RESUMEN
Most research on medical countermeasures for nerve agent exposure assumes a military scenario, in which (autoinjector) treatment is envisaged to be available immediately. In a civilian setting however, treatment is delayed until arrival of first-aid responders. This may significantly affect treatment efficacy and the requirements for secondary intensive care. The aim of the current study was to develop a guinea pig model to evaluate the efficacy of delayed treatment following nerve agent exposure. We identified a trigger-to-treat based on a progressive stage of the toxidrome following VX exposure, which was associated with the subsiding of clonic movements. This paradigm resulted in treatment consistently being administered between 15 and 25 min post-exposure. Using the model, we investigated the potential for the anticholinergic scopolamine to act as a delayed treatment either as a standalone treatment, or as an adjunct to delayed treatment with Standard of Care (SOC), containing atropine, 2-PAM, and midazolam. The study provides a framework for a small animal model for evaluating the efficacy of treatment administered at a specific stage of the toxidrome, when immediate treatment is absent. As an adjunct, scopolamine treatment did not result in improved survival, but did show a beneficial effect on recovery, in terms of general posture. As a standalone treatment, scopolamine showed a significant, dose-responsive, beneficial effect on survival and recovery. These promising results warrant additional studies to investigate which observed physiological improvements are relevant for the recovery process and residual injury.
Asunto(s)
Sustancias para la Guerra Química/toxicidad , Antagonistas Colinérgicos/administración & dosificación , Agentes Nerviosos/toxicidad , Compuestos Organotiofosforados/toxicidad , Escopolamina/administración & dosificación , Tiempo de Tratamiento , Animales , Atropina/administración & dosificación , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Quimioterapia Combinada , Cobayas , Masculino , Midazolam/administración & dosificación , Compuestos de Pralidoxima/administración & dosificación , Tasa de Supervivencia/tendenciasRESUMEN
Animal models of mild traumatic brain injury (mTBI) provide opportunity to examine the extent to which dietary interventions can be used to improve recovery after injury. Animal studies also suggest that matrix metalloproteinases (MMPs) play a role in tissue remodeling post-TBI. Because dietary zinc (Zn) improved recovery in nonblast mTBI models, and the MMPs are Zn-requiring enzymes, we evaluated the effects of low- (LoZn) and adequate-Zn (AdZn) diets on MMP expression and behavioral responses, subsequent to exposure to a single blast. MMP messenger RNA expression in soleus muscle and frontal cortex tissues were quantified at 48 h and 14 days post-blast. In muscle, blast resulted in significant upregulation of membrane-type (MT)-MMP, MMP-2, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 at 48 h post-injury in rats consuming AdZn. At 14 days post-blast, there were no blast or dietary effects observed on MMP levels in muscle, supporting the existence of a Zn-responsive, functional repair and remodeling mechanism. In contrast, blast resulted in a significant downregulation of MT-MMP, TIMP-1, and TIMP-2 and a significant upregulation of MMP-3 levels at 48 h post-injury in cortex tissue, whereas at 14 days post-blast, MT-MMP, MMP-2, and TIMP-2 were all downregulated in response to blast, independent of diet, and TIMP-1 were significantly increased in rats fed AdZn diets despite the absence of elevated MMPs. Because the blast injuries occurred while animals were under general anesthesia, the increased immobility observed post-injury in rats consuming LoZn diets suggest that blast mTBI can, in the absence of any psychological stressor, induce post-traumatic stress disorder-related traits that are chronic, but responsive to diet. Taken together, our results support a relationship between marginally Zn-deficient status and a compromised regenerative response post-injury in muscle, likely through the MMP pathway. However, in neuronal tissue, changes in MMP/TIMP levels after blast indicate a variable response to marginally Zn-deficient diets that may help explain compromised repair mechanism(s) previously associated with the systemic hypozincemia that develops in patients with TBI.