Preclinical Models of Parkinson's Disease

Bankiewicz, Krzysztof S.; Sánchez‐Pernaute, Rosario; Oiwa, Yoshitsugu; Kohutnicka, M; Cummins, Alex; Eberling, Jamie L.

doi:10.1002/0471140856.tx0108s18

Cited by 20 publications

(24 citation statements)

References 39 publications

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“…Unilateral ICA infusion of MPTP induces quite severe and stable parkinsonism, corresponding to more than 95% loss of striatal dopamine concentration and 90% loss of nigral dopamine neurons. 5,6,31) The severity of dopamine depletion corresponds to stage 5 of the Hoehn and Yahr classification in human Parkinson disease. 12) We suggest that the dose of GDNF, 50 mg × 2 infusions, is not sufficient for severe parkinsonism equivalent to stage 5.…”

Section: Discussionmentioning

confidence: 99%

“…The hemiparkinsonian model was induced by infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) into the unilateral internal carotid artery (ICA) as described previously. 5,6) In this model, the animals exhibit advanced parkinsonian signs in the limbs contralateral to the MPTP infusion with massive degeneration of the substantia nigra dopamine neurons. MPTP (2.5 mg in 50 ml saline) was infused into the ipsilateral ICA in the three monkeys with unilateral cannula implantation into the putamen.…”

Section: Models Of Parkinson Diseasementioning

confidence: 99%

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Histological Effects of Intraputaminal Infusion of Glial Cell Line-Derived Neurotrophic Factor in Parkinson Disease Model Macaque Monkeys

Oiwa

Nakai

Itakura

2006

Neurol. Med. Chir.(Tokyo)

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Glial cell line-derived neurotrophic factor (GDNF) is a potent neuroprotection and regeneration molecule for dopamine neurons in the substantia nigra. A recent clinical study showed that intraputaminal infusions of GDNF restored the striatal dopaminergic function, resulting in improvement in patients with Parkinson disease. To investigate the efficacy and the safety of this treatment, the histological changes associated with intraputaminal GDNF infusions were investigated in non-human primate models of Parkinson disease. Two types of Parkinson disease model were constructed: unilateral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) into the internal carotid artery to induce hemiparkinsonism and intermittent systemic injection to induce Parkinson disease. GDNF (50 mg) was infused into the putamen on the day of the first MPTP treatment and 4 weeks later. The monkey brains were examined by immunohistochemistry 2-4 weeks after the second GDNF infusion. Losses of the nigral dopamine neurons were mild (30-50% loss) on the side of GDNF infusion, and moderate (approximately 70% loss) on the side of vehicle infusion in the Parkinson disease model. The dopamine fibers were thick and dense in the striatum around the GDNF infusion sites. Both GDNF-and vehicle-treated monkeys of the hemiparkinsonian model showed severe decrease of dopamine neurons to 10% of the intact side. Although reactive astrocytes proliferated around the GDNF infusion sites, the densities of striatal neurons involving GABAergic and cholinergic neurons were not affected. Intraputaminal infusions of GDNF have beneficial effects in parkinsonian monkeys, but dose control is required according to the severity of the disease. The specificity for dopamine neurons is quite high and there are no serious histological changes.

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Section: Discussionmentioning

confidence: 99%

Section: Models Of Parkinson Diseasementioning

confidence: 99%

Histological Effects of Intraputaminal Infusion of Glial Cell Line-Derived Neurotrophic Factor in Parkinson Disease Model Macaque Monkeys

Oiwa

Nakai

Itakura

2006

Neurol. Med. Chir.(Tokyo)

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“…In addition, we collected baseline global motor activity using activity monitors (Actiwatch; Mini-Mitter, Bend, OR). Both tests provide objective measures of bradykinesia and hypokinesia, respectively, and are sensitive to MPTP-induced motor deficit in macaques (Bankiewicz et al, 1999).…”

Section: Methodsmentioning

confidence: 99%

Mapping Dopamine Function in Primates Using Pharmacologic Magnetic Resonance Imaging

