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Perspective

Nutraceutical induction and mimicry of heme oxygenase activity as a strategy for controlling excitotoxicity in brain trauma and ischemic stroke: focus on oxidative stress

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Pages 157-168 | Received 31 Oct 2020, Accepted 07 Dec 2020, Published online: 28 Dec 2020
 

ABSTRACT

Introduction: Ischemic stroke and traumatic brain injury are leading causes of acute mortality, and in the longer run, major causes of significant mental and physical impairment. Most of the brain neuronal cell death in the minutes and hours following an ischemic stroke or brain trauma is mediated by the process of excitotoxicity, in which sustained elevations of extracellular glutamate, reflecting a failure of ATP-dependent mechanism which sequester glutamate in neurons and astrocytes, drive excessive activation of NMDA receptors.

Areas covered: A literature search was undertaken to clarify the molecular mechanisms whereby excessive NMDA activation leads to excitotoxic neuronal death, and to determine what safe nutraceutical agents might have practical potential for rescuing at-risk neurons by intervening in these mechanisms.

Expert opinion: Activation of both NADPH oxidase and neuronal nitric oxide synthase in the microenvironment of activated NMDA receptors drives production of superoxide and highly toxic peroxynitrite. This leads to excessive activation of PARP and p38 MAP kinase, mitochondrial dysfunction, and subsequent neuronal death. Heme oxygenase-1 (HO-1) induction offers protection via inhibition of NADPH oxidase and promotion of cGMP generation. Phase 2-inductive nutraceuticals can induce HO-1, and other nutraceuticals can mimic the effects of its products biliverdin and carbon monoxide.

Article highlights

  • The first wave of neuronal death that follows brain trauma or stroke is mediated by excitotoxicity, in which excessive activation of neuronal NMDA receptors, driven by a large and sustained increase in extracellular glutamate, leads to substantial calcium influx associated with activation of NADPH oxidase and neuronal nitric oxide synthase in the microenvironment of the receptors.

  • Downstream consequences include generation of toxic peroxynitrite, activation of PARP and p38 MAP kinase, and mitochondrial dysfunction, culminating in neuronal death.

  • Rodent and cell culture studies show that phase 2-inducing chemicals confer important protection from excitotoxicity via induction of heme oxygenase-1 (HO-1). It is proposed that agents that either induce HO-1, or that mimic key effects of its products bilirubin and carbon monoxide, may be clinically useful for prevention and control of excitotoxicity.

  • In particular, ferulic acid – a clinically effective phase 2 inducer; phycocyanobilin – which mimics the NADPH oxidase activity of bilirubin; and high-dose biotin – which like carbon monoxide, stimulates soluble guanylate cyclase – may be useful in this regard.

  • In addition, astaxanthin may help to control excitotoxic mitochondrial dysfunction. Citrulline or arginine administration may diminish post-traumatic glutamate release by helping to maintain adequate brain perfusion.

  • Nutraceuticals which skew activated microglia toward a pro-healing M2 phenotype could also be used to mitigate the second wave of neuronal death associated with brain trauma and stroke.

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.

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