PT  - JOURNAL ARTICLE
AU  - Patrick A. Howson
AU  - Tom H. Johnston
AU  - Paula Ravenscroft
AU  - Michael P. Hill
AU  - Jin Su
AU  - Jonathan M. Brotchie
AU  - James B. Koprich
TI  - Beneficial Effects of Trehalose on Striatal Dopaminergic Deficits in Rodent and Primate Models of Synucleinopathy in Parkinson’s Disease
AID  - 10.1124/jpet.118.255695
DP  - 2019 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 364--374
VI  - 369
IP  - 3
4099  - http://jpet.aspetjournals.org/content/369/3/364.short
4100  - http://jpet.aspetjournals.org/content/369/3/364.full
SO  - J Pharmacol Exp Ther2019 Jun 01; 369
AB  - 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 α-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 Cmax of 8900 ng/ml and area under the curve from time 0 to infinity (AUC0–inf) 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 Cmax of 10,918 ng/ml and AUC0–inf 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+ve) cells in the SN or alter α-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.