Medical Aspects of Chemical Warfare (2008) - The Black Vault
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Medical Aspects of Chemical Warfare (2008) - The Black Vault

Medical Aspects of Chemical Warfare (2008) - The Black Vault Medical Aspects of Chemical Warfare (2008) - The Black Vault

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Neuroprotection as a Treatment for Nerve Agent SurvivorsFig. 6-1. Mechanisms contributing to nerve agent-induced SRBD. Calcium plays a pivotal role in glutamate excitotoxicity. Anumber of pharmacological approaches to neuroprotection have been investigated. Various sites in this pathway have beentargeted. NMDA receptor antagonists block calcium entry through this glutamate ionotropic receptor. Gangliosides promotecalcium extrusion indirectly by blocking PKC translocation (not indicated). PARP inhibitors enhance functionality of ionpumps and calcium extrusion by increasing ATP availability. Dantrolene blocks calcium release from intracellular stores.Free radical scavengers include free radical “traps” and endogenous free radical scavenging enzymes and small moleculesprevent oxidative damage.by Ballough et al in 1997 and definitively assessedby Baille et al is less important than the fact that bothforms of neuronal cell death are triggered by nerveagent–inducedseizures. 38,67,68Candidate drugs may alter the relative proportionsof neurons undergoing death by necrosis versusapoptosis. Studies have reported that insufficient ATPavailability is an important determinant of whethera cell that has been triggered to undergo apoptosisis instead forced to die by necrosis. 55,69,70 Therefore, itis conceivable that a neuroprotectant candidate thatenhances ATP availability (for example, poly(ADPribose)polymerase [PARP] inhibitors) could suppressnecrosis while facilitating apoptosis. Neither possibilityshould be excluded during pathological evaluationsof neuroprotectant candidates.Specific Relevance of Neuroprotection to Nerve Agent SurvivorsThe term “neuroprotection” is defined as “pharmacologicalintervention that produces enduring benefitsby favorably influencing underlying etiology or pathogenesisand thereby forestalling the onset of disease orclinical decline.” 71,72 Within this broad definition, neuroprotectionhas acquired many different connotations.As a result, a search of the term “neuroprotection” onthe National Library of Medicine’s PubMed searchpage produces several thousand studies, mostly ondisease states in which subsets of neurons are specificallyvulnerable and die prematurely (as happens inParkinson’s disease, Huntington’s disease, frontotemporaldementia, and a host of metabolic disorders) oraccumulate neuropathology seen to a slight degree in225

