Objective: We set out to evaluate potential neurorestorative effects of the GlyT1 inhibitor ACPPB vis-à-vis D-Serine in the intrastriatal 6-OHDA mouse model of Parkinson’s disease. Efficacy endpoints included: i) amelioration of animals’ motor performance; ii) regrowth of dopaminergic fibers into the highly denervated motor region of the striatum.

Background: Synaptic NMDA glutamate receptor activity is required to stimulate axonal sprouting. Glutamate-induced NMDA receptor activation requires a glycine modulatory site to be occupied by either Glycine or D-Serine. A previous study has shown that pharmacological inhibition of the Glycine transporter (GlyT) stimulates sprouting of dopaminergic axons both in vitro and in vivo (Schmitz et al. J Neurosci 2013).

Methods: Mice sustained unilateral 6-OHDA injections in the lateral striatum. Treatment with either ACPBB or D-Serine was started 3 weeks post-lesion and was administered 3 times per week for 5 weeks (subcutaneous injections at doses previously tested in mice). Tests of forelimb use (cylinder test) and postural asymmetry (spontaneous rotations test) were carried out at the end of each treatment week; one test of sensorimotor neglect (corridor test) was performed at the end of the treatment. Brains were processed immunohistochemically to analyse striatal tyrosine hydroxylase (TH)-positive fibers and nigral dopamine cells.

Results: Both compounds significantly ameliorated forelimb use and sensorimotor neglect. Improvements occurred particularly during the last 2 weeks of treatment, suggesting a dependence on neurorestorative effects that are time-dependent. No improvement was seen in the spontaneous rotation test (a behavior highly dependent on nigral dopamine levels). Optical density analysis of striatal TH-positive fibers revealed a pronounced restorative effect by D-Serine. Mice treated with ACPPB showed trends towards an increased striatal TH optical density. Stereological counts of nigral dopamine cells compacta did not reveal group differences. Striatal dopamine fiber growth is currently being examined using sensitive methods.

Conclusions: Both of the compounds under investigation produced functional neurorestoration. Our results provide a rationale for considering this class of compounds for clinical evaluaton in patients with PD.

References: Schmitz Y, Castagna C, Mrejeru A, Lizardi-Ortiz JE, Klein Z, Lindsley CW, Sulzer D. “Glycine transporter-1 inhibition promotes striatal axon sprouting via NMDA receptors in dopamine neurons”. J Neurosci. 2013 Oct 16;33(42):16778-89. doi: 10.1523/JNEUROSCI.3041-12.2013.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neurorestorative-effects-of-glycine-transporter-1-inhibitor-and-d-serine-in-a-mouse-model-of-nigrostriatal-dopaminergic-degeneration/