

100%

Smialowska M., Domin H.

Acta Neurobiologiae Experimentalis

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2011

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tom 71

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nr S

Neuropeptide Y (NPY) is a 36-amino acid neurotransmitter and neuromodulator widely distributed in the mammalian central and peripheral nervous system and has been associated with a number of physiological and pathological conditions. In the forebrain this peptide is preferentially expressed in interneurons and modulates, mainly inhibits, the release of other neurotransmitters. NPY acts on specific receptors coupled to G-proteins, and 6 types of NPY receptors (Y1 to Y6) have been identified based on different pharmacological profiles. It has been well documented that NPY inhibits glutamatergic transmission and decreases hippocampal epileptiform activity which may lead to neuroprotection. Our earlier studies demonstrated the neuroprotective activity of NPY injected into the hippocampus on kainate neurotoxicity in that structure. The neuroprotective action of NPY against excitotoxicity was also shown in neuronal cultures. Studies with specific Y receptor ligands revealed a crucial role of Y2 and Y5 receptors. Activation of those receptors diminished neuronal excitotoxic degenerations both in vitro and in vivo, but no protective effect was observed after Y1 agonist. One of the most promising finding of our study is that NPY or Y2 and Y5 ligands exert a significant neuroprotective effect after delayed treatment, 3 – 6 h after the onset of intoxication. Much less in known about the protective action of NPY on ischemic damage, both in vitro and in vivo, but some positive effects were also found. The role of NPY in chronic neurodegenerations such as Alzheimer, Parkinson and Huntington diseases has also been postulated but the results are divergent and unclear. Summing up, our data and other authors studies indicate the neuroprotective properties of NPY; moreover, the effectiveness of delayed treatment may open up a future possibility of the potential therapeutic use of such compounds in patients.

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Astrocyty a depresja

100%

Smialowska M., Domin H.

Wszechświat

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2015

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tom 116

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nr 10-12

3

Astrocyty a intelekt

100%

Smialowska M., Domin H.

Wszechświat

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2015

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tom 116

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nr 07-09

4

Degeneration of astrocytes in the prefrontal cortex induces depressive-like behavior in rats: Behavioral, immunochemical and histological studies

81%

Smialowska M., Szewczyk B., Wawrzak-Wlecial A., Domin H.

Acta Neurobiologiae Experimentalis

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2013

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tom 73

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nr 1

Postmortem studies of depressed patients showed that one of the most consistent findings is a decrease in the density of glial cells in human brain cortical regions, especially in the prefrontal and cingular areas. Furthermore, a decline in the number of astrocytes in the prefrontal cortex was found in rats after chronic unpredictable stress – one of the generally accepted animal models of depression. An important function of astrocytes in the brain tripartite synapse is the uptake of released glutamate. Hence the basic consequence of the loss of astrocytes is a reduction in glutamate uptake and an excess of glutamate in the synaptic cleft. The glutamatergic predominance in the excitator-inhibitory balance is postulated to be involved in the pathogenesis of depression. Recently, depressive-like behavior have been demonstrated in rats after astrocytes ablation. Therefore in the present study we tried to ascertain whether astroglial degeneration in the prefrontal cortex was sufficient to induce a depressive-like behavior and could serve as an animal model of depression. Astrocytic toxin L- or D,Lalpha-aminoadipic acid (AAA), 100 µg/2 µl, was microinjected bilaterally into rat medial prefrontal cortex (PFC). The toxins were injected twice, on day 1 and 2; afterwords depressive-like behavior was assessed by a forced swim test on day 5 of the experiment. Some rats were additionally treated with the antidepressant imipramine (30 mg/kg, i.p.) 24, 5 and 1 h before the forced swim test. The rats’ brains were taken out for an analysis on day eight. Histological verifications of the injection sites and immunohistochemical staining for the astrocytic marker glial fibrillary acidic protein (GFAP), were carried out. The GFAP positive cells were stereologically counted in the PFC. Also the level of GFAP expression was determined by the Western blot analysis in all the experimental groups. It was found that both L-AAA and DL-AAA induced a significant increase in immobility time in the forced swim test, without changing the overall locomotor activity, which indicates depressive-like effects of these compounds. The immunohistochemical and Western blot analyses showed a significant decrease in the number of GFAP-positive cells and GFAP level in the PFC of toxin-treated rats. The decrease amounted to ca. 50%. Both the behavioral and the GFAP changes were reversed or partially inhibited by imipramine injection. The obtained results suggest an important role of astrocytes in the PFC in mood regulation; moreover, they indicate that the degeneration of astrocytes in this structure may be used as an animal model of depression. This study was supported by Grant POIG.01.01.02-12-004/09Friday, November 23, 2012

5

MTEP, a selective mGluR5 antagonist, reduces excitotoxic neurodegeneration in rat hippocampus

81%

Domin H., Zieba B., Wieronska J. M., Smialowska M.

