title: Attenuation of MPTP/MPP(+) toxicity in vivo and in vitro by an 18-mer peptide derived from prosaposin.
abstract: Parkinson's disease (PD) is a chronic progressive neurological disorder with an increasing incidence in the aging population. Neuroprotective and/or neuroregenerative strategies remain critical in the treatment of this increasingly prevalent disease. Prosaposin is a neurotrophic factor whose neurotrophic activity is attributed to a stretch of 12 amino acids located at the N-terminal region of saposin C. The present study was performed to investigate the protective effect and mechanism of action of a prosaposin-derived 18-mer peptide (PS18: LSELIINNATEELLIKGL) in Parkinson's disease models. We used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium ion (MPP(+))-induced dopaminergic neurotoxicity in C57BL/6J mice or SH-SY5Y cells and explored the protective effect and mechanisms of action of PS18 on dopaminergic neurons. Treatment with 2.0mg/kg PS18 significantly improved behavioral deficits, enhanced the survival of tyrosine hydroxylase-positive neurons, and decreased the activity of astrocytes in the substantia nigra and striatum in MPTP-induced PD model mice. In vitro, a Cell Counting Kit-8 assay and Hoechst 33258 staining revealed that co-treatment with 300ng/mL PS18 and 5mM MPP(+) protected against MPP(+)-induced nuclear morphological changes and attenuated cell death induced by MPP(+). We also found that PS18-FAM entered the cells, and the retention time of PS18-FAM in the cytoplasm of MPP(+)-treated cells was shorter than that of untreated cells. In addition, PS18 showed protection from MPP(+)/MPTP-induced apoptosis in the SH-SY5Y cells and dopaminergic neurons in the PD model mice via suppression of the c-Jun N-terminal kinase/c-Jun pathway; upregulation of Bcl-2; downregulation of BAX, attenuating mitochondrial damage; and inhibition of caspase-3. These findings suggest that PS18 may provide a valuable therapeutic strategy for the treatment of progressive neurodegenerative diseases such as PD.
authors: Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors: H L
authors: HL
authors: Gao
authors: C
authors: C
authors: Li
authors: H
authors: H
authors: Nabeka
authors: T
authors: T
authors: Shimokawa
authors: S
authors: S
authors: Saito
authors: Z Y
authors: ZY
authors: Wang
authors: Y M
authors: YM
authors: Cao
authors: S
authors: S
authors: Matsuda
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D010455:Peptides / Q000494:pharmacology; D049231:Saposins / Q000494:pharmacology*
chemical_list: D018696:Neuroprotective Agents; D010455:Peptides; C483344:Psap protein, mouse; D049231:Saposins