Medical Aspects of Chemical Warfarenormal brains but in an accelerated fashion in somediseases (such as Alzheimer’s disease and trisomy 21).However, such interventions are unlikely to be relevantto the survivor of a single, brief nerve agent exposurethat has already caused sustained seizures and SE. Onthe other hand, research on neuroprotection followingstroke has provided valuable insights and clues thatdo apply to the nerve agent survivor.In this chapter, the term “neuroprotection” specificallyrefers to a putative intervention given over ashort period, ideally closely following the diagnosisof nerve agent exposure or before the acute toxicsyndrome of exposure has been adequately treated.The best neuroprotectant would have the longesttherapeutic window during which administrationwould be beneficial (even if the window is still only amatter of hours). At the same time, for logistical anddoctrinal reasons, the neuroprotection initiative doesnot extend to prophylactic treatments administeredto troops likely to experience nerve agent exposure(which would constitute a pretreatment, such as thebioscavenger initiative [see Chapter 7, Nerve AgentBioscavenger: Development of a New Approachto Protect Against Organophosphorus Exposure]).Therefore, in this chapter, neuroprotection refers onlyto postexposure treatment.There are similarities between brain damage resultingfrom nerve-agent–induced seizures and secondaryneuronal injury resulting from stroke. 73,74 Although theimmediate aspect of stroke-related neuronal injury isnecrosis, which stems from anoxia or hypoxia, thereis a secondary component to stroke damage that takes48 to 72 hours to become manifest. This componentaccounts for approximately 50% of the total damageresulting from the ischemic episode. Secondary strokeinjury involves brain tissue immediately surroundingthe necrotic core of primary injury (the penumbra).For the most part, glutamate excitotoxicity and ionicdestabilization, especially intracellular calcium, inducepenumbral damage. 73–75 Thus, the similarities betweensecondary stroke damage and damage resulting fromnerve-agent–induced seizures become apparent: theyboth involve glutamate excitotoxicity, hinge on intracellularcalcium destabilization, and lead to necroticor apoptotic neuronal death. This similarity raises thepossibility that neuroprotectants being developed forstroke may be useful for nerve agent survivors. Neuroprotectiveinterventions in stroke models have beenshown to save neurons that otherwise would have diedvia necrosis or apoptosis. There is hope, then, that atreatment can be found that can be administered afteragent exposure and that, although it may not haveany immediately discernible clinical effect, will producea significantly improved long-term neurologicaloutcome. Any of the many classes of compounds thathave been suggested as acute stroke neuroprotectantcandidates could be tried. This list is extensive; theInternet Stroke Center (http://www.strokecenter.org), maintained by Washington University, 76 offersa continuously updated list of compounds that havebeen tried in clinical stroke trials.The rationale for developing a protective agent,especially one based on dissimilar clinical situationsthat give rise to similar neuronal pathology, assumesthat preventing neuronal loss will produce a superiorclinical outcome. In the case of stroke, this assumption isprobably warranted. In the case of nerve-agent–inducednerve cell damage, this assumption has never beentested directly, but it is consistent with a wide varietyof animal data in multiple models and species. The assumptionthat preventing brain damage will producesuperior behavioral outcome is even supported byLashley and Hebb’s studies in the early to mid 1900s. 77A neuroprotectant in this restricted sense should demonstratethat neurons that might have been lost are nowsaved and that behavioral or neurological outcome isimproved. An ideal database to document such neuroprotectantswould include both neuropathologicalevidence of neuron survival and behavioral (in animals)or cognitive (in people) evidence that the neurologicoutcome is superior compared to subjects that did notreceive the neuroprotectant. Finally, the FDA must approveuse of the agent if it is a medication. (In clinicalmedicine, any FDA-approved medication can be usedoff-label by licensed physicians, but in military doctrine,specific on-label FDA approval is mandatory.)Neuroprotectants with Proven Efficacy Against Nerve-Agent–inducedSiezure-Related Brain DamageThis research comes from the consensus that nerveagent–inducedseizures and SE lead to the developmentof glutamate-mediated excitotoxicity, in whichdelayed calcium overload is the intracellular trigger ofthe final sequences leading to cell death. 1,24,42,43,47,49,56,78–81Classes of drugs that have been tested for their abilitiesto ameliorate nerve-agent–induced SRBD by specificallymitigating delayed calcium overload include thefollowing:• NMDA receptor antagonists that block extracellularcalcium influx;• glycosphingolipids that reduce intracellularcalcium by blocking the translocation of226

Neuroprotection as a Treatment for Nerve Agent SurvivorsFig. 6-1. Mechanisms contributing to nerve agent-induced SRBD. Calcium plays a pivotal role in glutamate excitotoxicity. Anumber <strong>of</strong> pharmacological approaches to neuroprotection have been investigated. Various sites in this pathway have beentargeted. NMDA receptor antagonists block calcium entry through this glutamate ionotropic receptor. Gangliosides promotecalcium extrusion indirectly by blocking PKC translocation (not indicated). PARP inhibitors enhance functionality <strong>of</strong> ionpumps and calcium extrusion by increasing ATP availability. Dantrolene blocks calcium release from intracellular stores.Free radical scavengers include free radical “traps” and endogenous free radical scavenging enzymes and small moleculesprevent oxidative damage.by Ballough et al in 1997 and definitively assessedby Baille et al is less important than the fact that bothforms <strong>of</strong> neuronal cell death are triggered by nerveagent–inducedseizures. 38,67,68Candidate drugs may alter the relative proportions<strong>of</strong> neurons undergoing death by necrosis versusapoptosis. Studies have reported that insufficient ATPavailability is an important determinant <strong>of</strong> whethera cell that has been triggered to undergo apoptosisis instead forced to die by necrosis. 55,69,70 <strong>The</strong>refore, itis conceivable that a neuroprotectant candidate thatenhances ATP availability (for example, poly(ADPribose)polymerase [PARP] inhibitors) could suppressnecrosis while facilitating apoptosis. Neither possibilityshould be excluded during pathological evaluations<strong>of</strong> neuroprotectant candidates.Specific Relevance <strong>of</strong> Neuroprotection to Nerve Agent Survivors<strong>The</strong> term “neuroprotection” is defined as “pharmacologicalintervention that produces enduring benefitsby favorably influencing underlying etiology or pathogenesisand thereby forestalling the onset <strong>of</strong> disease orclinical decline.” 71,72 Within this broad definition, neuroprotectionhas acquired many different connotations.As a result, a search <strong>of</strong> the term “neuroprotection” onthe National Library <strong>of</strong> Medicine’s PubMed searchpage produces several thousand studies, mostly ondisease states in which subsets <strong>of</strong> neurons are specificallyvulnerable and die prematurely (as happens inParkinson’s disease, Huntington’s disease, frontotemporaldementia, and a host <strong>of</strong> metabolic disorders) oraccumulate neuropathology seen to a slight degree in225

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