PUBLICATION
Neuroprotective and neuro-restorative effects of minocycline and rasagiline in a zebrafish 6-hydroxydopamine model of Parkinson's disease
- Authors
- Cronin, A., Grealy, M.
- ID
- ZDB-PUB-171029-4
- Date
- 2017
- Source
- Neuroscience 367: 34-46 (Journal)
- Registered Authors
- Grealy, Maura
- Keywords
- 6-OHDA, Immunohistochemistry, Locomotor activity, Neuro-restoration, Parkinsons's disease, Zebrafish
- MeSH Terms
-
- Disease Models, Animal
- Indans/therapeutic use*
- Parkinson Disease/drug therapy*
- Parkinson Disease/etiology
- Time Factors
- Embryo, Nonmammalian
- Levodopa/therapeutic use
- Minocycline/therapeutic use*
- Zebrafish
- Neuroprotective Agents/therapeutic use*
- Drug Administration Schedule
- Isradipine/therapeutic use
- Animals
- Locomotion/drug effects
- Dopaminergic Neurons/drug effects*
- Tyrosine 3-Monooxygenase/metabolism
- Analysis of Variance
- Adrenergic Agents/toxicity
- Oxidopamine/toxicity
- PubMed
- 29079063 Full text @ Neuroscience
Citation
Cronin, A., Grealy, M. (2017) Neuroprotective and neuro-restorative effects of minocycline and rasagiline in a zebrafish 6-hydroxydopamine model of Parkinson's disease. Neuroscience. 367:34-46.
Abstract
Parkinson's disease is a common, debilitating, neurodegenerative disorder for which the current gold standard treatment, levodopa (L-DOPA) is symptomatic. There is an urgent, unmet need for neuroprotective or, ideally, neuro-restorative drugs. We describe a 6-hydroxydopamine (6-OHDA) zebrafish model to screen drugs for neuroprotective and neuro-restorative capacity. Zebrafish larvae at two days post fertilization were exposed to 6-OHDA for three days, with co-administration of test drugs for neuroprotection experiments, or for 32 hours, with subsequent treatment with test drugs for neuro-restoration experiments. Locomotor activity was assessed by automated tracking and dopaminergic neurons were visualized by tyrosine hydroxylase immuno-histochemistry. Exposure to 6-OHDA for either 32 hours or 3 days induced similar, significant locomotor deficits and neuronal loss in 5 day-old larvae. L-DOPA (1 mM) partially restored locomotor activity, but was neither neuroprotective nor neuro-restorative, mirroring the clinical situation. The calcium channel blocker, isradipine (1 µM) did not prevent or reverse 6-OHDA induced locomotor deficit or neuronal loss. However, both the tetracycline analogue, minocycline (10 µM), and the monoamine oxidase B inhibitor, rasagiline (1 µM), prevented the locomotor deficits and neuronal loss due to three-day 6-OHDA exposure. Importantly, they also reversed the locomotor deficit caused by prior exposure to 6-OHDA; rasagiline also reversed neuronal loss and minocycline partially restored neuronal loss due to prior 6-OHDA, making them candidates for investigation as neuro-restorative treatments for Parkinson's disease. Our findings in zebrafish reflect preliminary clinical findings for rasagiline and minocycline. Thus, we have developed a zebrafish model suitable for high-throughput screening of putative neuroprotective and neuro-restorative therapies for the treatment of Parkinson's disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping