In Vivo Dopamine Neuron Imaging-Based Small Molecule Screen Identifies Novel Neuroprotective Compounds and Targets

Area of Science:

• Neuroscience
• Pharmacology
• Genetics

Background:

• Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by dopamine (DA) neuron loss.
• Current therapies for PD offer only symptomatic relief, necessitating the development of disease-modifying treatments.
• Genetic factors, such as mutations in glucocerebrosidase (GBA), are linked to increased PD risk.

Purpose of the Study:

• To identify novel small molecule compounds that can protect dopamine (DA) neurons.
• To discover new biological pathways and therapeutic targets involved in neuroprotection relevant to PD.
• To validate potential therapeutic candidates using secondary assays and disease models.

Main Methods:

• A high-throughput in vivo screening assay was performed using transgenic zebrafish larvae engineered to induce DA neuron loss.
• 1,403 bioactive small molecules were screened, followed by bioinformatic pathway analysis using the Reactome database.
• Promising compounds were validated through secondary imaging assays and tested in a Gaucher disease (GD) model mimicking a PD genetic risk factor.

Main Results:

• 57 compounds demonstrated significant brain health improvement in the primary screen.
• Pathway analysis implicated apoptosis, estrogen hormone, dipeptidyl-peptidase 4, and opioid receptor Mu1 in neuroprotection.
• Etodolac, nepafenac, aloperine, protionamide, and olmesartan showed significant DA neuroprotection, with aloperine, olmesartan, and nepafenac also effective in the GD model.

Conclusions:

• The study presents a novel in vivo screening approach for identifying hit-to-lead candidates for neurodegenerative diseases.
• The findings highlight previously unrecognized pathways and targets for DA neuron protection.
• Several validated compounds, including aloperine, olmesartan, and nepafenac, show potential as disease-modifying therapeutics for PD and related conditions.