Session Information
Date: Wednesday, June 7, 2017
Session Title: Neuropharmacology
Session Time: 1:15pm-2:45pm
Location: Exhibit Hall C
Objective: To evaluate the preclinical efficacy of trehalose and to identify a dosing regimen that can be used to clinically evaluate trehalose as a disease-modifying therapy for Parkinson’s disease (PD).
Background: Trehalose, a disaccharide approved for human use and an autophagy-enhancer, showed potential for disease-modification in several models of PD. In these studies, trehalose was administered in drinking water and therefore the profile and total amount of trehalose consumed are unknown, impeding translation of the preclinical results into an appropriate clinical study. Using an alpha-synuclein (aSYN) rat model of PD, we evaluated three regimens of trehalose administration.
Methods: Thirty female, Sprague-Dawley rats (280-325 g) split into 5 groups received unilateral injections of AAV1/2 delivering A53T aSYN or empty vector (EV) into the substantia nigra (SN). Commencing on day of surgery and continuing for 6 weeks, rats received vehicle (sterile drinking water) or trehalose (2.67 g/kg/day) administered in the drinking water (2% w/v), as three separate administrations 8 h apart (0.89 g/kg/t.i.d., p.o.) or as a single administration (2.67 g/kg/day, p.o).
Behaviour was assessed pre-surgery, 3 and 6 weeks post-surgery using the cylinder test of forelimb asymmetry. After 6 weeks the rats were killed and striatal tissue analysed for dopamine (HPLC) and aSYN (Western blotting) levels. The number of TH+ve cells in the SN was assessed stereologically.
Results: Rats receiving A53T aSYN and vehicle exhibited increased forelimb asymmetry at Weeks 3 and 6 compared to rats receiving EV. Furthermore, striatal dopamine levels were reduced and A53T aSYN load per TH+ve neuron were increased cf. rats receiving EV. Administration of trehalose as a single oral administration (2.67 g/kg/day, p.o) reduced asymmetry to a level similar to rats receiving EV, increased striatal dopamine levels (by 54%) and reduced the A53T aSYN load per TH+ve neuron (by 41%) cf. rats receiving A53T aSYN alone. Administration of the same amount of trehalose as either 3 doses, 8 h apart or ad libitum in the drinking water did not alter behaviour, striatal dopamine levels or the amount of A53T aSYN per TH+ve neuron.
Conclusions: In AAV aSYN rats, a single daily oral administration of trehalose was efficacious and thus is the most appropriate regimen to use in the clinical evaluation of trehalose in PD.
To cite this abstract in AMA style:
J. Koprich, P. Howson, T. Johnston, M. Hill, P. Ravenscroft, J. Brotchie. Identification of a trehalose treatment regimen with potential to be translated into a therapeutic for the treatment of Parkinson’s disease [abstract]. Mov Disord. 2017; 32 (suppl 2). https://www.mdsabstracts.org/abstract/identification-of-a-trehalose-treatment-regimen-with-potential-to-be-translated-into-a-therapeutic-for-the-treatment-of-parkinsons-disease/. Accessed November 5, 2024.« Back to 2017 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/identification-of-a-trehalose-treatment-regimen-with-potential-to-be-translated-into-a-therapeutic-for-the-treatment-of-parkinsons-disease/