Acta Neurobiologiae Experimentalis

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2006

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tom 66

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nr 4

6

The neuroprotective effect of MTEP, a potent and highly selective mGluRS antagonist, on excitotoxic neuronal death

81%

Domin H., Kajta M., Palucha A., Smialowska M.

Acta Neurobiologiae Experimentalis

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2005

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tom 65

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nr 3

7

Stres jako zagrożenie środowiskowe - jak sobie z nim radzić

81%

Stachowicz K., Domin H., Szewczyk B.

Wszechświat

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2022

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tom 123

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nr 01-03

8

The group III metabotropic glutamate receptor agonists attenuate neuronal cell death in primary cortical cultures exposed to oxygen-glucose deprivation

81%

Domin H., Jantas D., Smialowska M.

Acta Neurobiologiae Experimentalis

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2011

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tom 71

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nr 1

Oxygen-glucose deprivation (OGD) induces excitotoxic cell death mediated primarily by excessive release of glutamate. A growing body of evidence suggests that metabotropic glutamate (mGlu) receptors can modulate glutamatergic transmission, so these receptors are regarded as potential targets for neuroprotective drugs. Group III mGluRs (mGlu4, mGlu6, mGlu7 and mGlu8) agonists are known to reduce glutamatergic neurotransmission by inhibiting glutamate release. Therefore in the present study we tried to find out whether the agonist of group III mGluR (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-1) and the first selective allosteric mGlu7 receptor agonist, N,N’-bis (diphenylmethyl)-1,2- ethanediamine (AMN082) have neuroprotective potential in primary neuronal cortical cultures exposed to oxygen-glucose deprivation, as an in vitro ischemic injury paradigm. In order to evoke toxic effects cortical cultures were exposed to OGD for 1 - 5 h. ACPT-1, at concentrations of 1, 10, 100 and 200 µM, or AMN082, at concentrations of 0.01, 0.1, 0.5 and 1 µM, were applied in two ways: twice, just before the start of OGD and immediately after OGD or once, immediately after OGD. Neurotoxicity was measured by lactate dehydrogenase (LDH) efflux from the damaged cells into the culture media 24 h after the end of OGD. It was found that a double application of ACPT-1 or AMN082 significantly attenuated the LDH release by 20-30% and 30-43%, respectively. A particularly important finding is that AMN082, given once after the end of OGD also significantly decreased ischemic-induced LDH release by 30%. These data were confirmed by immunohistochemical staining for the presence of characteristic neuronal protein MAP-2. In conclusion, the above results indicate that group III mGlu receptor agonists may have neuroprotective potential and may play a potential therapeutic role in neurodegenerative disorders. The study was supported by Grant No N N401 091037 from the MSHE, Poland.

9

Anxiolytic activity of metabotropic glutamate receptor group II and III ligands in rat hippocampus:the putative role of neuropeptide Y

71%

Smialowska M., Wieronska J. M., Domin H., Zieba B., Obuchowicz E.

Acta Neurobiologiae Experimentalis

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2005

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tom 65

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nr 3

10

Neuroprotective effects of Y2 and Y5 neuropeptide Y receptor agonists

61%

Smialowska M., Domin H., Zieba B., Michalik R., Piotrowski P., Kozniewska E.

