Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by tremor, rigidity, bradykinesia, and gait impairment. In a previous study, we found that the marine-derived compound 11-dehydrosinulariolide (11-de) upregulates the Akt/PI3K pathway to protect cells against 6-hydroxydopamine (6-OHDA)-mediated damage. In the present study, SH-SY5Y, zebrafish and rats were used to examine the therapeutic effect of 11-de. The results revealed the mechanism by which 11-de exerts its therapeutic effect: the compound increases cytosolic or mitochondrial DJ-1 expression, and then activates the downstream Akt/PI3K, p-CREB, and Nrf2/HO-1 pathways. Additionally, we found that 11-de could reverse the 6-OHDA-induced downregulation of total swimming distance in a zebrafish model of PD. Using a rat model of PD, we showed that a 6-OHDA-induced increase in the number of turns, and increased time spent by rats on the beam, could be reversed by 11-de treatment. Lastly, we showed that 6-OHDA-induced attenuation in tyrosine hydroxylase (TH), a dopaminergic neuronal marker, in zebrafish and rat models of PD could also be reversed by treatment with 11-de. Moreover, the patterns of DJ-1 expression observed in this study in the zebrafish and rat models of PD corroborated the trend noted in previous in vitro studies.
Highlights
There are currently two general goals in the pharmacological treatment of Parkinson’s disease (PD)
We showed that 11-de-mediated modulation of DJ-1/Akt could promote the downstream Nrf2/HO-1 and p-CREB/Brain-Derived Neurotrophic Factor (BDNF) pathways
Our results show that 11-de may regulate expression of DJ-1, and activate the Akt/PI3K, p-CREB, and Nrf2/HO-1 pathways (Figure 8)
Summary
There are currently two general goals in the pharmacological treatment of Parkinson’s disease (PD). Our previous study indicated that 11-de protects neuronal-like cells against 6-OHDA-induced cytotoxicity through the PI3K/Akt pathway [8]. Some studies indicate that treatment with DJ-1 recombinant protein, or by overexpression of DJ-1, may ameliorate 6-OHDA-induced PD symptoms in rat models of the disease [14,15]. DJ-1 may enhance expression of p-Akt and its downstream antioxidative stress genes, namely Nrf2 [16]. Our study investigated the mechanism of action of 11-de in SH-SY5Y cells, by looking at the DJ-1, p-Akt, Nrf, and p-CREB pathways, and validating the therapeutic pathway with knockdown of DJ-1 expression. We attempted to further confirm the therapeutic effects of the compound in in vivo models by analyzing zebrafish larvae behavior. We hope to promote this therapeutic compound, taking it from bench to bedside to help treat patients diagnosed with Parkinson’s disease
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