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

Medical Aspects of Chemical Warfarefrom nerve agent exposure are directly responsiblefor the vast majority, if not all, of the neuropathologyproduced by these agents. The associated damage istypically bilaterally symmetrical and most severe intemporal lobe structures (ie, piriform and entorhinalcortices, hippocampus, and amygdala) as well as inthe thalamus.Brain damage resulting from agent-induced seizuresis the result of the complex, multiphasic responseof individual neurons to numerous extracelluar andintracellular events. Following inhibition of acetylcholinesteraseand accumulation of acetylcholine atcholinergic synapses, the hyperstimulation of cholinergicreceptors on postsynaptic membranes triggersseizures. 10,39,40 Subsequently, recruitment and excessiveactivation of the glutamatergic neurotransmitter systemoccurs. Glutamate, the most abundant excitatoryneurotransmitter in the brain, is responsible for sustainingsoman-induced seizures and promoting thedevelopment of SE. 1,24,41–44 Large pathological elevationsin the concentration of intracellular sodium and(especially) calcium are caused by excessive stimulationof ionotropic glutamate receptors, as is prolongeddepolarization of postsynaptic membranes. Thisinitiates a harmful cascade of pathological processes,most of which center around a prolonged increase inintracellular free calcium or delayed calcium overload,leading to excitotoxic cell death. 1,24,45–47Transient elevation in intracellular free calcium is aubiquitous signaling mechanism and regulator of intracellularprocesses, from cell growth and metabolismto cell death. 48–50 Cytosolic free calcium is also a criticalneuronal mediator of learning and memory. 51 However,when normal homeostatic control of intracellularcalcium is lost and a sustained elevation occurs, thedelayed calcium overload triggers neuronal cell deathby necrosis or apoptosis (a form of programmed celldeath). 52–56 In neurons, the majority of calcium influxoccurs through N-methyl d-aspartate (NMDA) ionotropicglutamate receptors as well as voltage-gated calciumchannels (eg, L-type). Calcium influx also occurs,though to a lesser extent, through the other two classesof ionotropic glutamate receptors (alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid andkainate receptors). 57 Excessive stimulation of NMDAreceptors is the first step in glutamate excitotoxicity. 24,45The release of intracellular stores is also responsiblefor increased cytosolic free calcium. The endoplasmicreticulum (ER) releases calcium following bindingof the second messenger, inositol triphosphate, toionotropic receptors located on the ER membrane.Calcium is released from the ER via ryanodine receptors.These ionotropic receptors are also located on theER membrane and open following binding of cytosoliccalcium; thus, cytosolic free calcium augments its ownconcentration by stimulating calcium release from theER. 49 The ER plays a critical role in normal calciumhomeostasis. Excessive release or impaired uptake ofcalcium has been implicated in pathology resultingfrom calcium overload. 49,52 Brain mitochondria areimportant for calcium buffering as cytosolic concentrationsrise, and their ability to sequester calcium is dependenton adenosine triphosphate (ATP). 58 However,when calcium overload occurs, mitochondria undergoa permeability transition characterized by loss ofmitochondrial transmembrane potential, curtailmentof ATP synthesis, mitochondrial swelling, release ofstored calcium, and neuronal death by necrosis. 59–62The majority of soman-induced SRBD results fromglutamate excitotoxicity and the delayed calcium overloadthat follows. 1,24,42,43 Delayed calcium overload inneurons initiates a pathological sequence characterizedby activation of several potentially damaging enzymes.These include oxygenases, phospholipases, and nitricoxide synthase, which produce reactive oxygen speciessuch as superoxide radical, hydrogen peroxide,hydroxyl radical, nitric oxide, and peroxynitrite.Neuronal injury induced by reactive oxygen speciesstems from direct damage to cell membranes, DNA,and intracellular proteins, and also induction of cytochromeC from mitochondria with subsequent caspaseactivation. 62 Release of cytochrome C, caspase activation,and DNA fragmentation are molecular hallmarksof apoptosis (Figure 6-1). 56,62,63Cysteine proteases called calpains are also activatedby sustained elevations in intracellular free calcium.Calpains degrade various intracellular proteins, includingthose of the cytoskeleton, membrane channels,and metabolic enzymes, and cause neuronal death bynecrosis. 56,62,63 (Necrosis produces localized inflammation,which exacerbates damage, while apoptosis isnot associated with inflammation.) The culminationof these events may result in cell death hours or daysafter the initial insult. 53–55Necrosis and apoptosis are not an either/or phenomena,that is, they are not completely distinct formsof cell death with no overlap; a necrosis versus apoptosisdichotomy is a misleading over-simplification. 64,65Martin and colleagues proposed an “apoptosis-necrosiscontinuum,” reporting that dying neurons can exhibitintermediate forms between apoptosis and necrosis. 66Recently, Baille and colleagues confirmed that neuronalinjury, resulting from soman-induced seizures, exhibitsa large variety of hybrid forms between necrosis andapoptosis, but that the majority show more necroticfeatures. 67 Whether soman-induced neuropathology ismostly necrotic, as it is in the piriform cortex of rats, 38or contains elements of apoptosis as first proposed224