The second phase of brain trauma can be controlled by nutraceuticals that suppress DAMP-mediated microglial activation.

The chief signaling pathway whereby DAMPs promote M1 microglial activation involves activation of toll-like receptor 4 (TLR4), NADPH oxidase, NF-kappaB, and the stress activated kinases JNK and p38. The green tea catechin EGCG can suppress TLR4 expression. Phycocyanobilin can inhibit NOX2-dependent NADPH oxidase, ferulate and melatonin can oppose pro-inflammatory signal modulation by NADPH oxidase-derived oxidants. Long-chain omega-3 fatty acids, the soy isoflavone genistein, the AMPK activator berberine, glucosamine, and ketone bodies can down-regulate NF-kappaB activation. Vitamin D activity can oppose JNK/p38 activation. A sophisticated program of nutraceutical supplementation may have important potential for mitigating the second phase of neuronal death and aiding subsequent healing.