Abstract
Agmatine, a metabolite generated by arginine decarboxylation, has been reported as neuromodulator and neuroactive substance. Several findings suggest that agmatine displays neuroprotective effects in several models of neurodegenerative disorders, such as Parkinson’s disease (PD). It has been hypothesized that biogenic amines may be involved in neuroprotection by scavenging oxygen radicals, thus preventing the generation of oxidative stress. Mitochondrial dysfunction, that leads to a reduction of oxygen consumption, followed by activation of prolyl hydroxylase and decrease of hypoxia-inducible factor 1 alpha (HIF-1α) levels, has been demonstrated to play a role in PD pathogenesis. Using rotenone-treated differentiated SH-SY5Y cells as the in vitro PD model, we here investigated the molecular mechanisms underlying agmatine neuroprotective effects. Our results showed that the preliminary addition of agmatine induces HIF-1α activation, and prevents the rotenone-induced production of free radical species, and the activation of apoptotic pathways by inhibiting mitochondrial membrane potential decrease and caspase 3 as well as cytochrome c increase. Notably, these effects are mediated by HIF-1α, as indicated by experiments using a HIF-1α inhibitor. The present findings suggest that the treatment with agmatine is able to counteract the neuronal cell injury evoked by mitochondrial toxins.
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Abbreviations
- H2DCF-DA:
-
2′,7′-Dichlorofluorescein diacetate
- RA:
-
All-trans retinoic acid
- MEM:
-
Eagle’s minimum essential medium
- FBS:
-
Fetal bovine serum
- F12:
-
Ham’s F-12 nutrient mixture
- HIF-1:
-
Hypoxia-inducible factor-1
- MTT:
-
3-(4,5-Methylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide
- PD:
-
Parkinson’s disease
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Ferlazzo, N., Currò, M., Giunta, M.L. et al. Up-regulation of HIF-1α is associated with neuroprotective effects of agmatine against rotenone-induced toxicity in differentiated SH-SY5Y cells. Amino Acids 52, 171–179 (2020). https://doi.org/10.1007/s00726-019-02759-6
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DOI: https://doi.org/10.1007/s00726-019-02759-6