Methyl 3,4-dihydroxybenzoate (MDHB), a kind of phenolic acid compounds, has been reported to have antioxidant effects. Moreover, our previous study found that it could promote neurite outgrowth and brain-derived neurotrophic factor expression in cortical neurons of neonatal rats. In the present study, we focused on the mechanism of its neurotrophic effect; the results showed that MDHB-induced upregulation of neuronal survival and neurite outgrowth in cultured primary cortical neurons could be blocked by the adenosine A2a receptor inhibitor (ZM241385) and the phosphoinositide 3-kinase (PI3K) inhibitor (LY294002). Subsequently, we found that the upregulation of Akt phosphorylation by MDHB could be suppressed by A2a-R and PI3K-specific inhibitor, but not the Trk-R inhibitor. Furthermore, MDHB could activate Akt in a concentration-dependent manner. These results suggested that activation of the PI3K/Akt signaling pathway may be involved in the MDHB-induced neurotrophic effects and MDHB could be a candidate compound to develop drugs for neurodegenerative disease.

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Amyloid-β peptides (Aβ), which can aggregate into oligomers or fibrils in neurons, play a critical role in the pathogenesis of Alzheimer's disease (AD). Methyl 3,4-dihydroxybenzoate (MDHB), a phenolic acid compound, has been reported to have antioxidative and neurotrophic effects. The present study investigated the neuroprotective effects of MDHB against Aβ-induced apoptosis in rat primary cortical neutons. The primary cortical neurons were pretreated with different concentrations of MDHB for 24 hr, then incubated with 10 μM Aβ25-35 for 24 hr. The results showed that Aβ25-35 could induce neurotoxicity as evidenced by the decreased cell viability and the increased apoptotic rate. In parallel, Aβ25-35 significantly increased the reactive oxygen species accumulation and decreased mitochondrial membrane potential. However, pretreatment of the primary cortical neurons with MDHB could effectively suppress these cellular events caused by Aβ25-35 exposure. In addition, MDHB could increase the level of Bcl-2, decrease the level of Bax, and inhibit the activation of caspase-9 and caspase-3 in Aβ25-35 -treated primary cortical neurons. All these results were beneficial in their protective effect against Aβ-induced neurotoxicity. Our results suggest that MDHB has a neuroprotective effect that provides a pharmacological basis for its clinical use in the treatment of AD.

Neurodegenerative diseases are frequently associated with the loss of synapses and neurons. Senegenin, extracted from the Chinese herb Polygala tenuifolia Willd, was previously found to promote neurite outgrowth and neuronal survival in primary cultured rat cortical neurons. The aim of the present study was to investigate the underlying mechanisms of senegenin-induced neurotrophic effects on rat cortical neurons. Primary cortical rat neurons were treated with various pharmacological antagonists and with or without senegenin, and subjected to MTT and western blot analysis to explore the effects of senegenin on cell survival as well as the activation of signaling pathways. Neurite outgrowth and neuronal survival induced by senegenin were significantly inhibited by A2A receptor antagonist ZM241385 and specific phosphoinositide-3 kinase (PI3K) inhibitor LY294002, but not by tropomyosin receptor kinase A receptor inhibitor K252a, mitogen-activated protein kinase kinase inhibitor PD98059 or protein kinase C inhibitor GÖ6976. Furthermore, senegenin enhanced the phosphorylation of Akt, which was blocked by LY294002. The present study revealed that the PI3K/Akt signaling pathway may be involved in the neurotrophic effects of senegenin.

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