Acta Neurobiologiae Experimentalis

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2009

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tom 69

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nr 1

Neuropeptide Y (NPY), a 36 amino acid peptide widely distributed in the nervous system, inhibits glutamatergic transmission and decreases hippocampal epileptiform activity which may lead to neuroprotection. Such effects were observed in some earlier studies, but results are divergent and the role of particular Y receptors remains unclear. In the present study we investigated a possibility of neuroprotective action of neuropeptide Y1, Y2 and Y5 receptor specifi c ligands in rats in two in vivo models of brain damage. In the fi rst model, kainic acid (KA)(2.5 nmol/1 μl) was microinjected into the CA1 region of the rat dorsal hippocampus and the peptide compounds (470 pmol/1 μl) were injected in the same region 30 min, 1 h or 3 h after the kainate. Seven days later the brains were taken for histology and number of neurons in CA pyramidal layer was evaluated by stereological counting. It was found that, Y2 agonist (NPY13- 36) and Y5R agonist ([CPP1-17,NPY19-23,Ala31,Aib32Gln34] hPP), injected 30 min or 1 h but not 3 h after the KA, signifi cantly diminished KA-induced hippocampal lesion. Contrary Y1 agonist ([Leu31,Pro34]-NPY) did not induced any protection but had a tendency towards an increase of the degeneration. The most promising Y2 agonist was tested also in the second model, focal cerebral ischemia after transient middle cerebral artery occlusion (MCAO). The peptide was injected icv (10 μg/6 μl,), 30 min after MCA occlusion. It signifi cantly diminished MCAO-induced brain damage evaluated by TTC staining. Our results indicated neuroprotective effects of Y2 and Y5 activation. Moreover we found that the peptides may be effective after delayed (30ñ60 min) application.

11

Pretreatment is not mandatory for neuroprotection with 1alpha,25-dihydroxyvitamin D3 in perinatal hypoxic-ischemic rat brain damage in vivo and in excitotoxic injury of primary neuronal cell cultures

51%

Makarewicz D., Kajta M., Zieminska E., Jantas D., Domin H., Lason W., Kutner A., Lazarewicz J. W.

Acta Neurobiologiae Experimentalis

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2009

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tom 69

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nr 1

Previous in vivo and in vitro studies demonstrated neuroprotective potential of pretreatment with 1α, 25-dihydroxyvitamin D3 (calcitriol). The aim of present study was to determine effectiveness of calcitriol administered in vivo after brain ischemic episode in the rat model of perinatal asphyxia, or co-applied with some delay during 24 h exposure to glutamate of the mice hippocampal, cortical and cerebellar neuronal cultures at 7th and 12th day in vitro. In some experiments calcitriol was given after acute exposure to glutamate of the rat cerebellar neurons. Our results demonstrated, that in the 7 day old rat pups submitted to hypoxia ñ ischemia acute application of calcitriol in one dose of 2 μg/kg 30 min after termination of the insult or sub-chronic, 7-day post-treatment with calcitriol effectively diminished brain damage. The rate of such accomplished neuroprotection exceeded that achieved by hypoxic preconditioning, used as the reference neuroprotective method. Moreover the results of our in vitro experiments revealed the ability of calcitriol to reduce excitotoxicity in a way dependent on origin of neuronal cells, stage of their development and duration of excitotoxic insult. Calcitriol was neuroprotective when it was applied together with glutamate or even with up to 6 h delay during 24-h excitotoxic challenge to the hippocampal and neocortical, but not cerebellar neuronal cultures. In addition calcitriol inhibited glutamate-induced caspase-3 activity in hippocampal cultures. We ascribe these protective effects of calcitriol to a rapid, possibly non-genomic modulation by this compound of the mechanisms that are instrumental in its direct neuroprotective action. The study was supported by Polish MNSW Scientifi c Network Fund no 26/E-40/SN-0023/2007

Ograniczanie wyników

The potential relevaceof neuropeptide Y (NPY) and NPY receptors in neuroprotection

Astrocyty a depresja

Astrocyty a intelekt

Degeneration of astrocytes in the prefrontal cortex induces depressive-like behavior in rats: Behavioral, immunochemical and histological studies

MTEP, a selective mGluR5 antagonist, reduces excitotoxic neurodegeneration in rat hippocampus

The neuroprotective effect of MTEP, a potent and highly selective mGluRS antagonist, on excitotoxic neuronal death

Stres jako zagrożenie środowiskowe - jak sobie z nim radzić

The group III metabotropic glutamate receptor agonists attenuate neuronal cell death in primary cortical cultures exposed to oxygen-glucose deprivation

Anxiolytic activity of metabotropic glutamate receptor group II and III ligands in rat hippocampus:the putative role of neuropeptide Y

Neuroprotective effects of Y2 and Y5 neuropeptide Y receptor agonists

Pretreatment is not mandatory for neuroprotection with 1alpha,25-dihydroxyvitamin D3 in perinatal hypoxic-ischemic rat brain damage in vivo and in excitotoxic injury of primary neuronal cell cultures