Secalonic acid A protects dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP⁺)-induced cell death via the mitochondrial apoptotic pathway.

Secalonic acid A (SAA) is a natural compound found in marine fungi. We have reported that SAA can attenuate the cytotoxicity of colchicine in rat cortical neurons. Whether SAA can also inhibit the neurotoxicity of 1-methyl-4-phenylpyridinium (MPP(+)) in dopaminergic neurons has not been investigated. Here, we show that pretreatment with 1 µM SAA significantly rescued tyrosine hydroxylase (TH)-positive neurons from MPP(+)-induced neurotoxicity in primary dopaminergic neuron culture. Moreover, SAA at doses of 0.15 mg/kg and 0.75 mg/kg increased the number of dopaminergic neurons and upregulated striatal dopamine in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mice experiments. We also show that SAA significantly attenuated cytotoxicity induced by 2.5 mM MPP(+) in SH-SY5Y cells. These results indicate that the activation of JNK, p38 mitogen activated protein kinase (MAPK) and caspase-3 during apoptosis triggered by MPP(+) could be suppressed by SAA; on the other hand, an MPP(+)-induced increase in the expression of Bax in SH-SY5Y cells was blocked by SAA. These results indicate that inhibition of the phosphorylation of JNK and p38 MAPK, down-regulation of Bax expression, and suppression of caspase-3 activation are involved in the protective effects of SAA against MPP(+) toxicity in SH-SY5Y cells. SAA may rescue dopaminergic neurons from MPP(+)-induced cell death through the mitochondrial apoptotic pathway.

Secalonic acid A reduced colchicine cytotoxicity through suppression of JNK, p38 MAPKs and calcium influx.

There are few articles about the cytotoxicity evoked by secalonic acid A (SAA) in some tumor cells. It has not yet been reported whether SAA has any action on neurons of the central nervous system. The aim of this study was to investigate the protective effect of SAA against apoptosis of rat cortical neurons induced by colchicine. The protective action of SAA on the cortical neurons treated with colchicine at 1 µM was examined by Hoechst 33258, LDH release and flow cytometry methods. The results from the above tests indicated that SAA at 3 and 10 µM significantly prevented colchicine-induced apoptosis of the cortical neurons. Further studies from Western blot and confocal microscopy experiments showed that the activation of JNK, p38 MAPKs and caspase-3 during neuron apoptosis triggered by 1 µM colchicine could be obviously suppressed by SAA; on the other hand, an increase in the intracellular free Ca(2+) by 1 µM colchicine in the cortical neuron was blocked evidently by SAA. The above results suggested that SAA could antagonize the cytotoxicity of colchicine in the rat cortical neurons, which may be through inhibition of phosphorylation of JNK and p38 MAPKs, calcium influx, and the activation of caspase-3.