Jenkins¹,

Sánchez‐Pernaute²,

Brownell³

et al. 2004

J. Neurosci.

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Dopamine (DA) receptors play a central role in such diverse pathologies as Parkinson's disease, schizophrenia, and drug abuse. We used an amphetamine challenge combined with pharmacologic magnetic resonance imaging (phMRI) to map DA-associated circuitry in nonhuman primates with high sensitivity and spatial resolution. Seven control cynomolgous monkeys and 10 MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated parkinsonian primates were studied longitudinally using both positron emission tomography (PET) and phMRI. Amphetamine challenge (2.5 mg/kg, i.v.) in control monkeys increased relative cerebral blood volume (rCBV) in a number of brain regions not described previously, such as parafascicular thalamus, precentral gyrus, and dentate nucleus of the cerebellum. With the high spatial resolution, we were also able to readily identify changes in rCBV in the anterior cingulate, substantia nigra, ventral tegmental area, caudate (tail and head), putamen, and nucleus accumbens. Amphetamine induced decreases in rCBV in occipital and posterior parietal cortices. Parkinsonian primates had a prominent loss of response to amphetamine, with relative sparing of the nucleus accumbens and parafascicular thalamus. There was a significant correlation between rCBV loss in the substantia nigra and both PET imaging of dopamine transporters and behavioral measures. Monkeys with partial lesions as defined by 2␤-carbomethoxy-3␤-(4-fluorophenyl) tropane binding to dopamine transporters showed recruitment of premotor and motor cortex after amphetamine stimulus similar to what has been noted in Parkinson's patients during motor tasks. These data indicate that phMRI is a powerful tool for assessment of dynamic changes associated with normal and dysfunctional DA brain circuitry in primates.

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“…Ten adult female rhesus monkeys (Macaca mulatta, 5.2-12.8 kg) were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as previously described (Bankiewicz et al, 1986(Bankiewicz et al, , 2000Eberling et al, 1998). Briefly, MPTP lesioning consisted of one right intracarotid artery infusion of 2.0-4.0 mg of MPTP-HCl.…”

Section: Animalsmentioning

confidence: 99%

“…CED is a pressurized parenchymal infusion technique that allows therapeutic agents to be distributed throughout large volumes of brain (Bobo et al, 1994). CED of AAV2-hAADC results in robust, essentially permanent, gene expression in the striatum and its beneficial effect has been demonstrated in several preclinical studies in rodent and nonhuman primate (NHP) models of PD (Bankiewicz et al, 2000(Bankiewicz et al, , 2006SanchezPernaute et al, 2001;Forsayeth et al, 2006;Hadaczek et al, 2010). These preclinical studies led to a phase I clinical trial in patients with PD (Eberling et al, 2008;Christine et al, 2009;Valles et al, 2010), in which two cohorts of patients with moderately advanced PD received a bilateral infusion of either a low or high dose of AAV2-hAADC vector into the putamen.…”

mentioning

confidence: 99%

Safety and Tolerability of Magnetic Resonance Imaging-Guided Convection-Enhanced Delivery of AAV2-hAADC with a Novel Delivery Platform in Nonhuman Primate Striatum

et al. 2012

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Degeneration of nigrostriatal neurons in Parkinson's disease (PD) causes progressive loss of aromatic l-amino acid decarboxylase (AADC), the enzyme that converts levodopa (l-DOPA) into dopamine in the striatum. Because loss of this enzyme appears to be a major driver of progressive impairment of response to the mainstay drug, l-DOPA, one promising approach has been to use gene therapy to restore AADC activity in the human putamen and thereby restore normal l-DOPA response in patients with PD. An open-label phase I clinical trial of this approach in patients with PD provided encouraging signs of improvement in Unified Parkinson's Disease Rating Scale scores and reductions in antiparkinsonian medications. However, such improvement was modest compared with the results previously reported in parkinsonian rhesus macaques. The reason for this discrepancy may have been that the relatively small volume of vector infused in the clinical study restricted the distribution of AADC expression, such that only about 20% of the postcommissural putamen was covered, as revealed by l-[3-18 F]-a-methyltyrosine-positron emission tomography. To achieve more quantitative distribution of vector, we have developed a visual guidance system for parenchymal infusion of AAV2. The purpose of the present study was to evaluate the combined magnetic resonance imaging-guided delivery system with AAV2-hAADC under conditions that approximate the intended clinical protocol. Our data indicate that this approach directed accurate cannula placement and effective vector distribution without inducing any untoward effects in nonhuman primates infused with a high dose of AAV2-hAADC.

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Preclinical Models of Parkinson's Disease

Cited by 20 publications

References 39 publications

Histological Effects of Intraputaminal Infusion of Glial Cell Line-Derived Neurotrophic Factor in Parkinson Disease Model Macaque Monkeys

Histological Effects of Intraputaminal Infusion of Glial Cell Line-Derived Neurotrophic Factor in Parkinson Disease Model Macaque Monkeys

Mapping Dopamine Function in Primates Using Pharmacologic Magnetic Resonance Imaging

Safety and Tolerability of Magnetic Resonance Imaging-Guided Convection-Enhanced Delivery of AAV2-hAADC with a Novel Delivery Platform in Nonhuman Primate Striatum

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