Abstract
Parkinson’s disease (PD) is an age-related neurodegenerative disease (NDD) characterized by the degenerative loss of dopaminergic neurons in the substantia nigra along with aggregation of α-synuclein (α-syn). Neurogenic differentiation of human adipose-derived stem cells (NI-hADSCs) by supplementary factors for 14 days activates different biological signaling pathways. In this study, we evaluated the therapeutic role of NI-hADSC-conditioned medium (NI-hADSC-CM) in rotenone (ROT)-induced toxicity in SH-SY5Y cells. Increasing concentrations of ROT led to decreased cell survival at 24 and 48 h in a dose- and time-dependent manner. Treatment of NI-hADSC-CM (50% dilution in DMEM) against ROT (0.5 μM) significantly increased the cell survival. ROT toxicity decreased the expression of tyrosine hydroxylase (TH). Western blot analysis of the Triton X-100-soluble fraction revealed that ROT significantly decreased the oligomeric, dimeric, and monomeric phosphorylated Serine129 (p-S129) α-syn, as well as the total monomeric α-syn expression levels. ROT toxicity increased the oligomeric, but decreased the dimeric and monomeric p-S129 α-syn expression levels. Total α-syn expression (in all forms) was increased in the Triton X-100-insoluble fraction, compared to the control. NI-hADSC-CM treatment enhanced the TH expression, stabilized α-syn monomers, reduced the levels of toxic insoluble p-S129 α-syn, improved the expression of neuronal functional proteins, regulated the Bax/Bcl-2 ratio, and upregulated the expression of pro-caspases, along with PARP-1 inactivation. Moreover, hADSC-CM treatment decreased the cell numbers and have no effect against ROT toxicity on SH-SY5Y cells. The therapeutic effects of NI-hADSC-CM was higher than the beneficial effects of hADSC-CM on cellular signaling. From these results, we conclude that NI-hADSC-CM exerts neuroregenerative effects on ROT-induced PD-like impairments in SH-SY5Y cells.
Highlights
Neurodegenerative diseases (NDDs) including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are characterized by the chronic loss of different neuronal subtypes [1]
The ROT-induced decrease in cell survival was ameliorated by NI-hADSCCM treatment
Mitochondrial dysfunction was detected by evaluating the changes in the Bax/Bcl-2 ratio and decreased Mcl-1 expression levels, which resulted in the activation of caspases-9, -3, and -7, and PARP-1
Summary
Neurodegenerative diseases (NDDs) including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are characterized by the chronic loss of different neuronal subtypes [1]. PD is an age-related NDD characterized by the progressive loss of dopaminergic (DAergic) neurons in the substantia nigra (SN) pars compacta (SNpc) and the formation of misfolded protein aggregates [2]. Progressive and abnormal protein aggregation results in the accumulation of intracellular α-synuclein (α-syn) inclusions known as Lewy bodies (LBs) and Lewy neurites (LNs) composed of aggregated α-syn fibrils, which seems to be associated with PD [2]. ROT has been reported for its ability to induce the formation of α-syn-positive cytoplasmic inclusions resembling LBs in nigral neurons, accompanied by PD-like neurodegeneration [5]
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