Abstract
Parkinson’s Disease (PD) is characterized by the massive loss of dopaminergic neurons, leading to the appearance of several motor impairments. Current pharmacological treatments, such as the use of levodopa, are yet unable to cure the disease. Therefore, there is a need for novel strategies, particularly those that can combine in an integrated manner neuroprotection and neuroregeneration properties. In vitro and in vivo models have recently revealed that the secretome of mesenchymal stem cells (MSCs) holds a promising potential for treating PD, given its effects on neural survival, proliferation, differentiation. In the present study, we aimed to access the impact of human bone marrow MSCs (hBM-MSCs) secretome in 6-hydroxydopamine (6-OHDA) PD model when compared to levodopa administration, by addressing animals’ motor performance, and substantia nigra (SN), and striatum (STR) histological parameters by tyrosine hydroxylase (TH) expression. Results revealed that hBM-MSCs secretome per se appears to be a modulator of the dopaminergic system, enhancing TH-positive cells expression (e.g., dopaminergic neurons) and terminals both in the SN and STR when compared to the untreated group 6-OHDA. Such finding was positively correlated with a significant amelioration of the motor outcomes of 6-OHDA PD animals (assessed by the staircase test). Thus, the present findings support hBM-MSCs secretome administration as a potential therapeutic tool in treating PD, and although we suggest candidate molecules (Trx1, SEMA7A, UCHL1, PEDF, BDNF, Clusterin, SDF-1, CypA, CypB, Cys C, VEGF, DJ-1, Gal-1, GDNF, CDH2, IL-6, HSP27, PRDX1, UBE3A, MMP-2, and GDN) and possible mechanisms of hBM-MSCs secretome-mediated effects, further detailed studies are needed to carefully and clearly define which players may be responsible for its therapeutic actions. By doing so, it will be reasonable to presume that potential treatments that can, per se, or in combination modulate or slow PD may lead to a rational design of new therapeutic or adjuvant strategies for its functional modeling and repair.
Highlights
Parkinson’s Disease (PD) represents the second most prevalent neurodegenerative disorder and is characterized by the progressive degeneration of dopaminergic neurons (DAn) in several dopaminergic networks [1]
Taking advantage of the proteomic databases previously generated by our group [15,16,27], and in order to further explore possible underlying mechanisms behind the secretome effects, by using the STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) bioinformatics tool, we found a (PD) protein association network composed by 21 proteins, namely Thioredoxin-1 (Trx1/TXN), Semaphorin-7A (SEMA7A), Ubiquitin carboxy-terminal hydrolase L1 (UCHL1), Pigment epithelium-derived factor (PEDF/SERPINF1), Brain-derived neurotrophic factor (BDNF), Clusterin (CLU), Stromal cell-derived factor 1 (SDF-1/CXCL12), Cyclophilin A (CypA/PPIA), Cyclophilin B
Genes/Proteins) bioinformatics research tool analysis, from those databases we identified a cluster of 21 interconnected proteins, namely Trx1 (TXN), SEMA7A, UCHL1, PEDF (SERPINF1), BDNF, Clusterin (CLU), SDF-1 (CXCL12), CypA (PPIA), CypB (PPIB), Cys C (CST3), Vascular endothelial growth factor (VEGF), DJ-1 (PARK7), Gal-1 (LGALS1), Glial cell line-derived neurotrophic factor (GDNF), Cadherin 2 (CDH2), Interleukin 6 (IL-6), HSP27 (HSPB1), Peroxiredoxin 1 (PRDX1), Ubiquitin-protein ligase 3A (UBE3A), MMP-2, and GDN (SERPINE2), which from the (A) biological processes and (B) molecular function analysis revealed important actions to PD modeling and repair
Summary
Parkinson’s Disease (PD) represents the second most prevalent (worldwide) neurodegenerative disorder and is characterized by the progressive degeneration of dopaminergic neurons (DAn) in several dopaminergic networks [1]. Its extended use, frequently associated with an increase in dosage due to the natural progression of the disease, has been associated with the appearance of nausea, vomiting, low blood pressure, restlessness, drowsiness or sudden onset of sleep, as well as impulsive and addiction behavioral changes [5]. This ‘pathophysiological’ effect of levodopa has been described as being due to a combination of disease-related factors, as well as to levodopa pharmacokinetics itself [8]. There is an urgent need to find novel therapeutic strategies that can overcome the limitations posed by levodopa, to delay the progression of PD and to improve and maintain PD patients’ quality of life
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