Progressive and extensive dopaminergic degeneration induced by convection-enhanced delivery of 6-hydroxydopamine into the rat striatum: a novel rodent model of Parkinson disease

Oiwa, Yoshitsugu; Sánchez‐Pernaute, Rosario; Harvey−White, Judith; Bankiewicz, Krzysztof S.

doi:10.3171/jns.2003.98.1.0136

Cited by 30 publications

(23 citation statements)

References 32 publications

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“…Male SD rats (225-300 g) underwent stereotactic 6-hydroxydopamine (6-OHDA) lesions of bilateral striata by using a convectionenhanced delivery approach to minimize mechanical and nonspecific damage to striatal neurons (Oiwa et al, 2003). In brief, under isoflurane anesthesia (1-2% in O 2 for maintenance), the rats' heads were placed in a stereotactic frame (David Kopf Instruments, Tujunga, CA), the scalp was exposed by a midline incision, and burr holes were drilled through the skull at anterior-posterior ϩ 0.7 mm; lateral Ϯ 2.8 mm relative to Bregma (Paxinos and Watson, 1997).…”

Section: In Vivo Studiesmentioning

confidence: 99%

A Potent and Selective Metabotropic Glutamate Receptor 4 Positive Allosteric Modulator Improves Movement in Rodent Models of Parkinson's Disease

Poul

Boléa²,

Girard³

et al. 2012

J Pharmacol Exp Ther

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Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGluR4) have been proposed as a novel therapeutic approach for the treatment of Parkinson's disease. However, evaluation of this proposal has been limited by the availability of appropriate pharmacological tools to interrogate the target. In this study, we describe the properties of a novel mGluR4 PAM. 5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine (ADX88178) enhances glutamate-mediated activation of human and rat mGluR4 with EC 50 values of 4 and 9 nM, respectively. The compound is highly selective for mGluR4 with minimal activities at other mGluRs. Oral administration of ADX88178 in rats is associated with high bioavailability and results in cerebrospinal fluid exposure of Ͼ50-fold the in vitro EC 50 value. ADX88178 reverses haloperidol-induced catalepsy in rats at 3 and 10 mg/kg. It is noteworthy that this compound alone has no impact on forelimb akinesia resulting from a bilateral 6-hydroxydopamine lesion in rats. However, coadministration of a low dose of L-DOPA (6 mg/kg) enabled a robust, dosedependent reversal of the forelimb akinesia deficit. ADX88178 also increased the effects of quinpirole in lesioned rats and enhanced the effects of L-DOPA in MitoPark mice. It is noteworthy that the enhancement of the actions of L-DOPA was not associated with an exacerbation of L-DOPA-induced dyskinesias in rats. ADX88178 is a novel, potent, and selective mGluR4 PAM that is a valuable tool for exploring the therapeutic potential of mGluR4 modulation. The use of this novel tool molecule supports the proposal that activation of mGluR4 may be therapeutically useful in Parkinson's disease.

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Section: In Vivo Studiesmentioning

confidence: 99%

A Potent and Selective Metabotropic Glutamate Receptor 4 Positive Allosteric Modulator Improves Movement in Rodent Models of Parkinson's Disease

Poul

Boléa²,

Girard³

et al. 2012

J Pharmacol Exp Ther

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“…Early versions of the intrastriatal 6-OHDA model relied upon single or multiple sites of toxin injection, which results in a partial lesion and considerable variation in the extent and location of the lesion within the striatum [3][4][5][6]. Recently, a novel delivery paradigm, employing convection enhanced delivery (CED) of 6-OHDA to the striatum, was developed as a more uniform model of DA neuron degeneration [7]. In the CED model, 6-OHDA administration to the striatum results in distribution of the toxin throughout the striatum leading to less animal to animal variation and potentially making this model more suitable for neuroprotection studies [7].…”

Section: Introductionmentioning

confidence: 99%

Molecular Profiling of a 6-Hydroxydopamine Model of Parkinson’s Disease

DiLella

Lis

et al. 2010

Neurochem Res

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Convection enhanced delivery of 6-hydroxydopamine (6-OHDA) to the rat striatum results in a model of Parkinson's disease. An important feature of this unilateral model is the progressive loss of dopaminergic (DA) neurons over the course of several weeks. To improve the understanding of this model, gene expression changes in the substantia nigra, which contains the DA neuron cell bodies, and the striatum, which contains the DA neuron synaptic terminals, were examined using DNA microarrays. Samples were collected and behavior was analyzed from vehicle and toxin treated animals at 3 days, 1 week, 2 weeks and 4 weeks following 6-OHDA treatment. Tissue DA content was determined and samples from animals which exhibited a substantial depletion of striatal DA were included in the subsequent gene expression analysis. The results of the gene expression analysis indicated that 6-OHDA elicits a vigorous inflammatory response, comprised of several distinct pathways, in the striatum at the earliest time point tested. In contrast, relatively few gene expression changes were observed in the SN at the 3-day time point. In both tissues examined there was evidence for a vigorous inflammatory response at the 1- and 2-week time points, which was substantially diminished by the 4-week time point. Inflammation plays a prominent role in the 6-OHDA model of Parkinson's disease.

