Fingolimod (FTY720) is not protective in the subacute MPTP mouse model of Parkinson's disease and does not lead to a sustainable increase of brain‐derived neurotrophic factor. Issue 5 (13th November 2018)

• Record Type: Journal Article
• Authors: Komnig, Daniel; Dagli, Toruntay Cem; Habib, Pardes; Zeyen, Thomas; Schulz, Jörg B.; Falkenburger, Björn H.
• Is Part Of: Journal of neurochemistry. Volume 147:Issue 5(2018)
• Page Start: 678
• Page End: 691
• Publication Date: 2018-11-13
• Subjects: animal models -- neurotrophic factors -- Parkinson disease; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.14575
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: Parkinson's disease (PD) is characterized by the loss of midbrain dopaminergic neurons and aggregates of α‐synuclein termed Lewy bodies. Fingolimod (FTY720) is an agonist of sphingosine‐1 phosphate receptors and an approved oral treatment for multiple sclerosis. Fingolimod elevates brain‐derived neurotrophic factor (BDNF), an important neurotrophic factor for dopaminergic neurons. BDNF and fingolimod are beneficial in several animal models of PD. In order to validate the therapeutic potential of fingolimod for the treatment of PD, we tested its effect in the subacute MPTP mouse model of PD. MPTP or vehicle was applied i.p. in doses of 30 mg/kg MPTP on five consecutive days. In order to recapitulate the combination of dopamine loss and α‐synuclein aggregates found in PD, MPTP was first administered in Thy1‐A30P‐α‐synuclein transgenic mice. Fingolimod was administered i.p. at a dose of 0.1 mg/kg every second day. Nigrostriatal degeneration was assayed by stereologically counting the number of dopaminergic neurons in the substantia nigra pars compacta, by analysing the concentration of catecholamines and the density of dopaminergic fibres in the striatum. MPTP administration produced a robust nigrostriatal degeneration, comparable to previous studies. Unexpectedly, we found no difference between mice with and without fingolimod treatment, neither at baseline, nor at 14 or 90 days after MPTP. Also, we found no effect of fingolimod in the subacute MPTP mouse model when we used wildtype mice instead of α‐synuclein transgenic mice, and no effect with an increased dose of 1 mg/kg fingolimod administered every day. In order to explain these findings, we analysed BDNF regulation by fingolimod. We did find an increase of BDNF protein after a single injection of fingolimod 0.1 or 1.0 mg/kg, but not after multiple injections, indicating that the BDNF response to fingolimod is unsustainable over time. Taken together we did not observe a neuroprotective effect of fingolimod in the subacute MPTP mouse model of PD. We discuss possible explanations for this discrepancy with previous findings and conclude fingolimod might be beneficial for the nonmotor symptoms of PD. Open Science Badges: This article has received a badge for *Open Materials * and *Open Data * because it provided all relevant information to reproduce the study in the manuscript and because it made the data publicly available. The data can be accessed athttps://osf.io/6xgfn/ . The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found athttps://cos.io/our-services/open-science-badges/ . Abstract : Fingolimod is an approved oral drug for multiple sclerosis. Its systemic adminstration increases brain‐derived neurotrophic factor in the brain (a, left). We tested whether fingolimod has beneficial effects in the MPTP mouse model of Parkinson's disease. Repeated administration of fingolimod in different dosing regimens did not alter the degeneration of dopaminergic neurons or dopaminergic axon terminals (b). This result differs from previous findings in other models of Parkinson's disease. It can be explained by the fact that repeated administration of fingolimod did not lead to a sustained rise in brain‐derived neurotrophic factor (a, right). Open Science: This manuscript was awarded with the Open Materials and Open Data Badge (https://osf.io/6xgfn/ ) For more information see:https://cos.io/our-services/open-science-badges/