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Lercanidipine boosts the efficacy of mesenchymal stem cell therapy in 3-NP-induced Huntington's disease model rats via modulation of the calcium/calcineurin/NFATc4 and Wnt/β-catenin signalling pathways.
- Source :
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Neurochemistry international [Neurochem Int] 2019 Dec; Vol. 131, pp. 104548. Date of Electronic Publication: 2019 Sep 17. - Publication Year :
- 2019
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Abstract
- 3-Nitropropionic acid (3-NP) induces a spectrum of Huntington's disease (HD)-like neuropathologies in the rat striatum. The present study aimed to demonstrate the neuroprotective effect of lercanidipine (LER) in rats with 3-NP-induced neurotoxicity, address the possible additional protective effect of combined treatment with bone marrow-derived mesenchymal stem cells (BM-MSCs) and LER, and investigate the possible involvement of the Ca <superscript>2+</superscript> /calcineurin (CaN)/nuclear factor of activated T cells c4 (NFATc4) and Wnt/β-catenin signalling pathways. Rats were injected with 3-NP (10 mg/kg/day, i.p.) for two weeks and were divided into four subgroups; the first served as the control HD group, the second received a daily dose of LER (0.5 mg/kg, i.p.), the third received a single injection of BM-MSCs (1 x 106/rat, i.v.) and the last received a combination of both BM-MSCs and LER. The combined therapy improved motor and behaviour performance. Meanwhile, this treatment led to a marked reduction in striatal cytosolic Ca <superscript>2+,</superscript> CaN, tumour necrosis factor-alpha, and NFATc4 expression and the Bax/Bcl2 ratio. Combined therapy also increased striatal brain-derived neurotrophic factor, FOXP3, Wnt, and β-catenin protein expression. Furthermore, haematoxylin-eosin and Nissl staining revealed an amelioration of striatum tissue injury with the combined treatment. In conclusion, the current study provides evidence for a neuroprotective effect of LER and/or BM-MSCs in 3-NP-induced neurotoxicity in rats. Interestingly, combined LER/BM-MSC therapy was superior to cell therapy alone in inhibiting 3-NP-induced neurological insults via modulation of the Ca <superscript>2+</superscript> /CaN/NFATc4 and Wnt/β-catenin signalling pathways. LER/BM-MSC combined therapy may represent a feasible approach for improving the beneficial effects of stem cell therapy in HD.<br /> (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Behavior, Animal drug effects
Calcineurin drug effects
Calcium Signaling drug effects
Cytosol drug effects
Cytosol metabolism
Huntington Disease chemically induced
Huntington Disease drug therapy
Male
NFATC Transcription Factors drug effects
Nerve Tissue Proteins drug effects
Nitro Compounds
Propionates
Proto-Oncogene Proteins c-bcl-2 metabolism
Rats
Rats, Wistar
Tumor Necrosis Factor-alpha metabolism
Wnt Signaling Pathway drug effects
bcl-2-Associated X Protein metabolism
beta Catenin drug effects
Calcium Channel Blockers therapeutic use
Dihydropyridines therapeutic use
Huntington Disease therapy
Mesenchymal Stem Cell Transplantation methods
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1872-9754
- Volume :
- 131
- Database :
- MEDLINE
- Journal :
- Neurochemistry international
- Publication Type :
- Academic Journal
- Accession number :
- 31539560
- Full Text :
- https://doi.org/10.1016/j.neuint.2019.104548