Protection of Brain Injury from Cyanide Poisoning by Carnosic Acid

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DESCRIPTION (provided by applicant): Cyanide poisoning is a potential bioterrorist agent, is life threatening, and acute exposure results in hypoxic brain injury, cardiopulmonary failure, and death within minutes to hours. Such acute toxicity is treatable by various antidotes, but success depends on rapid administration and effective penetration of the various tissues. However, even with treatment, acute or chronic cyanide intoxication in humans can induce a delayed neurological syndrome, including dystonia. Typically, these patients show Parkinsonian symptoms after weeks to months, with progressive rigidity and predominant features of flexed upper limbs and extended lower limbs. CT and MRI examinations of these patients have consistently revealed lesions in the basal ganglia, including the globus pallidus and putamen. Damage in the human brain has been confirmed via autopsy. Similar observations have been reported following both acute and chronic cyanide exposure. Multiple mechanisms are thought to underlie cyanide-induced neuronal damage, including inhibition of Cytochrome C oxidase (CcOX) and generation of reactive oxygen species (ROS) in response to cyanide- induced lipid peroxidation. Particularly harmful to neurons is dysfunctional glutamate transport and ionic pump failure, contributing to excitotoxic neuronal cell death by overstimulation of NMDA-type glutamate receptors (NMDARs). Furthermore, cyanide induces chemical reduction of the redox site(s) of the NMDAR, which were originally discovered in our laboratory, and result in additional activation of NMDAR-operated ion channels, Ca2+ influx, and consequent neuronal damage; these mechanistic considerations account for the fact that anti- oxidants and NMDAR antagonists can prevent cyanide-induced neuronal damage. As both toxic effects of cyanide by inhibition of CcOX and potentiation of NMDARs converge on oxidative stress, one possible strategy for the development of neuroprotective drugs for cyanide poisoning is to search for low-molecular-weight compounds that can counter oxidative damage. Here, as potential countermeasures against CNS toxicity by cyanide, we propose to use carnosic acid (CA), an electrophilic compound from rosemary extract, which crosses the blood-brain-barrier to exert effects by up-regulating endogenous anti-oxidant enzymes via the Nrf2 transcriptional pathway. We hypothesize that such electrophilic compounds have an advantage over antioxidant molecules for counteract the toxic effect of cyanide in brain because their action is more sustained and amplified by transcription-mediated signaling pathways. We will test this hypothesis by investigating the neuroprotective activity of CA in culture neurons exposed to cyanide and in a mouse model of cyanide poisoning. Specific Aims of this proposal are as follows: Specific Aim 1. To investigate neuroprotective effects of CA in an in vitro model of cyanide poisoning. Specific Aim 2. To examine neuroprotective effects of CA in an in vivo mouse model mimicking the effects of cyanide ingestion. PUBLIC HEALTH RELEVANCE: Cyanide poisoning is a potential bioterroristic agent and life threatening. Sublethal doses of cyanide poisoning administered in a subchronic fashion result in brain injury causing Parkinsonian symptoms, and result from converging metabolic pathways causing oxidative stress in neurons. Here, we propose to use carnosic acid, a pro-electrophilic compound found in the herb rosemary, to prevent brain injury from cyanide subchronic poisoning.