Beneficial Effects of Trehalose on Striatal Dopaminergic Deficits in Rodent and Primate Models of Synucleinopathy in Parkinson's Disease

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 369; no. 3; p. 364
• Main Authors: Howson, Patrick A, Johnston, Tom H, Ravenscroft, Paula, Hill, Michael P, Su, Jin, Brotchie, Jonathan M, Koprich, James B
• Format: Journal Article
• Language: English
• Published: United States 01-06-2019
• Subjects: Animals; Behavior, Animal - drug effects; Brain - drug effects; Brain - metabolism; Disease Models, Animal; Dopamine - metabolism; Dose-Response Relationship, Drug; Female; Gene Expression Regulation - drug effects; Macaca fascicularis; Neostriatum - drug effects; Neostriatum - metabolism; Parkinson Disease - blood; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson Disease - pathology; Rats; Tissue Distribution; Trehalose - blood; Trehalose - pharmacokinetics; Trehalose - pharmacology; Trehalose - therapeutic use
• ISSN: 1521-0103
• DOI: 10.1124/jpet.118.255695

Disease modification in Parkinson's disease (PD) is an unmet medical need. In the current study, we evaluated trehalose, a safe and well-tolerated disaccharide that has previously demonstrated efficacy in rodent models of neurodegenerative diseases, including PD. In a rat model of PD, based on delivery of adeno-associated virus serotype 1/2 containing the mutated human A53T
-synuclein gene (AAV1/2-hourA53T-aSyn) to the substantia nigra (SN), we showed that rats administered trehalose (2.67 g/kg per day, by mouth) for 6 weeks had less forelimb asymmetry (93% reduction) and higher striatal dopamine (54% increase) compared with rats receiving vehicle. In a pharmacokinetic study, we determined that efficacy was associated with plasma
of 8900 ng/ml and area under the curve from time 0 to infinity (AUC
) of 11,136 hour⋅ng/ml. We then showed, in macaques, that oral administration of trehalose (2.67 g/kg per day) produced plasma exposures of similar magnitude, with plasma
of 10,918 ng/ml and AUC
of 27,445 hour⋅ng/ml. In a macaque model of PD, also based on delivery of AAV1/2-hourA53T-aSyn to the SN, trehalose (2.67 g/kg per day, by mouth), administered for 142 days, produced higher striatal dopamine (by 39%) and dopamine transporter levels (by 50%), compared with macaques receiving vehicle. In neither model did trehalose treatment prevent loss of tyrosine hydroxylase (TH) positive (TH
) cells in the SN or alter
-synuclein levels in the striatum. These studies demonstrated that trehalose reduces striatal dopaminergic deficits in a rodent and macaque model of synucleinopathy in PD. Furthermore, we have determined the pharmacokinetic parameters associated with efficacy, and thus defined exposures to target in future clinical trials.