Oxidative stress leads to neurodegenerative diseases such as Parkinson's, Alzheimer's, and Huntington's diseases. Therefore, we isolated Lactiplantibacillus plantarum and Pediococcus pentosaceus strains from kimchi and investigated the neuroprotective effects of the heat-killed lactic acid bacteria (LAB) strains against oxidative stress. All LAB strains demonstrated suitable probiotic characteristics. The heat-killed LAB strains exhibited strong antioxidant activities by effectively scavenging free radicals. To mimic gut-brain axis communication, conditioned medium (CM) was generated by incubating the heat-killed LAB strains with HT-29 intestinal cells. The LAB-CM was then applied to SH-SY5Y neuroblastoma cells to evaluate their neuroprotective effects against oxidative stress. The LAB-CM protected SH-SY5Y cells against hydrogen peroxide (HO)-induced oxidative stress, as evidenced by improved cell viability, reduced lactate dehydrogenase (LDH) release, morphological preservation, and suppression of reactive oxygen species (ROS) production. The heat-killed LAB strains enhanced brain-derived neurotrophic factor (BDNF) and tyrosine hydroxylase (TH) mRNA expression in HT-29 cells, contributing to increased BDNF and TH levels in the LAB-CM. Furthermore, the LAB-CM activated Kelch-like ECH-associated protein 1 (Keap1)/Nuclear factor erythroid 2-related factor 2 (Nrf2)/Heme oxygenase-1 (HO-1) signaling pathway, increasing the expression of antioxidant enzymes, including NAD(P)H quinone oxidoreductase 1 (NQO1), thioredoxin reductase 1 (TXNRD1), superoxide dismutase 1 (SOD1), and catalase (CAT). It also modulated Bcl-2-associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2) and inhibited the activation of cysteine-aspartic acid protease-9 (caspase-9) and caspase-3, thereby alleviating oxidative stress-induced neuronal apoptosis. Thus, L. plantarum WB3809 and P. pentosaceus WB3812 have the potential to be used as functional food ingredients with neuroprotective effects via antioxidant and anti-apoptotic mechanisms. 2 2
