Brain Research Bulletin 68 (2005) 54–58 Evidence for dopaminergic re-innervation by embryonic allografts in an optimized rat model of the Parkinsonian variant of multiple system atrophy Zoe Puschban a,b , Nadia Stefanova a , ˚ Asa Peters´ en b , Christian Winkler c , Patrik Brundin b , Werner Poewe a , Gregor K. Wenning a,∗ a Experimental Neurodegeneration Laboratory, Department of Neurology, University Hospital Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria b Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund, Sweden c Department of Neurology, Hannover Medical School, Hannover, Germany Available online 3 October 2005 Abstract Embryonic transplantation has been considered as an alternative treatment strategy for drug resistant parkinsonian symptoms in multiple system atrophy. So far our group has created a number of animal models of striatonigral degeneration, the core pathology underlying progressive Parkinsonism associated with multiple system atrophy, as testbed for neurorestaurative and neuroprotective approaches. Using embryonic allografts of either nigral, striatal, or combined nigro-striatal tissue we were able to consistently show graft survival in a denervated and lesioned striatum as well as improvement of rotational behaviour. However, due to severe lesions of the striatum and the chosen time window of 3–6 weeks between lesion and grafting, severe gliosis led to demarcation of the graft and prevented re-innervation of the remaining adult striatum. The aim of the present study was to modify our “double toxin-double lesion” rat model by reducing the dose of quinolinic acid injected into the striatum from 150 to 75 nmol and shortening the interval between lesion and grafting to 1–2 weeks. Injection of 75 nmol quinolinic acid still led to a significant reduction of DARPP-32 positive neurons and volume in the striatum. Analysis of embryonic mesencephalic grafts revealed survival of dopaminergic neurons and outgrowth of fibres re-innervating the adult striatum. Rotation behaviour was improved in the graft group. Considering embryonic transplantation a possible future antiparkinson therapeutic intervention in multiple system atrophy patients our data stress the necessity of optimal patient selection, i.e. early stage disease with limited striatal dysfunction. © 2005 Elsevier Inc. All rights reserved. Keywords: Transplantation; Rotometer; Striatonigral degeneration; Stereology 1. Introduction and background Failure of conservative drug treatment to ameliorate dis- abling Parkinsonism associated with multiple system atrophy (MSA-P) creates a strong need for alternative treatment strate- gies [14]. In order to test neurorestaurative and neuroprotec- tive approaches our group has created a number of “double lesion” rodent models of striatonigral degeneration (SND), the core pathology underlying MSA-P, using either intracerebral or systemic injections of nigral and striatal toxins such as 6- hydroxydopamine (6-OHDA), quinolinic acid (QA), 1-methyl- ∗ Corresponding author. Tel.: +43 512 504 81811; fax: +43 512 504 23852. E-mail address: gregor.wenning@uibk.ac.at (G.K. Wenning). 4-phenyl-1,2,3,6-tetrahydropyridine or 3-nitropropionic acid [2,6,7,9–11]. Embryonic allografts of either mesencephalic, striatal, or combined mesencephalic-striatal cell suspensions consistently survive and function in the double lesioned rat striatum as shown by behavioural tests, in vivo MR imaging and histological as well as autoradiographic analyses [6,9,11,12]. However, due to the formation of large striatal lesions and the extended time win- dow of up to 6 weeks between lesion surgery and grafting in these previous studies most animals showed a marked astroglial response encapsulating the graft tissue and substantially lim- iting the degree of graft-derived dopaminergic re-innervation of lesioned host striatum. The aim of the present study was to achieve dopaminergic re-innervation by reducing the stri- atal lesion size (using 75 nmol instead of 150 nmol QA) and 0361-9230/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.brainresbull.2005.08.025