Search

Organophosphate (OP) poisoning can trigger cholinergic crisis, a life-threatening toxidrome that includes seizures and status epilepticus. These acute toxic responses are associated with persistent neuroinflammation and spontaneous recurrent seizures (SRS), also known as acquired epilepsy. Blood-brain barrier (BBB) impairment has recently been proposed as a pathogenic mechanism linking acute OP intoxication to chronic adverse neurologic outcomes. In this review, we briefly describe the cellular and molecular components of the BBB, review evidence of altered BBB integrity following acute OP intoxication, and discuss potential mechanisms by which acute OP intoxication may promote BBB dysfunction. We highlight the complex interplay between neuroinflammation and BBB dysfunction that suggests a positive feedforward interaction. Lastly, we examine research from diverse models and disease states that suggest mechanisms by which loss of BBB integrity may contribute to epileptogenic processes. Collectively, the literature identifies BBB impairment as a convergent mechanism of neurologic disease and justifies further mechanistic research into how acute OP intoxication causes BBB impairment and its role in the pathogenesis of SRS and potentially other long-term neurologic sequelae. Such research is critical for evaluating BBB stabilization as a neuroprotective strategy for mitigating OP-induced epilepsy and possibly seizure disorders of other etiologies. SIGNIFICANCE STATEMENT: Clinical and preclinical studies support a link between blood-brain barrier (BBB) dysfunction and epileptogenesis; however, a causal relationship has been difficult to prove. Mechanistic studies to delineate relationships between BBB dysfunction and epilepsy may provide novel insights into BBB stabilization as a neuroprotective strategy for mitigating epilepsy resulting from acute organophosphate (OP) intoxication and non-OP causes and potentially other adverse neurological conditions associated with acute OP intoxication, such as cognitive impairment.

Abstract: Acute intoxication with organophosphorus (OP) cholinesterase inhibitors can produce seizures that rapidly progress to life-threateningstatus epilepticus. Significant research effort has been invested investigating the involvement of muscarinic acetylcholine receptors (mAChRs) in OP-induced seizure activity. In contrast, there has been far less effort focused on nicotinic AChRs (nAChRs) in this context. Here, we address this data gap using a combination ofin vitroandin vivomodels. Pharmacological antagonism and genetic deletion of α4, but not α7, nAChR subunits prevented or significantly attenuated OP-induced electrical spike activity in acute hippocampal slices and seizure activity in mice, indicating that α4 nAChR activation is necessary for neuronal hyperexcitability triggered by acute OP exposures. These findings not only suggest that therapeutic strategies for inhibiting the α4 nAChR subunit warrant further investigation as prophylactic and acute treatments for acute OP-induced seizures, but also provide mechanistic insight into the role of the nicotinic cholinergic system in seizure generation.

Acute organophosphate (OP) intoxication can trigger seizures that progress to status epilepticus (SE), and survivors often develop chronic morbidities, including spontaneous recurrent seizures (SRS). The pathogenic mechanisms underlying OP-induced SRS are unknown, but increased BBB permeability is hypothesized to be involved. Previous studies reported BBB leakage following OP-induced SE, but key information regarding time and regional distribution of BBB impairment during the epileptogenic period is missing. To address this data gap, we characterized the spatiotemporal progression of BBB impairment during the first week post-exposure in a rat model of diisopropylfluorophosphate-induced SE, using MRI and albumin immunohistochemistry. Increased BBB permeability, which was detected at 6 h and persisted up to 7 d post-exposure, was most severe and persistent in the piriform cortex and amygdala, moderate but persistent in the thalamus, and less severe and transient in the hippocampus and somatosensory cortex. The extent of BBB leakage was positively correlated with behavioral seizure severity, with the strongest association identified in the piriform cortex and amygdala. These findings provide evidence of the duration, magnitude and spatial breakdown of the BBB during the epileptogenic period following OP-induced SE and support BBB regulation as a viable therapeutic target for preventing SRS following acute OP intoxication.

Background: The judicious use of antimicrobials in the livestock industry has become a topic of increasing interest over the last few years. Bovine respiratory disease (BRD) is considered mainly a problem of feedlot cattle or dairy calves, but a survey on the use of antimicrobials in California cow-calf operations revealed that BRD is in the top three diseases that ranchers treat most frequently with antimicrobials. There are both viral and bacterial causative agents that are associated with BRD. The pathogenesis of these agents often depends on the immune status of the animals and stress is considered to play major role in exacerbating the problem. In cow-calf operations these stressors can be in the form of management procedures such as processing of calves where they may be castrated, vaccinated, receive ear tags or being branded. Weaning is another stressful event in the life of a calf where the effects can be synergized if the calf is also transported at the same time. Due to the climate and landscape in California, cattle are often transported to different pastures in the summer and winter to take advantage of availability of feed year-round in different parts of the state at different times of the year. Vaccination, immune modulation, improving immune status through mineral supplementation and good colostrum[1] can all play a role in prevention of the disease relative to transportation. In this review we explore the available literature for evidence of effective methods to prevent BRD in cattle in California after transportation.Objectives:  The objective of this scoping review is to examine and describe the existing literature on methods for the prevention of BRD that can be implemented in cow-calf operations in California and therefore reduce the use of antimicrobials due to BRD.Design: Primary research on prevention of BRD due to shipping stress will be considered for inclusion. The process for selection and inclusion of the studies will be reported in a flow chart according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). The results will be summarized in tables and charts describing study types, interventions and outcomes.