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

ABSTRACT

Introduction

A delayed second wave of brain trauma is mediated in large part by microglia that are activated to a pro-inflammatory M1 phenotype by DAMP proteins released by dying neurons. These microglia can promote apoptosis or necrosis in neighboring neurons by producing a range of pro-inflammatory cytokines and the deadly oxidant peroxynitrite. This second wave could therefore be mitigated with agents that blunt the post-traumatic M1 activation of microglia and that preferentially promote a pro-healing M2 phenotype.

Areas covered

The literature on nutraceuticals that might have clinical potential in this regard.

Expert opinion

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.

KEYWORDS:

• Brain trauma
• neuronal death
• damp-mediated microglial activation
• peroxynitrite
• nutraceuticals

Abbreviations

CTE, chronic traumatic encephalopathy; TBI, traumatic brain injury, DAMP-damage-associated molecular patterns, TLR- toll-like receptor, HDAC, histone deacetylase, EGCG-epigallocatechin gallate, Erβ-estrogen receptor, NF-nuclear factor, PhyCB-Phycocyanobilin, LPS-lipopolysaccharide, H2S-hydrogen sulfide, AMPK-AMP-activated kinase, MKP-1-MAP kinase phosphatase-1, BHB-beta-hydroxybutyrate,

Article highlights

• The first wave of neuronal death following TBI begins within minutes of injury and reflects excitotoxicity. An elevation of extracellular glutamate leads to sustained activation of NMDA receptors, excessive calcium influx, oxidative stress, and subsequent cell death by necroptosis. Hypothermia is currently the best clinical tool for addressing this.

• In the hours after TBI, release of DAMP proteins from dead or dying neurons leads to pro-inflammatory M1 activation of microglia in the trauma region. The resulting release of pro-inflammatory cytokines and cytotoxic oxidants such as peroxynitrite brings on a second wave neuronal death within 24 h of the injury.

• Agents that intervene in the signaling pathways promoting an M1 microglial phenotype have potential not only for blunting the second wave of neuronal death, but also for promoting a pro-healing M2 phenotype that aids neuronal survival and neurogenesis, re-myelination, and angiogenesis.

• A review of the molecular biology underlying post-traumatic microglial activation, and of the pertinent rodent literature on TBI, suggests that a number of nutraceuticals have potential for skewing microglial differentiation toward an M2 phenotype, thereby minimizing second-wave neuronal death and aiding healing.

• These agents include: phycocyanobilin (a spirulina chromophore), the phase 2 inducers ferulic acid and melatonin, the green tea catechin EGCG, long-chain omega-3 fatty acids, glucosamine, the AMPK activator berberine, the soy isoflavone genistein, vitamin D, taurine, and NAC.

• Complex nutraceutical regimens featuring a combination of these agents may have clinical potential for ameliorating the clinical course of TBI. The complementary utility of these agents could be explored in rodent studies.

Declaration of interest

MF McCarty is co-inventor and co-owner of a US patent on PhyCB oligopeptides derived from spirulina, as well as a European patent application on parenteral use of PhyCB in oxidative stress emergencies. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Authors’ contributions

MF McCarty- screened the literature, designed and wrote the manuscript. A Lerner- screened the literature, edited and revised the manuscript.

Additional information

Funding

This paper was not funded.