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. (December 2019)

• Record Type: Journal Article
• Authors: Elbaz, Eman M.; Helmy, Hebatullah S.; El-Sahar, Ayman E.; Saad, Muhammed A.; Sayed, Rabab H.
• Is Part Of: Neurochemistry international. Volume 131(2019)
• Publication Date: 2019-12
• Subjects: Huntington's disease -- 3-Nitropropionic acid -- Lercanidipine -- BM-MSCs -- Ca2+/CaN/NFATc4 -- Wnt/β-catenin; Neurochemistry -- Periodicals; Neurochemistry -- Periodicals; Neurochimie -- Périodiques; Neurochemistry; Periodicals; 612.804205
• DOI: 10.1016/j.neuint.2019.104548
• Languages: English
• ISSNs: 0197-0186

Abstract

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 2+ /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 2+, 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 2+ /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. Highlights: Lercanidipine boosts the efficacy of BM-MSCs therapy in 3-NP-induced HD model rats. Combined treatment reduces striatal tumour necrosis factor alpha and Bax/Bcl2 ratio. H&E and Nissl staining revealed an amelioration of striatum tissue injury. Lercanidipine/BM-MSC combined therapy modulates Ca 2+ /CaN/NFATc4 signalling pathway. Lercanidipine/BM-MSC combined therapy modulates Wnt/β-catenin signalling pathway.