Abstract
Previous studies have demonstrated that the marine compound austrasulfone, isolated from the soft coral Cladiella australis, exerts a neuroprotective effect. The intermediate product in the synthesis of austrasulfone, dihydroaustrasulfone alcohol, attenuates several inflammatory responses. The present study uses in vitro and in vivo methods to investigate the neuroprotective effect of dihydroaustrasulfone alcohol-modified 1-tosylpentan-3-one (1T3O). Results from in vitro experiments show that 1T3O effectively inhibits 6-hydroxydopamine-induced (6-OHDA-induced) activation of both p38 mitogen-activated protein kinase (MAPK) and caspase-3 in SH-SY5Y cells; and enhances nuclear factor erythroid 2–related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression via phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling. Hoechst staining and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining results reveal that 1T3O significantly inhibits 6-OHDA-induced apoptosis. In addition, the addition of an Akt or HO-1 inhibitor decreases the protective effect of 1T3O. Thus, we hypothesize that the anti-apoptotic activity of 1T3O in neuronal cells is mediated through the regulation of the Akt and HO-1 signaling pathways. In vivo experiments show that 1T3O can reverse 6-OHDA-induced reduction in locomotor behavior ability in zebrafish larvae, and inhibit 6-OHDA-induced tumor necrosis factor-alpha (TNF-α) increase at the same time. According to our in vitro and in vivo results, we consider that 1T3O exerts its anti-apoptotic activities at SH-SY5Y cells after 6-OHDA challenges, probably via the regulation of anti-oxidative signaling pathways. Therefore, this compound may be a promising therapeutic agent for neurodegenerations.
Highlights
Parkinson’s disease (PD) is a common neurodegenerative disease (ND) whose global incidence is second only to that of Alzheimer’s disease (AD) [1,2]
Deprenyl is a type of monoamine oxidase B (MAO-B) inhibitor that has been shown to show an antioxidant effect in the nuclear factor erythroid 2–related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway [26,51]
That study showed that co-treatment with ranitidine effectively protects SH-SY5Y cells from damage caused by rotenone [61], and this mechanism involves the activation of p-Extracellular signal-regulated kinase (ERK) and its downstream antiapoptotic protein, Bcl-1, inhibiting the production of rotenone-induced p38 and downstream caspase-3, to exert a protective effect
Summary
Parkinson’s disease (PD) is a common neurodegenerative disease (ND) whose global incidence is second only to that of Alzheimer’s disease (AD) [1,2]. Akt phosphorylation can promote the activation of the downstream Nrf2/HO-1 antioxidant pathway to protect cells from oxidative stress, and promote the activation of B-cell lymphoma-extra-large (Bcl-xL) to inhibit the apoptosis factor, caspase-3 [25]. A study showed that the clinical drug selegiline can effectively reverse neurotoxin-induced decrease in Akt phosphorylation and activate the downstream Nrf2/HO-1 pathway [26], thereby protecting damaged dopaminergic neruons [27,28,29]. Effect of 1T3O on the Akt (Phospho-Akt), Phospho-Extracellular Signal-Regulated Kinase (Phospho-ERK), and Phospho-p38 Protein Expression in SH-SY5Y Cells 2.3. IOnnmthaeinottahienrinhgancde,llpvreitarbeailtimtye.ntRwesiuthlt1sTs3hOow(1 tμhMat), fcoorm30pamriend with the sciognitfriocal,nt1l5y amttiennuoaftetrdea6-tOmHeDntAw(2it0hμ6M-O)-iHndDuAced(2r0edμuMct)iosniginnipfihcoasnpthlyordyleactreedaAsekdt ltehveele(xFpigruersesion of 4A) These results demonstrate that 1T3O can significantly inhibit 6-OHDA-induced reduction in Akt phosphorylation. Pretreatment with 1T3O (1 μM) for 30 min significantly attenuated 6-OHDA (20 μM)-induced reduction in phosphorylated Akt level (Figure 4A).
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