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1.
Front Neurosci ; 15: 732213, 2021.
Article in English | MEDLINE | ID: mdl-34566572

ABSTRACT

Nerve agents (NAs) induce a severe cholinergic crisis that can lead to status epilepticus (SE). Current guidelines for treatment of NA-induced SE only include prehospital benzodiazepines, which may not fully resolve this life-threatening condition. This study examined the efficacy of general clinical protocols for treatment of SE in the specific context of NA poisoning in adult male rats. Treatment with both intramuscular and intravenous benzodiazepines was entirely insufficient to control SE. Second line intervention with valproate (VPA) initially terminated SE in 35% of rats, but seizures always returned. Phenobarbital (PHB) was more effective, with SE terminating in 56% of rats and 19% of rats remaining seizure-free for at least 24 h. The majority of rats demonstrated refractory SE (RSE) and required treatment with a continuous third-line anesthetic. Both ketamine (KET) and propofol (PRO) led to high levels of mortality, and nearly all rats on these therapies had breakthrough seizure activity, demonstrating super-refractory SE (SRSE). For the small subset of rats in which SE was fully resolved, significant improvements over controls were observed in recovery metrics, behavioral assays, and brain pathology. Together these data suggest that NA-induced SE is particularly severe, but aggressive treatment in the intensive care setting can lead to positive functional outcomes for casualties.

2.
J Neuroinflammation ; 16(1): 93, 2019 Apr 30.
Article in English | MEDLINE | ID: mdl-31039819

ABSTRACT

BACKGROUND: The anti-inflammatory cytokine interleukin-10 (IL-10) has been explored previously as a treatment method for spinal cord injury (SCI) due to its ability to attenuate pro-inflammatory cytokines and reduce apoptosis. Primary limitations when using systemic injections of IL-10 are that it is rapidly cleared from the injury site and that it does not cross the blood-spinal cord barrier. OBJECTIVE: Here, mineral-coated microparticles (MCMs) were used to obtain a local sustained delivery of IL-10 directly into the injury site after SCI. METHODS: Female Sprague-Dawley rats were contused at T10 and treated with either an intraperitoneal injection of IL-10, an intramedullary injection of IL-10, or MCMs bound with IL-10 (MCMs+IL-10). After treatment, cytokine levels were measured in the spinal cord, functional testing and electrophysiology were performed, axon tracers were injected into the brainstem and motor cortex, macrophage levels were counted using flow cytometry and immunohistochemistry, and lesion size was measured. RESULTS: When treated with MCMs+IL-10, IL-10 was significantly elevated in the injury site and inflammatory cytokines were significantly suppressed, prompting significantly less cells expressing antigens characteristic of inflammatory macrophages and significantly more cells expressing antigens characteristic of earlier stage anti-inflammatory macrophages. Significantly more axons were preserved within the rubrospinal and reticulospinal tracts through the injury site when treated with MCMs+IL-10; however, there was no significant difference in corticospinal tract axons preserved, regardless of treatment group. The rats treated with MCMs+IL-10 were the only group with a significantly higher functional score compared to injured controls 28 days post-contusion. CONCLUSION: These data demonstrate that MCMs can effectively deliver biologically active IL-10 for an extended period of time altering macrophage phenotype and aiding in functional recovery after SCI.


Subject(s)
Inflammation/pathology , Interleukin-10/administration & dosage , Neuroprotective Agents/administration & dosage , Spinal Cord Injuries/pathology , Animals , Dosage Forms , Female , Random Allocation , Rats , Rats, Sprague-Dawley , Recovery of Function/drug effects
3.
Neural Regen Res ; 14(1): 7-19, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30531063

ABSTRACT

Rats have been the primary model to study the process and underlying mechanisms of recovery after spinal cord injury. Two weeks after a severe spinal cord contusion, rats can regain weight-bearing abilities without therapeutic interventions, as assessed by the Basso, Beattie and Bresnahan locomotor scale. However, many human patients suffer from permanent loss of motor function following spinal cord injury. While rats are the most understood animal model, major differences in sensorimotor pathways between quadrupeds and bipeds need to be considered. Understanding the major differences between the sensorimotor pathways of rats, non-human primates, and humans is a start to improving targets for treatments of human spinal cord injury. This review will discuss the neuroplasticity of the brain and spinal cord after spinal cord injury in rats, non-human primates, and humans. A brief overview of emerging interventions to induce plasticity in humans with spinal cord injury will also be discussed.

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