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This study is the first demonstration of the neuroprotective activity of the marine alga, Spirulina maxima, fermented by Lactobacillus plantarum HY-08, which was freshly isolated from fermented vegetables. The combined process of the fermentation with ultrasonic extraction at 40 kHz for 4 hr greatly increased the amounts of β-carotene in the extract up to 1.62 mg/g, along with a high extraction yield of 18.26%, compared to 1.03 mg/g and 12.8% from ultrasonic extraction itself, and even much higher than 0.81 mg/g and 10.6% from conventional water extraction. It was also proved that the neuroprotective activities of the extract were enhanced possibly by higher contents of β-carotene in the extract, compared to those from water extraction or ultrasonic extraction itself. This extract was found to have strong antioxidant properties, with 49.01% 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, which resulted in 90.30% neuroprotective activity. Specifically, the fermented extract markedly enhanced the brain-derived neurotrophic factor (BDNF)/p-CREB signaling pathways, which can effectively prevent memory impairment in mice caused by oxidative stress. β-Carotene also increased the expression of p-CREB and BDNF, and a mechanism of their upregulation by β-carotene is first proposed in this study. It can be concluded that the strong neuroprotective effect of the extract was markedly influenced by the antioxidant activities, due to the synergistic effects of high amounts of β-carotene and other biologically active substances in the extract that can be obtained by lactic acid fermentation, combined with ultrasonic processing.

Enhancement of the Neuroprotective Effect of Fermented Spirulina maxima Associated with Antioxidant Activities by Ultrasonic Extraction