A quantitative approach to developing Parkinsonian monkeys ( Macaca fascicularis ) with intracerebroventricular 1-methyl-4-phenylpyridinium injections

Li, Hao; Xu, Lei; Huang, Bo; Rizak, Joshua D.; Yang, Le; Yang, Sharon S.; Wu, Jing; Lü, Longbao; Wang, Jianhong; Yan, Ting; Li, Hongwei; Wang, Zhengbo; Hu, Yingzhou; Deng, Xingli; Li, Jiali; Xu, Lin; Zhang, Baorong; Hu, Xintian

doi:10.1016/j.jneumeth.2015.05.008

Cited by 14 publications

(15 citation statements)

References 42 publications

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“…To induce parkinsonism in cynomolgus monkeys, a quantitative approach was used to develop parkinsonian monkeys with intracerebroventricular injections of MPP + , as previously reported to specifically damage brain dopaminergic neurons 11 . We first administered low-dose (0.05 mg each monkey) MPP + twice a week from the 1.5th month and then increased every one or two months up to 0.18 mg at the 9th month ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…MPP + has been shown to inhibit complex I and produce free radicals, resulting in the death of the neurons. Recently, a new approach was used to develop Parkinsonian monkeys with intracerebroventricular injections of MPP + 11 . This new method avoids the damage of gastrointestinal dopamine neurons induced by MPTP and specifically targets brain dopamine neurons 11 .…”

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confidence: 99%

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Neuroprotective Effects of 7, 8-dihydroxyflavone on Midbrain Dopaminergic Neurons in MPP+-treated Monkeys

Xiang

Zhu

et al. 2016

Sci Rep

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Parkinson’s disease (PD) is one common neurodegenerative disease caused by a significant loss of midbrain dopaminergic neurons. Previous reports showed that 7, 8- dihydroxyflavone (7, 8-DHF) as a potent TrkB agonist can mimic BDNF and play neuroprotective roles for mouse dopaminergic neurons. Nonetheless, the safety and neuroprotective effects are unclear in monkey models of PD. Here, we find that 7, 8-DHF could be absorbed and metabolized into 7-hydroxy-8-methoxyflavone through oral administration in monkeys. The half-life time of 7, 8-DHF in monkey plasma is about 4–8 hrs. Furthermore, these monkeys maintain health state throughout the course of seven-month treatments of 7, 8-DHF (30 mg/kg/day). Importantly, 7, 8-DHF treatments can prevent the progressive degeneration of midbrain dopaminergic neurons by attenuating neurotoxic effects of MPP+ and display strong neuroprotective effects in monkeys. Our study demonstrates that this promising small molecule may be transited into a clinical useful pharmacological agent.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Neuroprotective Effects of 7, 8-dihydroxyflavone on Midbrain Dopaminergic Neurons in MPP+-treated Monkeys

Xiang

Zhu

et al. 2016

Sci Rep

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“…In accordance with the MPTP intoxication protocols, the 12 monkeys were divided into three groups: group I ( n = 5, intramuscular MPTP administration), group II ( n = 3, intracerebroventricular MPTP administration) and the control group ( n = 4, intramuscular saline administration). Because previous study has demonstrated that intracerebroventricular saline administration does not impair monkey’s motor ability (Li et al, 2015 ), no control group receiving intracerebroventricular saline administration had been designed in this study. Before any MPTP administration, each monkey in group II received surgery and had a silicon tube inserted into the lateral cerebral ventricle.…”

Section: Methodsmentioning

confidence: 99%

Severe dopaminergic neuron loss in rhesus monkey brain impairs morphine-induced conditioned place preference

Yan

Rizak

Wang

et al. 2015

Front. Behav. Neurosci.

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It is well known that dopamine (DA) is critical for reward, but the precise role of DA in reward remains uncertain. The aim of this study was to determine what percentage of dopaminergic neurons in the primate brain is required for the expression of conditioned reward by measuring the performance of DA-deficient rhesus monkeys in a morphine-induced conditioned place preference (CPP) paradigm. Animals with mild Parkinsonian symptoms successfully developed and retained a morphine preference that was equivalent to control monkeys. However, these monkeys could not maintain the preference as well as controls when they retained severe Parkinsonian symptoms. On the other hand, monkeys initially in a severe Parkinsonian state developed a preference for morphine, but this preference was weaker than that of the controls. Histological results showed that the loss of dopaminergic neurons in monkeys that had severe Parkinsonian symptoms was about 80% in comparison to the control monkeys. All these data suggest that a severely impaired DA system alters rewarding-seeking behavior in non-human primates.

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“…The next step of video analyzing process was based on previous studies (27,44). Here, two well trained observers were involved in the video clips analyzing.…”

Section: )mentioning

confidence: 99%

“…In monkeys Young 1 and Old 1, sections including the target brain areas were selected and mounted onto slides for staining based on our previous protocols (44,47). In TH staining, sections of the SN were treated with 3% H2O2 (5 min, Maixin, Fuzhou, China), 3% triton X-100 (4 min, Solarbio, Beijing, China), and goat serum (15 min, Maixin, Fuzhou, China) and then incubated with rabbit anti-TH antibody (1: 1,000, AB152, Millipore, USA) overnight at 4 °C.…”

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confidence: 99%

Co-editingPINK1andDJ-1genes via AAV-delivered CRISPR/Cas9 system in adult monkey brains elicits classic Parkinsonian phenotypes

et al. 2020

Preprint

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Whether direct manipulation of Parkinson’s disease (PD) risk genes in monkey brain can elicit Parkinsonian phenotypes remains an unsolved issue. Here, we employed an adeno-associated virus (AAV)-delivered CRISPR/Cas9 system to directly co-edit PINK1 and DJ-1 genes in the substantia nigra (SN) region of four adult monkey brains. After the operation, two of the monkeys exhibited all classic PD symptoms, including bradykinesia, tremor, and postural instability, accompanied by severe nigral dopaminergic neuron loss (over 60%) and α-synuclein pathology. The aged monkeys were more vulnerable to gene editing by showing faster PD progression, higher final total PD scores, and severer pathologic changes compared with their younger counterparts, suggesting both the genetic and aging factors played important roles in PD development. This gene editing system can be used to develop a large quantity of genetically edited PD monkeys over a short period, thus providing a practical transgenic monkey model for future PD studies.

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A quantitative approach to developing Parkinsonian monkeys ( Macaca fascicularis ) with intracerebroventricular 1-methyl-4-phenylpyridinium injections

Cited by 14 publications

References 42 publications

Neuroprotective Effects of 7, 8-dihydroxyflavone on Midbrain Dopaminergic Neurons in MPP+-treated Monkeys

Neuroprotective Effects of 7, 8-dihydroxyflavone on Midbrain Dopaminergic Neurons in MPP+-treated Monkeys

Severe dopaminergic neuron loss in rhesus monkey brain impairs morphine-induced conditioned place preference

Co-editingPINK1andDJ-1genes via AAV-delivered CRISPR/Cas9 system in adult monkey brains elicits classic Parkinsonian phenotypes

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