Preclinical Validation of FTY720 and FTY720-Mitoxy in Mouse Models of Parkinsons Disease and Multiple System Atrophy (MSA): Evidence for Treating Lewy Body Disease Synucleinopathies Including MSA

Abstract

We assessed FTY720 and our patented-mitochondria-localizing-FTY720-derivative, FTY720-Mitoxy, in mouse models of Parkinson’s disease (PD) and MSA. FTY720 and FTY720-Mitoxy were given by gavage, injection, or osmotic pump. We used symptomatic transgenic alpha-Synuclein (aSyn) PD mice (A53T aSyn) and MSA mice (CNP-aSyn), as well as transgenic GM2 +/− PD mice. We also tested toxin PD and MSA models. We measured movement, constipation, gut motility, sweat ability, and bladder function. We counted blood lymphocytes 24 h after FTY720 or FTY720-Mitoxy. We measured Brain Derived Neurotrophic Factor (BDNF), Glial Cell Line Derived Neurotrophic Factor (GDNF), and Nerve Growth Factor (NGF) mRNA and protein. We assessed aSyn insolubility in gut, brain, and spinal cord by sequential protein extraction and immunoblot. We assessed fecal genomic DNA using 16S rRNA sequencing. In PD mice FTY720 normalized body and gut movement, urinary bladder function while increasing trophic factors and eliminating synucleinopathy. In MSA mice FTY720-Mitoxy normalized body and gut movement, sweat ability, mitochondrial function, improved microbiota while increasing trophic factors and eliminating synucleinopathy. FTY720 and FTY720-Mitoxy improve function and counteract synucleinopathy. As FTY720-Mitoxy is not immunosuppressive, it may be safer for treating PD and/or MSA.