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

Abstract

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 a-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 C max of 8900 ng/ml and area under the curve from time 0 to infinity (AUC 0-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 C max of 10,918 ng/ml and AUC 0-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 1ve) cells in the SN or alter a-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.

The Vicious Cycle Between α‐Synuclein Aggregation and Autophagic‐Lysosomal Dysfunction

“…Similar effects were observed in a neurotoxin MPTP‐induced PD mouse model . Recently, trehalose has been tested in parallel on rat and nonhuman primate PD models overexpressing A53T α‐syn . In both models, trehalose prevented the development of striatal dopamine loss and behavioral deficits.…”

“…140 Recently, trehalose has been tested in parallel on rat and nonhuman primate PD models overexpressing A53T α-syn. 143 In both models, trehalose prevented the development of striatal dopamine loss and behavioral deficits. Considering the safety of trehalose in humans 144 and its long half-life in the brain, where levels of trehalase are low, 145 further investigations aimed at evaluating the efficacy of this disaccharide in PD treatment and/or prevention are recommended.…”

Protective effects of trehalose against Mn‐induced α‐synuclein oligomerization in mice: Involvement of oxidative stress and autophagy

“…However, Howson found that Tre reduces striatal dopaminergic deficits in a rodent model of PD synucleinopathy. However, Tre did not affect the α‐Syn expression levels . First, under physiological conditions, α‐Syn functions in its native conformation as a soluble monomer.…”

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

“…The mechanisms behind trehalose-mediated MA activation were further investigated and demonstrated that trehalose activated MA through the inhibition of the glucose transporter SLC2A, finally leading to the activation of the AMPK protein [325]. More recently, a pharmacokinetic study showed that a daily oral administration of trehalose was more efficient than administration of the same dose by drinking water in A53T α-syn rat model of PD, and prevented from α-syn-mediated neurodegeneration and motor deficits [326]. They also showed that trehalose oral administration was efficient to prevent from α-syn-induced striatal dopaminergic deficits in a macaque model overexpressing human A53T α-syn, although they failed to show beneficial effects on α-syn levels [326].…”

“…More recently, a pharmacokinetic study showed that a daily oral administration of trehalose was more efficient than administration of the same dose by drinking water in A53T α-syn rat model of PD, and prevented from α-syn-mediated neurodegeneration and motor deficits [326]. They also showed that trehalose oral administration was efficient to prevent from α-syn-induced striatal dopaminergic deficits in a macaque model overexpressing human A53T α-syn, although they failed to show beneficial effects on α-syn levels [326]. Altogether, trehalose has been identified as an interesting drug to target α-syn, but the correct dose and administration remains to be identified.…”