Exercise Promotes Neurite Extensions from Grafted Dopaminergic Neurons in the Direction of the Dorsolateral Striatum in Parkinson’s Disease Model Rats

Abstract

Background: Cell transplantation is expected to be a promising treatment for Parkinson's disease (PD), in which reinnervation of the host striatum by grafted dopamine (DA) neurons is essential. In particular, the dorsolateral part of the striatum is important because it is the target of midbrain A9 DA neurons, which are degenerated in PD pathology. The effect of exercise on the survival and maturation of grafted neurons has been reported in several neurological disease models, but never in PD models. Objective: We investigated how exercise influences cell transplantation for PD, especially from the viewpoint of cell survival and neurite extensions. Methods: Ventral mesencephalic neurons from embryonic (E12.5) rats were transplanted into the striatum of adult 6-OHDA-lesioned rats. The host rats then underwent treadmill training as exercise after the transplantation. Six weeks after the transplantation, they were sacrificed, and the grafts in the striatum were analyzed. Results: The addition of exercise post-transplantation significantly increased the number of surviving DA neurons. Moreover, it promoted neurite extensions from the graft toward the dorsolateral part of the striatum. Conclusions: This study indicates a beneficial effect of exercise after cell transplantation in PD.

Pluripotent Stem Cell Therapies for Parkinson Disease: Present Challenges and Future Opportunities

“…In human fetal tissue grafting studies, SN injections have been attempted but only in combination with striatal injections (Mendez et al, 2005), which makes it difficult to assess the relative contribution of each site to any clinical parameters. However, the technology to deliver hPSC-derived mDA progenitors in the SN will likely improve, and optimization of graft composition, the addition of growth promoting factors or even exercise of the host brain may contribute to achieve reliable restoration of the nigro-striatal circuit (Torikoshi et al, 2020).…”

The impact of aerobic and resistance training intensity on markers of neuroplasticity in health and disease

“…Animal models of PD suggest that exercise improves motor and mitochondrial function, nerve growth and glial cell line-derived neurotrophic factors, levels of nigrostriatal neurotrophic factor, and reduced excitotoxic effects of glutamate and aberrant cortical spike-local field potential synchronization (Feng et al, 2021;Ferreira et al, 2021;Lau et al, 2011;Shi et al, 2021). Perhaps exercise training can even rescue dopamine neurons (Ferreira et al, 2020;Torikoshi et al, 2020). In animal models of stroke, forced exercise at moderate to high intensity increased levels of growth factors and synaptogenesis in multiple brain regions but moderate instead of high-intensity exercise seemed to facilitate dendritic branching (Ploughman et al, 2015).…”

Enriched Environment and Exercise Enhance Stem Cell Therapy for Stroke, Parkinson’s Disease, and Huntington’s Disease

“…These neurite extensions specifically grew in the same pathway taken by A9 dopaminergic neurons, which project into the striatum and are crucial for improved behavior (Figure 4). This is an important finding as A9 dopaminergic neurons preferentially degenerate in PD (Björklund and Dunnett, 2007;Torikoshi et al, 2020). Additionally, hemispheric dominance plays an influential role in dopaminergic neuroplasticity post-transplantation.…”