title: 6-Hydroxydopamine leads to T2 hyperintensity, decreased claudin-3 immunoreactivity and altered aquaporin 4 expression in the striatum.
abstract: The neurotoxin 6-hydroxydopamine (6-OHDA) is frequently used in animal models to mimic Parkinson's disease. Imaging studies describe hyperintense signalling in regions close to the site of the 6-OHDA injection in T2-weighted (T2w) magnetic resonance imaging (MRI). The nature of this hyperintense signal remains elusive and still is matter of discussion. Here we demonstrate hyperintense signalling in T2w MRI and decreased apparent diffusion coefficient (ADC) values following intraventricular injection of 6-OHDA. Moreover, we show decreased GFAP immunoreactivity in brain regions corresponding to the region revealing the hyperintense signalling, probably indicating a loss of astrocytes due to a toxic effect of 6-OHDA. In the striatum, where no hyperintense signalling in MRI was observed following intraventricular 6-OHDA injection, immunohistochemical and molecular analyses revealed an altered expression of the water channel aquaporin 4 and the emergence of vasogenic edema, indicated by an increased perivascular space. Moreover, a significant decrease of claudin-3 immunoreactivity was observed, implying alterations in the blood brain barrier. These findings indicate that intraventricular injection of 6-OHDA results (1) in effects close to the ventricles that can be detected as hyperintense signalling in T2w MRI accompanied by reduced ADC values and (2) in effects on brain regions not adjacent to the ventricles, where a disturbance of water homeostasis occurs. We clearly demonstrate that 6-OHDA leads to brain edema that in turn may affect the overall results of experiments (e.g. behavioral alterations). Therefore, when using 6-OHDA in Parkinson's models effects that are not mediated by degeneration of catecholaminergic neurons have to be considered.
authors.affiliation: Institute of Anatomy, Department of Cellular Neurobiology, University of Tübingen, Österbergstr. 3, 72074 Tübingen, Germany. Wachter@anatu.uni-tuebingen.de
authors.forename: Britta
authors.initials: B
authors.lastname: Wachter
authors.forename: Sonja
authors.initials: S
authors.lastname: Schürger
authors.forename: Andreas
authors.initials: A
authors.lastname: Schmid
authors.forename: Adriane
authors.initials: A
authors.lastname: Gröger
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Sadler
authors.forename: Anna
authors.initials: A
authors.lastname: Speidel
authors.forename: Jens
authors.initials: J
authors.lastname: Rolinger
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Pichler
authors.forename: Daniela
authors.initials: D
authors.lastname: Berg
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Wagner
authors.forename: Andreas
authors.initials: A
authors.lastname: von Ameln-Mayerhofer
authors.forename: Eva
authors.initials: E
authors.lastname: Küppers
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000473:pathology*; D001923:Brain Chemistry / Q000187:drug effects*; D002395:Catecholamines / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects; D062465:Claudin-3; D057167:Claudins / Q000378:metabolism*; D003342:Corpus Striatum / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D005911:Gliosis / Q000139:chemically induced / Q000473:pathology; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D013028:Space Perception / Q000187:drug effects; D013565:Sympatholytics / Q000494:pharmacology*
chemical_list: D051401:Aquaporin 4; D002395:Catecholamines; D062465:Claudin-3; D057167:Claudins; C568124:Cldn3 protein, rat; D012333:RNA, Messenger; D013565:Sympatholytics; D016627:Oxidopamine