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“…Adenoassociated virus serotype 2 (AAV2) vectors were produced by means of the triple transfection method (Matsushita et al, 1998). Vectors were infused bilaterally into the striatum (10 l of a 1 ϫ 10 13 vector genome per milliliter of solution per striatum) of adult rats (n ϭ 6 per group) by convection-enhanced delivery (CED) as described previously (Oiwa et al, 2003). Four weeks after vector delivery, 10 g of 6-hydroxydopamine (6-OHDA) suspended in 20 l of sterile saline with 0.2% w/v ascorbate was infused into the right striatum by CED.…”

Section: Methodsmentioning

confidence: 99%

“…AAV2-rGDNF-ZFP or AAV2-GFP control vectors were infused bilaterally into the striatum of adult rats (n ϭ 6 per group) by CED. Four weeks after vector delivery, 10 g of 6-OHDA was infused into the right striatum by CED, triggering the loss of dopaminergic neurons in the ipsilateral substantia nigra that is manifested by a series of behavioral abnormalities (Oiwa et al, 2003). Our experimental design for examining the effect of AAV2-rGDNF-ZFP on 6-OHDA-induced defects is shown in Figure 3B.…”

Section: Zfp-driven Activation Of Rat Gdnfmentioning

confidence: 99%

“…3D). Finally, 15 d after 6-OHDA administration, rats were subjected to a drug-induced rotational test, in which rats with unilateral substantia nigra lesion rotate toward the lesioned side after intraperitoneal injection of amphetamine (Oiwa et al, 2003). AAV2-rGDNF-ZFP-treated rats exhibited a significant reduction in the rotational behavior (2.0 Ϯ 0.6 rotations/min) compared to the AAV2-GFP-treated rats (10.6 Ϯ 2.0 rotations/min) ( p ϭ 0.001) (Fig.…”

Section: Zfp-driven Activation Of Rat Gdnfmentioning

confidence: 99%

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An Engineered Zinc Finger Protein Activator of the Endogenous Glial Cell Line-Derived Neurotrophic Factor Gene Provides Functional Neuroprotection in a Rat Model of Parkinson's Disease

Laganière¹,

Kells²,

Lai³

et al. 2010

J. Neurosci.

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Loss of dopaminergic neurons is primarily responsible for the onset and progression of Parkinson's disease (PD); thus, neuroprotective and/or neuroregenerative strategies remain critical to the treatment of this increasingly prevalent disease. Here we explore a novel approach to neurotrophic factor-based therapy by engineering zinc finger protein transcription factors (ZFP TFs) that activate the expression of the endogenous glial cell line-derived neurotrophic factor (GDNF) gene. We show that GDNF activation can be achieved with exquisite genome-wide specificity. Furthermore, in a rat model of PD, striatal delivery of an adeno-associated viral vector serotype 2 encoding the GDNF activator resulted in improvements in forelimb akinesia, sensorimotor neglect, and amphetamine-induced rotations caused by 6-hydroxydopamine (6-OHDA) lesion. Our results suggest that an engineered ZFP TF can drive sufficient GDNF expression in the brain to provide functional neuroprotection against 6-OHDA; therefore, targeted activation of the endogenous gene may provide a method for delivering appropriate levels of GDNF to PD patients.

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Progressive and extensive dopaminergic degeneration induced by convection-enhanced delivery of 6-hydroxydopamine into the rat striatum: a novel rodent model of Parkinson disease

Cited by 30 publications

References 32 publications

A Potent and Selective Metabotropic Glutamate Receptor 4 Positive Allosteric Modulator Improves Movement in Rodent Models of Parkinson's Disease

A Potent and Selective Metabotropic Glutamate Receptor 4 Positive Allosteric Modulator Improves Movement in Rodent Models of Parkinson's Disease

Molecular Profiling of a 6-Hydroxydopamine Model of Parkinson’s Disease

An Engineered Zinc Finger Protein Activator of the Endogenous Glial Cell Line-Derived Neurotrophic Factor Gene Provides Functional Neuroprotection in a Rat Model of Parkinson's Disease

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