Objective

Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and Amyotrophic lateral sclerosis (ALS) have an increasing socio-economic impact due to an increasingly ageing population. Yet, few drugs have been approved for clinical use in the last two decades. One important mechanism thought to result in the death of neurons in the aging brain is glutamate excitotoxicity. Here, we present a phenotypic cell screening strategy for the identification of novel chemical matter that prevents glutamate excitotoxicity. A robust cellular assay (z’ >0.7; S:B >50) was miniaturised to a 384-well plate and ~1300 compounds were delivered (at 10M) using acoustic dispensing. Glutamate was subsequently added to induce cell death and intracellular ATP content was evaluated 24 h later, as a surrogate marker of cell viability. Using this phenotypic assay, 49 active compounds were identified across two independent experiments which maintained greater than 80% cell viability. Further pharmacological characterisation identified active compounds which displayed a range of potencies, with one compound having a submicromolar IC50 value. Interestingly, this screen identified compounds associated with dopamine, GABA and opioid signalling but not NMDA receptor antagonists. In conclusion, we present a robust cellular assay applicable to the identification of novel neuroprotective agents for the potential treatment of neurodegenerative diseases.