| 1. |
- Gotzsche, Casper R., et al.
(författare)
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Combined gene overexpression of neuropeptide Y and its receptor Y5 in the hippocampus suppresses seizures
- 2012
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 45:1, s. 288-296
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Tidskriftsartikel (refereegranskat)abstract
- We recently demonstrated that recombinant adeno-associated viral vector-induced hippocampal overexpression of neuropeptide Y receptor, Y2, exerts a seizure-suppressant effect in kindling and kainate-induced models of epilepsy in rats. Interestingly, additional overexpression of neuropeptide Y in the hippocampus strengthened the seizure-suppressant effect of transgene Y2 receptors. Here we show for the first time that another neuropeptide Y receptor, Y5, can also be overexpressed in the hippocampus. However, unlike Y2 receptor overexpression, transgene Y5 receptors in the hippocampus had no effect on kainate-induced motor seizures in rats. However, combined overexpression of Y5 receptors and neuropeptide Y exerted prominent suppression of seizures. This seizure-suppressant effect of combination gene therapy with Y5 receptors and neuropeptide Y was significantly stronger as compared to neuropeptide Y overexpression alone. These results suggest that overexpression of Y5 receptors in combination with neuropeptide Y could be an alternative approach for more effective suppression of hippocampal seizures. (C) 2011 Elsevier Inc. All rights reserved.
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| 2. |
- Kanter Schlifke, Irene, et al.
(författare)
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GDNF released from encapsulated cells suppresses seizure activity in the epileptic hippocampus.
- 2009
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 216, s. 413-419
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Tidskriftsartikel (refereegranskat)abstract
- To date, a variety of pharmacological treatments exists for patients suffering epilepsy, but systemically administered drugs offer only symptomatic relief and often cause unwanted side effects. Moreover, available drugs are not effective in one third of the patients. Thus, more local and more effective treatment strategies need to be developed. Gene therapy-based expression of endogenous anti-epileptic agents represents a novel approach that could interfere with the disease process and result in stable and long-term suppression of seizures in epilepsy patients. We have reported earlier that direct in vivo viral vector-mediated overexpression of the glial cell line-derived neurotrophic factor (GDNF) in the rat hippocampus suppressed seizures in different animal models of epilepsy. Here we explored whether transplantation of encapsulated cells that release GDNF in the hippocampus could also exert a seizure-suppressant effect. Such ex vivo gene therapy approach represents a novel, more clinically safe approach, since the treatment could be terminated by retrieving the transplants from the brain. We demonstrate here that encapsulated cells, which are genetically modified to produce and release GDNF, can suppress recurrent generalized seizures when implanted into the hippocampus of kindled rats.
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| 3. |
- Woldbye, David P D, et al.
(författare)
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Adeno-associated viral vector-induced overexpression of neuropeptide Y Y2 receptors in the hippocampus suppresses seizures.
- 2010
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 133:Pt 9, s. 2778-2788
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Tidskriftsartikel (refereegranskat)abstract
- Gene therapy using recombinant adeno-associated viral vectors overexpressing neuropeptide Y in the hippocampus exerts seizure-suppressant effects in rodent epilepsy models and is currently considered for clinical application in patients with intractable mesial temporal lobe epilepsy. Seizure suppression by neuropeptide Y in the hippocampus is predominantly mediated by Y2 receptors, which, together with neuropeptide Y, are upregulated after seizures as a compensatory mechanism. To explore whether such upregulation could prevent seizures, we overexpressed Y2 receptors in the hippocampus using recombinant adeno-associated viral vectors. In two temporal lobe epilepsy models, electrical kindling and kainate-induced seizures, vector-based transduction of Y2 receptor complementary DNA in the hippocampus of adult rats exerted seizure-suppressant effects. Simultaneous overexpression of Y2 and neuropeptide Y had a more pronounced seizure-suppressant effect. These results demonstrate that overexpression of Y2 receptors (alone or in combination with neuropeptide Y) could be an alternative strategy for epilepsy treatment.
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| 4. |
- Ängehagen, Mikael
(författare)
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Anti-epileptic and neuroprotective mechanisms by Topiramate and Levetiracetam evaluated in primary cultures
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to evaluate plausible intracellular mechanisms of action for antiepileptic drugs, Topiramate (TPM) and Levetiracetam (LEV), and to investigate if TPM possesses neuroprotective properties. The thesis is based on results from calcium imaging, immunohistochemical stainings, viability tests, and Western blot using primary cortical or hippocampal cultures, or hippocampal brain slices. The results demonstrate that TPM protects neurons from glutamate (Glu) and kainate induced excitotoxicity in mixed neuronal/astroglial cortical cultures. Further it was shown that this neuroprotective effect could be in part due to TPMs ability to inhibit the accumulation of free Ca2+ and that this ability is inversely related to the level of protein kinase A (PKA) mediated phosphorylation of kainate activated receptors. This thesis also demonstrates that TPM inhibits AMPA induced accumulation of free Ca2+ in astrocytes and that TPM inhibits PKA mediated phosphorylation of the GluR1 subunit of AMPA receptors in astrocytes. The novel antiepileptic drug LEV has been reported to exert several non-conventional effects on neurons and special attention has been directed whether LEV opposes the release of Ca2+ from intraneuronal stores. The results demonstrate that LEV was able to prevent caffeine induced ryanodine receptor mediated Ca2+ release from intracellular Ca2+ stores from hippocampal cultures. Cells treated with the R-enantiomer of LEV (ucb LO60) had no effect on caffeine induced intracellular calcium transients ([Ca2+]i) transients. Levetiracetam significantly inhibited the amplitudes and the number of caffeine induced repeated population spikes and delayed the appearance of spontaneous bursts in rat hippocampal slices in vitro while ucb LO60 was devoid of anticonvulsant activity. The results presented in this thesis demonstrate that TPM protects neurons against Glu and kainate induced excitotoxicity and provide evidence that TPM modulates phosphorylation of kainate activated receptors in both neurons and astrocytes. This thesis also points to that the inhibition of caffeine induced Ca2+ release from intra-neuronal stores might be an excitability-reducing effect of LEV, contributing to its antiepileptic activity.
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