Human interleukin-10 gene transfer is protective in a rat model of Parkinson's disease.
In Parkinson's disease (PD) chronic inflammation occurs in the substantia nigra (SNc) concurrently with dopaminergic neurodegeneration. In models of PD, microglial activation precedes neurodegeneration in the SNc, suggesting that the underlying pathogenesis involves a complex response in the nigrostriatal pathway, and that the innate immune system plays a significant role. We have investigated the neuroprotective effect of an adeno-associated viral type-2 (AAV2) vector containing the complementary DNA (cDNA) for human interleukin-10 (hIL-10) in the unilateral 6-hydroxydopamine (6-OHDA) rat model of PD. AAV2-hIL-10 reduced the 6-OHDA-induced loss of tyrosine hydroxylase (TH)-positive neurons in the SNc, and also reduced loss of striatal dopamine (DA). Pretreatment with AAV2-hIL-10 reduced glial activation in the SNc but did not attenuate striatal release of the inflammatory cytokine IL-1beta. Assessment of rotational behavior in response to apomorphine challenge showed absence of asymmetry, confirming protection of dopaminergic innervation of the lesioned striatum. At baseline, 6-OHDA-lesioned animals displayed a deficit in contralateral forelimb use, but pretreatment with AAV2-hIL-10 reduced this forelimb akinesia. Transcriptional analyses revealed alteration of a few genes by AAV2-hIL-10; these alterations may contribute to neuroprotection. This study supports the need for further investigations relating to gene therapies aimed at reducing neuroinflammation in early PD.
Department of Neurosurgery, University of California San Francisco, San Francisco, California, USA.
Louisa C
LC
Johnston
Xiaomin
X
Su
Kathleen
K
Maguire-Zeiss
Karen
K
Horovitz
Irina
I
Ankoudinova
Dmitry
D
Guschin
Piotr
P
Hadaczek
Howard J
HJ
Federoff
Krystof
K
Bankiewicz
John
J
Forsayeth
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005552:Forelimb / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D006892:Hydroxydopamines / Q000494:pharmacology; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D006892:Hydroxydopamines; D016753:Interleukin-10; D001058:Apomorphine