Combined gene overexpression of neuropeptide Y and its receptor Y5 in the hippocampus suppresses seizures

Gøtzsche, Casper René; Nikitidou, Litsa; Sørensen, Andreas T.; Olesen, Mikkel Vestergaard; Sørensen, G.; Christiansen, Søren H.; Ängehagen, Mikael; Woldbye, David P. D.; Kokaia, Mérab

doi:10.1016/j.nbd.2011.08.012

Cited by 42 publications

(32 citation statements)

References 41 publications

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“…While receptor overexpression was effective based on endogenous ligand activation, overexpressing both the Y2 receptor and NPY produced a more pronounced seizure-suppressant effect (Woldbye, et al, 2010). Recently, similar findings were also demonstrated using NPY and Y5 receptor overexpression in a KA model (Gotzsche, et al, 2011). …”

Section: Neuropeptidessupporting

confidence: 76%

Current prospects and challenges for epilepsy gene therapy

Weinberg¹,

McCown²

2013

Experimental Neurology

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This review addresses the state of gene therapy research for the treatment of epilepsy. Preclinical studies have demonstrated the anti-seizure efficacy of viral vector-based gene transfer through the use of a variety of strategies – from modulating classic neurotransmitter systems to targeting or overexpressing of neuropeptide receptors in seizure-specific brain regions. While these studies provide substantive proof of principle for viral vector gene therapy, future studies must address the challenges of vector immunity, cellular specificity and effective global delivery. As these issues are resolved, viral vector gene therapy should significantly impact the treatment of intractable epilepsy.

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Section: Neuropeptidessupporting

confidence: 76%

Current prospects and challenges for epilepsy gene therapy

Weinberg¹,

McCown²

2013

Experimental Neurology

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“…Y2 has predominantly presynaptic localization while Y1 and Y5 reside on postsynaptic neurons [70] possibly with different excitatory or inhibitory nature. Y1 receptor overexpression aggravated kainate-induced seizures [71] while Y5 receptor overexpression together with NPY overexpression had stronger seizure-suppressant effect than NPY overexpression alone [72]. In addition, mice lacking the Y5 receptor had enhanced sensitivity for kainateinduced seizures [73].…”

Section: Neuropeptide Ymentioning

confidence: 94%

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Dobolyi¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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Neuropeptides are signaling molecules participating in the modulation of synaptic transmission. Neuropeptides are stored in dense core synaptic vesicles, the release of which requires profound excitation. Only in the extracellular space, neuropeptides act on G-protein coupled receptors to exert a relatively slow action both pre-and postsynaptically. Consequently, neuropeptide modulators are ideal candidates to influence epileptic tissue overexcited during seizures. Indeed, a number of neuropeptides have been implicated in epilepsy and many of them are considered to have endogenous neuroprotective actions. Neuropeptides, present in the hippocampus, the most frequent focus of seizures in temporal lobe epilepsy, received the largest attention as potential anti-epileptic substances. Hippocampal neuropeptides, somatostatin, neuropeptide Y, galanin, dynorphin, enkephalin, substance P, cholecystokinin, vasoactive intestinal polypeptide, and some neuropeptides, which are also hormones such as ghrelin, angiotensins, corticotropin-releasing hormone, adrenocorticotropin, thyrotropin-releasing hormone, oxytocin and vasopressin involved in epilepsy are discussed in the review article. Oral application of neuropeptides as drugs is typically not efficient because of low bioavailability: rapid degradation and insufficient penetration through the blood-brain barrier. Recent progress in the development of non-peptide agonists and antagonists of neuropeptide receptors as well as gene therapeutic approaches leading to the local production of neuropeptides within the central nervous system will also be discussed.

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“…Consequently, the reason why the mice needed less food to maintain body weight in the hippocampus group does not seem to be related to spread to the lateral hypothalamus. No previous studies have reported weight gains after intrahippocampal rAAV-NPY administration in freefeeding rats and mice (Gøtzsche et al, 2012;Lin et al, 2006bLin et al, , 2010Richichi et al, 2004;Sørensen et al, 2009), but these studies did not display data on food intake that might address whether metabolic rate could have been affected. Further studies are needed to clarify this issue.…”

Section: Discussionmentioning

confidence: 99%

“…Human preproNPY cDNA was subcloned into a chimeric serotype 1/2 rAAV expression cassette consisting of the neuronspecific enolase (NSE) promoter, woodchuck post-transcriptional regulatory element (WPRE) and a bovine growth hormone polyA (bGHpA) signal flanked by AAV2 inverted terminal repeats (NSE-NPY-WPRE-bGHpA) (Genedetect, Auckland, New Zealand) (Gøtzsche et al, 2012;Richichi et al, 2004;Woldbye et al, 2010). The same expression cassette without the transgene (NSE-empty-WPREbGHpA) was used as control.…”

Section: Vector Injectionsmentioning

confidence: 99%