Characterising a New Sheep Model of Parkinson's Disease Using Unilateral Intracerebral Injection of 6-Hydroxydopamine Into the Substantia Nigra

Abstract

New therapeutic agents developed for treating neurological disorders are often tested successfully on rodents. Testing in an appropriate large animal model where there is longer lifespan and comparable brain size to humans should improve translational success and is frequently expected by regulatory bodies. In this project, we aimed to establish a novel sheep model of Parkinson's disease as a large-brained experimental model for translational research. Our objective was to create a sheep model of Parkinson's disease by unilaterally infusing the neurotoxin 6-hydroxydopamine into the substantia nigra pars compacta. This approach, previously used to induce parkinsonism in rat and non-human primate models, causes dopaminergic imbalance and induces rotational behaviour in quadrupeds challenged with dopaminergic receptor agonists. In the present sheep study, the mixed dopamine receptor agonist apomorphine, 0.25 mg/kg, and dopamine D2 agonist ropinirole, 0.16 mg/kg, were used to induce rotational behaviour and confirm dopamine depletion. Behavioural signs were then measured and characterised in the field using automated movement tracking with simultaneous video recordings. Post-mortem, the extent of the 6-hydroxydopamine lesions was evaluated through tyrosine hydroxylase immunohistochemistry and quantifying levels of catecholamines (dopamine, 3,4-dihydroxyphenylacetic acid and homovanilic acid) quantified using high-performance liquid chromatography. Our new sheep model of Parkinson's disease using 6-hydroxydopamine is safe and offers a number of regulatory, ethical and financial advantages over non-human primate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine models. It provides a platform to evaluate novel antiparkinsonian agents and medical devices in a large brain with the promise of greater success for translation into clinical application.