title: Differential Effect of Neuropeptides on Excitatory Synaptic Transmission in Human Epileptic Hippocampus.
abstract: Development of novel disease-modifying treatment strategies for neurological disorders, which at present have no cure, represents a major challenge for today's neurology. Translation of findings from animal models to humans represents an unresolved gap in most of the preclinical studies. Gene therapy is an evolving innovative approach that may prove useful for clinical applications. In animal models of temporal lobe epilepsy (TLE), gene therapy treatments based on viral vectors encoding NPY or galanin have been shown to effectively suppress seizures. However, how this translates to human TLE remains unknown. A unique possibility to validate these animal studies is provided by a surgical therapeutic approach, whereby resected epileptic tissue from temporal lobes of pharmacoresistant patients are available for neurophysiological studies in vitro. To test whether NPY and galanin have antiepileptic actions in human epileptic tissue as well, we applied these neuropeptides directly to human hippocampal slices in vitro. NPY strongly decreased stimulation-induced EPSPs in dentate gyrus and CA1 (up to 30 and 55%, respectively) via Y2 receptors, while galanin had no significant effect. Receptor autoradiographic binding revealed the presence of both NPY and galanin receptors, while functional receptor binding was only detected for NPY, suggesting that galanin receptor signaling may be impaired. These results underline the importance of validating findings from animal studies in human brain tissue, and advocate for NPY as a more appropriate candidate than galanin for future gene therapy trials in pharmacoresistant TLE patients.
authors.affiliation: Experimental Epilepsy Group, Epilepsy Center, Department of Clinical Sciences, Lund University Hospital, 22184 Lund, Sweden.
authors.forename: Marco
authors.identifier: http://orcid.org/0000-0001-8317-7976
authors.initials: M
authors.lastname: Ledri
authors.affiliation: Experimental Epilepsy Group, Epilepsy Center, Department of Clinical Sciences, Lund University Hospital, 22184 Lund, Sweden.
authors.forename: Andreas T
authors.initials: AT
authors.lastname: Sørensen
authors.affiliation: Experimental Epilepsy Group, Epilepsy Center, Department of Clinical Sciences, Lund University Hospital, 22184 Lund, Sweden.
authors.forename: Marita G
authors.initials: MG
authors.lastname: Madsen
authors.affiliation: Laboratory of Neural Plasticity, Department of Neuroscience and Pharmacology, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Søren H
authors.initials: SH
authors.lastname: Christiansen
authors.affiliation: Experimental Epilepsy Group, Epilepsy Center, Department of Clinical Sciences, Lund University Hospital, 22184 Lund, Sweden.
authors.forename: Litsa Nikitidou
authors.initials: LN
authors.lastname: Ledri
authors.affiliation: Experimental Epilepsy Group, Epilepsy Center, Department of Clinical Sciences, Lund University Hospital, 22184 Lund, Sweden.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cifra
authors.affiliation: Lund Stem Cell Center, BMC B10, and Division of Neurosurgery, Department of Clinical Sciences and.
authors.forename: Johan
authors.initials: J
authors.lastname: Bengzon
authors.affiliation: Division of Pathology, Department of Clinical Sciences, Lund University Hospital, 22184 Lund, Sweden, and.
authors.forename: Eva
authors.identifier: http://orcid.org/0000-0002-0602-3815
authors.initials: E
authors.lastname: Lindberg
authors.affiliation: Epilepsy Clinic & Neurobiology Research Unit and.
authors.forename: Lars H
authors.identifier: http://orcid.org/0000-0001-9024-7936
authors.initials: LH
authors.lastname: Pinborg
authors.affiliation: Department of Neurosurgery, Rigshospitalet, Copenhagen University Hospital, 2200 Copenhagen, Denmark.
authors.forename: Bo
authors.identifier: http://orcid.org/0000-0002-6417-1234
authors.initials: B
authors.lastname: Jespersen
authors.affiliation: Laboratory of Neural Plasticity, Department of Neuroscience and Pharmacology, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Casper R
authors.initials: CR
authors.lastname: Gøtzsche
authors.affiliation: Laboratory of Neural Plasticity, Department of Neuroscience and Pharmacology, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: David P D
authors.initials: DP
authors.lastname: Woldbye
authors.affiliation: Experimental Epilepsy Group, Epilepsy Center, Department of Clinical Sciences, Lund University Hospital, 22184 Lund, Sweden.
authors.forename: My
authors.initials: M
authors.lastname: Andersson
authors.affiliation: Experimental Epilepsy Group, Epilepsy Center, Department of Clinical Sciences, Lund University Hospital, 22184 Lund, Sweden, Merab.Kokaia@med.lu.se.
authors.forename: Merab
authors.identifier: http://orcid.org/0000-0001-7984-3921
authors.initials: M
authors.lastname: Kokaia
mesh_terms: D000293:Adolescent; D000328:Adult; D004827:Epilepsy / Q000473:pathology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D019004:Galanin / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008869:Microtubule-Associated Proteins; D008875:Middle Aged; D009478:Neuropeptide Y / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011869:Radioligand Assay; D044088:Receptors, Galanin / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000378:metabolism; D013460:Sulfur Isotopes / Q000493:pharmacokinetics; D013569:Synapses / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects*; D055815:Young Adult
chemical_list: D008869:Microtubule-Associated Proteins; D009478:Neuropeptide Y; D044088:Receptors, Galanin; D017476:Receptors, Neuropeptide Y; D013460:Sulfur Isotopes; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019004:Galanin
keywords: NPY; galanin; gene therapy; hippocampus; temporal lobe epilepsy