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. 2021 Mar 16;4(2):858-869.
doi: 10.1021/acsptsci.1c00013. eCollection 2021 Apr 9.

Sustained Release GLP-1 Agonist PT320 Delays Disease Progression in a Mouse Model of Parkinson's Disease

Vicki Wang  1 , Tung-Tai Kuo  2 , Eagle Yi-Kung Huang  3 , Kuo-Hsing Ma  4 , Yu-Ching Chou  5 , Zhao-Yang Fu  6 , Li-Wen Lai  7 , Jin Jung  8 , Hoi-Ii Choi  8 , Doo-Sup Choi  9 , Yazhou Li  10 , Lars Olson  11 , Nigel H Greig  10 , Barry J Hoffer  12 , Yuan-Hao Chen  6
Affiliations

Sustained Release GLP-1 Agonist PT320 Delays Disease Progression in a Mouse Model of Parkinson's Disease

Vicki Wang et al. ACS Pharmacol Transl Sci. .

Abstract

GLP-1 agonists have become increasingly interesting as a new Parkinson's disease (PD) clinical treatment strategy. Additional preclinical studies are important to validate this approach and define the disease stage when they are most effective. We hence characterized the efficacy of PT320, a sustained release formulation of the long acting GLP-1 agonist, exenatide, in a progressive PD (MitoPark) mouse model. A clinically translatable biweekly PT320 dose was administered starting at 5 weeks of age and longitudinally evaluated to 24 weeks, and multiple behavioral/cellular parameters were measured. PT320 significantly improved spontaneous locomotor activity and rearing in MitoPark PD mice. "Motivated" behavior also improved, evaluated by accelerating rotarod performance. Behavioral improvement was correlated with enhanced cellular and molecular indices of dopamine (DA) midbrain function. Fast scan cyclic voltammetry demonstrated protection of striatal and nucleus accumbens DA release and reuptake in PT320 treated MitoPark mice. Positron emission tomography showed protection of striatal DA fibers and tyrosine hydroxylase protein expression was augmented by PT320 administration. Early PT320 treatment may hence provide an important neuroprotective therapeutic strategy in PD.

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Conflict of interest statement

The authors declare the following competing financial interest(s): J.J. and H.C. are employees of Peptron Inc. D.S.C. is a scientific advisor to Peptron, Inc. The Intramural Research Program of the National Institute on Aging, NIH, and Peptron, Inc., have a Cooperative Research and Development Agreement to develop Ex-4 as a treatment strategy for neurodegenerative disorders for which NIA and Peptron, Inc., hold patent rights via the work of H.C. and N.G. L.O. is a former co-owner of a company owning commercial rights to the MitoPark mouse.

Figures

Figure 1
Figure 1
Schematic time line of biweekly administration of PT320 to MitoPark animals and behavioral as well as cellular and molecular tests.
Figure 2
Figure 2
(A) Overall locomotor activity and rearing events in MitoPark mice at early time points (8 and 10 weeks). PT320 administration was initiated at 5 weeks, as this time is in line with the first described changes in mitochondrial morphology. Unpaired t-test; **, p < 0.01, and ***, p < 0.001. (B) Rearing of 10–16 week old MitoPark animals. These time points were selected to coincide with described changes in TH immunocytochemistry and DA levels in striatum, as previously measured with HPLC. Unpaired t-test; *, p < 0.05; **, p < 0.01; and ***, p < 0.001. (C) Rearing at later ages (16–24 weeks) of MitoPark mice when there is significant DA loss. Note the changes in ordinate values from those in A and B, since rearing is much impaired at these older ages. Unpaired t-test; *, p < 0.05; **, p < 0.01; and ***, p < 0.001.
Figure 3
Figure 3
(A) Time course of changes in accelerating rotarod performance at different ages. Note that MitoPark mice treated with PT320 have values almost equal to those of WT animals, whereas untreated MitoPark mice are significantly impaired at later ages (red dashed circle). Two-way analysis of variance (ANOVA) followed by a Bonferroni post hoc test for multiple comparisons. WT male compared to MitoPark (MP) male: #, p < 0.05; ##, p < 0.01; and ###, p < 0.001. MP male compared to PT320-treated MP male: *, p < 0.05; **, p < 0.01. (B) Accelerating rotarod performance in 20, 22, and 24 week old MP mice. Unpaired t-test: *, p < 0.05, and **, p < 0.01.
Figure 4
Figure 4
(A) DA release in striatum, studied with FSCV in MitoPark and WT mice at 8 weeks, an age when there is little change in striatal DA, at 12 and 16 weeks, where the changes in DA are significant, and at 22 weeks when changes in behavior and loss of nigrostriatal innervation are still more pronounced. One-way analysis of variance (ANOVA) followed by Bonferroni post hoc test for multiple comparisons. MP vs MP+PT320: ***, p < 0.001; WT vs MP: ##, p < 0.01, and ###, p < 0.001; WT vs MP+PT320: $, p < 0.05, and $$$, p < 0.001. (B) DA release in nucleus accumbens (NAc) measured by FSCV at 8, 12, 16, and 22 weeks old MitoPark mice. The PT320-induced changes in DA release at 12 and 16 weeks are less than in striatum and are in accord with smaller reductions in the DA input to NAc in MitoPark mice at this age, compared with striatal DA input. One-way analysis of variance (ANOVA) followed by a Bonferroni post hoc test for multiple comparisons. *, p < 0.05. Unpaired t-test analysis.
Figure 5
Figure 5
(A) DA Transporter (DAT) expression as a marker of striatal DA fibers in 8, 12, 16, and 20 week old MitoPark animals using PET scans. Although values in the PT320-treated MitoPark mice are less than in WT mice at these ages, they still are significantly greater than the values in untreated MitoPark mice. One-way analysis of variance (ANOVA) followed by a Bonferroni post hoc test for multiple comparisons: *, p < 0.05, and **, p < 0.01. (B) Changes in TH expression in 8, 12, 16, and 22 week old MitoPark mice. Again, we note little change at 8 weeks but major changes with PT320 in 12, 16, and 22 week old MitoPark mice, as compared to untreated MitoPark animals. Unpaired t-test analysis: ###, p < 0.001; *, p < 0.05; **, p < 0.01; and ***, p < 0.001. One-way analysis of variance (ANOVA) followed by Bonferroni post hoc test for multiple comparisons. MP vs MP+PT320: *p < 0.05, **p < 0.01; ***, p < 0.001. WT vs MP: ##, p < 0.01, and ###, p < 0.001. WT vs MP+PT320: $$, p < 0.01, and $$$, p < 0.001.
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