Intoxication with organophosphate (OP) acetylcholinesterase inhibitors represent a chemical threat and a global public health issue. Acute OP intoxication triggers a cholinergic crisis that can progress to seizures, status epilepticus (SE) and death. Current standard of care increases the survival rate of patients acutely intoxicated with OPs, but does not prevent long-term neurological sequelae, specifically, epilepsy and cognitive impairment. SE induced by etiologies other than OP intoxication similarly progress to long-term adverse neurological consequences, and to date there are no effective therapeutic strategies for these situations either. Progress in addressing this clinical gap has been stymied by significant data gaps regarding the pathogenic mechanism(s) underlying the persistent neurological consequences associated with acute SE. Predominant hypothesis include neuroinflammation, oxidative stress and/or damage to the blood-brain barrier (BBB). The BBB is vital for the maintenance of a regulated brain milieu required for normal neurological function; the BBB also protects brain cells from toxic blood-borne compounds. BBB impairment has been reported following acute OP-induced SE and SE caused by other etiologies. A dysfunctional BBB has also been documented in patients with epilepsy and cognitive deficits. It is hypothesized that BBB disruption is involved in the pathogenesis of epilepsy and cognitive impairment, and, therefore, stabilization of the BBB following acute SE could mitigate such neuropathologies. This dissertation focuses on characterizing the disruption of the BBB following OP-induced SE using a rat model of acute intoxication with the OP diisopropylfluorophosphate (DFP). It further seeks to determine whether repurposing Cmpd10357, a drug that targets the plasminogen activating system (PAS), mitigates BBB dysfunction in rats acutely intoxicated with DFP.Chapter 2 identified breach of the BBB as determined by contrast MRI and immunohistochemical localization of serum albumin in the brain parenchyma as early as 6 h post-exposure in the piriform cortex (PRC) and amygdala (AMY) of male rats and remained severe until 7 days post-exposure (DPE). This BBB leakiness was mild to moderate and transient in the thalamus, hippocampus and somatosensory cortex. Chapter 3 characterized the spatiotemporal profile of OP-induced BBB instability in the PRC and AMY of male and female rats, observing a leakage of sodium fluorescein, MRI contrast and serum albumin that persisted up to 28 DPE. Female rats presented less severe signs of BBB dysfunction when inspected by MRI. The components of the neurovascular unit (NVU) were examined and general dysregulation of all elements of the NVU were evident by 3 to 7 DPE and persisted up to 28 DPE. Chapter 3 also revealed that the BBB dysfunction post-DFP poisoning is SE-dependent, and occurs largely independent of OP-induced cholinergic crisis. Lastly, chapter 4 showed Cmpd10357 is ineffective in protecting the BBB in rats acutely intoxicated with DFP. There were no differences in serum albumin leakage in the PRC and AMY of DFP-intoxicated rats treated with this drug vs. those that were not treated. Interestingly, treatment with Cmpd10357 also had no effect on the expression of tissue and urokinase plasminogen activators (tPA and uPA), or the count of astrocytes expressing plasminogen activator inhibitor 1 (PAI-1). In conclusion, the findings of this dissertation strengthen the hypothesis that BBB disruption is associated with long-term neurological consequences of acute OP-induced SE. These data provide insight regarding a temporal window for administration of therapeutics to stabilize the BBB, potential biomarkers for quantifying effectiveness of these therapies, and even novel therapeutic targets. In addition, the results presented here enhance the translatability of data generated from the rat acute model of DFP intoxication to other models of SE and, to some extent, to clinical settings. Lastly, the lack of therapeutic efficacy of Cmpd10357 suggests that mechanistically different PAS-targeting drugs be considered for stabilizing the BBB post-DFP intoxication.