Delivery of a GDNF Gene into the Substantia Nigra after a Progressive 6-OHDA Lesion Maintains Functional Nigrostriatal Connections

Kozlowski, Dorothy A.; Connor, Bronwen; Tillerson, Jennifer L.; Schallert, Timothy; Bohn, Martha C.

doi:10.1006/exnr.2000.7463

Cited by 98 publications

(62 citation statements)

References 41 publications

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“…[19][20][21] In our model, the number of CTB-positive neurons on the lesioned side of SN was 28.9% of contralateral value at 4 weeks postlesion. This is consistent with the previous studies using Fluorogold (FG)-retrograde labelling that demonstrated 28.8% (35 days post-lesion) 22 or 34% (4 weeks postlesion) 17 of FG-positive cells in the lesioned SN. In addition, most CTB-labeled neurons were TH-positive, suggesting that part of the nigrostriatal projection remained intact at the time of AAV vector injection.…”

Section: Discussionsupporting

confidence: 93%

“…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. Conversely, expression of GDNF in the striatum did not exhibit significant ameliorative effects at 35 days postlesion.…”

Section: Discussionmentioning

confidence: 99%

“…Optical density of TH-IR fibers was quantified on sections every 300 m rostro-caudally throughout the striatum using NIH Image 1.59 software. 22 …”

Section: Biochemical Analysismentioning

confidence: 99%

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

et al. 2002

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Glial cell line-derived neurotrophic factor (GDNF) is a strong candidate agent in the neuroprotective treatment of Parkinson's disease (PD). We investigated whether adeno-associated viral (AAV) vector-mediated delivery of a GDNF gene in a delayed manner could prevent progressive degeneration of dopaminergic (DA) neurons, while preserving a functional nigrostriatal pathway. Four weeks after a unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA), rats received injection of AAV vectors expressing GDNF tagged with FLAG peptide (AAV-GDNFflag) or ␤-galactosidase (AAV-LacZ) into the lesioned striatum. Immunostaining for FLAG demonstrated retrograde transport of GDNFflag to the substantia nigra (SN). The density of tyrosine hydroxylase

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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

et al. 2002

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“…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.…”

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confidence: 99%

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

Smith

Amalric²,

Koob

et al. 2002

Neuropsychopharmacology

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Overt symptoms of Parkinson's disease do not manifest themselves until there is a substantial loss of the dopaminergic nigrostriatal projection. However, as neuroprotective strategies are developed, it will be essential to detect the disease in its preclinical phase. Performance on conditioned reaction time tasks is known to be impaired by extensive 6-hydroxydopamine-induced lesions of theThe primary neuropathology of Parkinson's disease is the loss of dopamine (DA) neurons within the substantia nigra (SN) and massive depletion of DA in the striatum, the terminal region of the SN. This loss of DA appears to be responsible for the most prominent symptoms of Parkinson's disease. The degree of neurological deficit is related to the loss of striatal DA (Hornykiewicz and Kish 1987). The neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), used extensively to induce selective loss of DA neurons within the SN, provide animal models that share several of the characteristics of Parkinson's disease (see reviews by Zigmond and Keefe 1997;Jenner and Marsden 1986;Gerlach and Riederer NO . 6 Bilateral 6-OHDA on Reaction Time 7571996; Przedborski and Jackson-Lewis 1998). In addition, whereas intrastriatal injection of indirect DA agonists induces stereotypy (Costall et al. 1973;Statton and Solomon 1984), 6-OHDA lesions of the striatum block this stereotyped behavior (Price and Fibiger 1974). Finally, chronic administration of DA receptor antagonists produce extrapyramidal effects reminiscent of Parkinson's disease, and this is believed to be due to their action at D 2 receptors located in the striatum (Coffin et al. 1989). Although resting tremor and muscular rigidity are generally not reported in rodents after pharmacological manipulation of the nigrostriatal pathway, deficits in movement initiation and execution have been studied using several tests including a conditioned reaction time task. In this task, animals are typically required to respond in a particular way and within a limited period in order to receive a reward, such as a food pellet. This behavioral paradigm is responsive to pharmacological manipulation of dopaminergic neurotransmission mediated by the D 2 subtype of DA receptors Koob 1987, 1989;Amalric et al. 1993Amalric et al. , 1995Smith et al. 2000). For example, we have shown that low dose blockade of D 2 receptors, but not D 1 or D 3 receptors, decreased correct responses in the conditioned reaction time task, increased delayed responses, and lengthened reaction time in a manner suggestive of dysfunctions in movement initiation (Amalric et al. 1993;Smith et al. 2000). Moreover, deficits in reaction time have also been reported in Parkinson's disease (Evarts et al. 1981;Gauntlett-Gilbert and Brown 1998;Berry et al. 1999). These deficits appear to be mediated by the nigrostriatal dopaminergic pathway, as 6-OHDA-induced loss of SN neurons and striatal DA, and not accumbal DA, produces impairments in this task (Amalric and Koob 1987), and intrastriatal infusion...

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“…Adenoviral vector delivery of GDNF into or close to the substantia nigra [46,47] or into the striatum [48,49] of rats with intrastriatal 6-OHDA lesions resulted in significant motor improvements and protection of nigral dopaminergic neurones. Adenoviral-delivered GDNF induced behavioural and neuroprotective effects when injected into the substantia nigra, but not into the striatum, in rats that had intrastriatal 6-OHDA lesions [50]. In MPTP-treated mice, adenoviral vector-mediated GDNF delivery to the striatum prevented depletion of striatal dopamine levels [51].…”

Section: Effects Of Gdnf In Vivomentioning

confidence: 99%

Neurotrophic factors for the treatment of Parkinson's disease

Sullivan

Toulouse

2011

Cytokine & Growth Factor Reviews

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Delivery of a GDNF Gene into the Substantia Nigra after a Progressive 6-OHDA Lesion Maintains Functional Nigrostriatal Connections

Cited by 98 publications

References 41 publications

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

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

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

Neurotrophic factors for the treatment of Parkinson's disease

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