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

Medical Aspects of Chemical Warfare40 minutes and 8 hours after seizure onset, with atotal injection volume approximating 1 mL per rat. Aunique formulation of dantrolene (Lyotropic Therapeutics,Inc, Ashland, Va) as a nanocrystal dispersionhas also been used to obviate solubility problems. Withthis formulation, it is possible to administer a muchhigher dose of dantrolene in a much lower injectionvolume. This is critical because when dantrolene isadministered by IP injection, liver enzymes lower theconcentration of dantrolene reaching the brain. Thenanocrystal formulation of dantrolene minimizes theeffects of the liver enzymes.Our results with the dantrolene nanocrystal formulationnot only overcame the insolubility problems ofour previous dantrolene study, but corroborated andextended the results of that study. The nanocrystal studywas unable to demonstrate significant protection in thepiriform cortex, the most severely damaged region, butin this study the nanocrystal dispersion of dantrolene(40 mg/kg, IP) plus diazepam (20 mg/kg, IM) reducedpiriform cortical necrosis by 15.6% more than diazepamalone (unpublished study by US Army Medical ResearchInstitute of Chemical Defense). In these experiments, allsoman-exposed rats also received HI-6 (125 mg/kg, IP, 30min after soman) and AMN (2 mg/kg, IM, < 1 min aftersoman) to protect against the peripheral effects of somanand ensure survival. Neuroprotection by dantrolene inthe above experiments occurred without changes in seizureintensity or duration, and dantrolene produced nodiscernible effects on the electrocorticographic profilesof soman-exposed subjects. These findings are consistentwith those of Frandsen and Schouosboe, 115 who reportedthat dantrolene prevented glutamate neurotoxicity byblocking release of calcium from intracellular stores.The results are also consistent with those of Niebauerand Gruenthal, 87 who examined the protective effects ofdantrolene on hippocampal neuronal damage producedby SE in rats. In their study, dantrolene (10 mg/kg, IP)was administered either 30 or 140 minutes after the onsetof SE. Niebauer and Gruenthal reported that early administrationproduced a significant reduction in neuronalinjury in all hippocampal subregions. When dantroleneadministration was delayed until 140 minutes after SEonset, some protection was still seen in hippocampal fieldCA3, but not the other subregions. 87 Protection againstkainic-acid–induced apoptosis has also been reported. 116N-methyl-d-aspartate Receptor AntagonistsMK-801 (Dizocilpine)The first NMDA receptor antagonist to showpromise as a putative neuroprotectant was MK-801(dizocilpine); however, it has been shown to have toxiceffects. When given in conjunction with PB, AMN,and 2-PAM, noncompetitive MK-801 was reportedto reduce nerve-agent–induced SRBD in the piriformcortex, amygdala, hippocampus, and thalamus. 43 Asmentioned, these are among the most severely damagedbrain regions in SRBD resulting from somanexposure. 29–32,35,37,38,90 In the Sparenborg study, MK-801(0.5, 1.0, or 5 mg/kg, IP) reduced brain damage anddiminished or arrested seizures in guinea pigs whenadministered as a pretreatment 30 minutes before soman,and the effects were dose-dependent. The anticonvulsantprofile of MK-801 against soman-inducedseizures was definitively characterized by Shih. 11 Heshowed that the anticonvulsant effect of MK-801 is fourtimes greater than that of diazepam, but at doses of 1mg/kg or higher, MK-801 potentiated the lethal effectsof soman. Some concern arose about the use of NMDAantagonists when it was reported that MK-801 inducesneuronal degeneration in the posterior cingulate, retrosplenialcortices, and other corticolimbic regions. 117,118This damage evidently occurs by disinhibition of multipleconverging excitatory pathways. 119 Specifically,excessive blockage of glutamatergic pathways leadsto excessive stimulation of cholinergic function. 120 Thisexplanation is supported by the findings that neurotoxicityby MK-801 is augmented when cholinergicreceptors (ie, muscarinic) are activated. 121MemantineMemantine is a noncompetitive NMDA receptorantagonist 122 that has also been tested for its anticonvulsanteffects against soman-induced seizures.Studies have suggested that memantine’s pharmacokineticsmake it a safer candidate than MK-801. 123,124McLean et al 125 reported that memantine alone (18 mg/kg, subcutaneous [SC]) blocked the onset of somaninducedseizures and was able to terminate seizureswhen administered 15 minutes after soman injection.These findings, however, are inconsistent with thoseof Shih et al 17 who reported that memantine by itselfis completely ineffective as an anticonvulsant againstsoman-induced seizures. The latter authors pointedto a need for EEG monitoring when determining anticonvulsantefficacy and suggested that McLean et almay have mistaken diminished convulsive behavioras evidence of reduced seizure activity. Neither studyaddressed the possible neuroprotective effects of memantine(ie, reduced neuropathology independent ofanticonvulsant activity). On the other hand, Koplovitzet al 126 observed a modest reduction in piriform corticaldamage following soman in rats treated with atropineand memantine, compared to those that received atropinealone. There were no differences between the228