Differential effects of glial cell line-derived neurotrophic factor (GDNF) in the striatum and substantia nigra of the aged Parkinsonian rat

Abstract

Injection of an adenoviral (Ad) vector encoding human glial intrastriatal injection of 6-OHDA on the same side as the cell line-derived neurotrophic factor (GDNF) protects dopavector injection. AdGDNF injection into either the striatum minergic (DA) neurons in the substantia nigra (SN) of or SN significantly reduced the loss of FG labelled DA neuyoung rats. As Parkinson's disease occurs primarily in rons 5 weeks after lesion (P р 0.05). However, only striatal aged populations, we examined whether chronic biosyninjections of AdGDNF protected against the development thesis of GDNF, achieved by adenovirus-mediated delivery of behavioral deficits characteristic of unilateral DA of a GDNF gene (AdGDNF), can protect DA neurons and depletion. Striatal AdGDNF injections also reduced tyroimprove DA-dependent behavioral function in aged (20 sine hydroxylase fiber loss and increased amphetaminemonths) rats with progressive 6-OHDA lesions of the nigroinduced striatal Fos expression. These results demonstrate striatal projection. Furthermore, the differential effects of that increased levels of striatal, but not nigral, GDNF injecting AdGDNF either near DA cell bodies in the SN or biosynthesis prevents DA neuronal loss and protects DA at DA terminals in the striatum were compared. AdGDNF terminals from 6-OHDA-induced damage, thereby or control vector was injected unilaterally into either the strimaintaining DA function in the aged rat. atum or SN. One week later, rats received a unilateral

Delayed delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson's disease

“…[5][6][7][8][9][10][11][12] However, when GDNF is administered with a delay after the insult, sparing of DA neurons is only marginal and the magnitude of functional recovery probably reflects the number of DA neurons still surviving and maintaining nigrostriatal connections. 10,[23][24][25] In contrast with previous studies 10,26 in which three or four deposits of 6-OHDA were injected to create more extensive striatal lesions, 6-OHDA was injected at only one site in our model and less damage might have been incurred to nigrostriatal connections. Using adenoviral vectors Kozlowski et al 22 demonstrated that delivering GDNF gene to the SN 1 week after lesioning rescued DA neurons and increased the number of DA neurons maintaining a connection to the striatum.…”

Effect of Bilateral 6-Hydroxydopamine Lesions of the Medial Forebrain Bundle on Reaction Time

“…However, the ability to detect deficits prior to a majority loss of striatal DA would be quite useful. Recent evidence shows that several trophic factors are neuroprotective in animal models of Parkinson's disease when these factors are administered either before or after appreciable loss of striatal DA and SN neurons (Choi-Lundberg et al 1997Rosenblad et al 1998;Connor et al 1999;Kozlowski et al 2000). Should these or other treatments prove to be clinically efficacious, it will be essential to develop neurological tests that detect nigrostriatal degeneration in the "preclinical" phase of Parkinson's disease so that neuroprotective strategies can be used to delay or even prevent the appearance of more disruptive functional deficits.…”

Delivery of GDNF by an E1,E3/E4 deleted adenoviral vector and driven by a GFAP promoter prevents dopaminergic neuron degeneration in a rat model of Parkinson's disease

“…The results obtained in this work are consistent with previous studies by our group 11 and others 9,14 using Ad/AAV-GDNF injected in the striatum. In addition, these authors 9,11,14 found (1) that the intensity of the TH immunoreactivity was increased in the injected striatum, as compared to control 9,11,14 and (2) that the axonal sprouting was present in the striatum and the globus pallidus. 9 In our rats treated with Ad-GFAP-GDNF, although the sprouting was observed in the striatum and the globus pallidus (Figures 7 and 8), the intensity of the striatal TH staining was not modified in the injected side.…”

“…The effects obtained in vivo depend on the time and site of administration of recombinant virus. 14,15 Although these results were encouraging for gene therapy, the first-generation adenovirus had a toxic effect for transduced cells by inducing the synthesis of viral proteins within these cells. These proteins elicit an immune response in the injected brains, which generates toxicity.…”