Promising Neuroprotective Function for M2 Microglia in Kainic Acid-Induced Neurotoxicity Via the Down-Regulation of NF-κB and Caspase 3 Signaling Pathways.

Activated microglia have two functional states (M1 and M2) which play dual roles in neurodegenerative diseases. In the present study, we explored a possible neuroprotective function of M2 microglia against kainic acid (KA)-induced neurodegeneration in primary neurons co-cultured with different microglial populations. Neurons were isolated from the hippocampi and cortices of C57BL/6 embryos (embryonic day 16) and microglia were extracted from neonatal pups (postnatal days 0-2). Microglia were either unstimulated (M0-phenotype) or stimulated with lipopolysaccharide and interferon-γ to form the M1-phenotype, or with interleukin (IL)-4, IL-10, and transforming growth factor -β for the M2-phenotype. Neurons were co-cultured with each of the three microglial phenotypes and treated with KA for 24 h. Next, we analyzed the cell survival rate, nitric oxide (NO) levels, and lactate dehydrogenase production, cytokines levels, and expression of nuclear factor κB (NF-κB) and caspase 3 among the three groups before and after KA insult. Our results indicated that M2 microglia played a neuroprotective role in KA-induced neurotoxicity, as demonstrated by high neuronal survival as well as decreased production of NO and pro-inflammatory cytokines. In contrast, neurons co-cultured with M1 microglia exhibited the lowest survival rate as well as increased levels of NO and pro-inflammatory cytokines. Further, the expression of NF-κB and caspase 3 were significantly decreased in M2 microglia co-cultures compared to M1 or M0 microglia co-cultures after KA insult. Therefore, M2 microglia may exert a neuroprotective function in KA-induced neurotoxicity via the down-regulation of NF-κB and caspase 3 signaling pathways.