Matrix Metalloproteinase-Mediated Blood-Brain Barrier Dysfunction in Epilepsy.

The blood-brain barrier is dysfunctional in epilepsy, thereby contributing to seizure genesis and resistance to antiseizure drugs. Previously, several groups reported that seizures increase brain glutamate levels, which leads to barrier dysfunction. One critical component of barrier dysfunction is brain capillary leakage. Based on our preliminary data, we hypothesized that glutamate released during seizures mediates an increase in matrix-metalloproteinase (MMP) expression and activity levels, thereby contributing to barrier leakage. To test this hypothesis, we exposed isolated brain capillaries from male Sprague Dawley rats to glutamate ex vivo and used an in vivo/ex vivo approach of isolated brain capillaries from female Wistar rats that experienced status epilepticus as an acute seizure model. We found that exposing isolated rat brain capillaries to glutamate increased MMP-2 and MMP-9 protein and activity levels, and decreased tight junction protein levels, which resulted in barrier leakage. We confirmed these findings in vivo in rats after status epilepticus and in brain capillaries from male mice lacking cytosolic phospholipase A2 Together, our data support the hypothesis that glutamate released during seizures signals an increase in MMP-2 and MMP-9 protein expression and activity levels, resulting in blood-brain barrier leakage.SIGNIFICANCE STATEMENT The mechanism leading to seizure-mediated blood-brain barrier dysfunction in epilepsy is poorly understood. In the present study, we focused on defining this mechanism in the brain capillary endothelium. We demonstrate that seizures trigger a pathway that involves glutamate signaling through cytosolic phospholipase A2, which increases MMP levels and decreases tight junction protein expression levels, resulting in barrier leakage. These findings may provide potential therapeutic avenues within the blood-brain barrier to limit barrier dysfunction in epilepsy and decrease seizure burden.

Optimization of inpatient medication administration among persons with Parkinson's disease: recommendations on pharmacy technology and workflow.

Individuals with Parkinson's disease (PD) are vulnerable during hospitalizations due to the underlying complexities o1f symptoms, and acute illness or medication changes often lead to decompensation. Complications during hospitalizations are often due to worsening motor and nonmotor symptoms and commonly result from inaccurate medication regimens. Although the accuracy of medication administration relies on an interplay of factors, including patient status, transitions of care, coordination between the hospital prescriber and outpatient neurologist, etc., hospital pharmacists play an integral role in pharmacotherapy. The main aspects of pharmacy strategies aim to achieve timely administration of levodopa-containing medications, reduction of substitution and omissions of antiparkinsonian medications, and avoidance of antidopaminergic medications. This paper highlights critical areas for improvement and recommendations to minimize the impact of other factors from the pharmacy standpoint.

Use of anti-TNF-α therapy in Crohn's disease is associated with increased incidence of multiple sclerosis.

OBJECTIVE: We investigated if anti-tumor necrosis factor-α (anti-TNF-α) drugs used in the treatment of inflammatory bowel disease (IBD) alter the incidence of MS and if so, to understand the magnitude of such an effect. METHODS: This is a retrospective cohort study of data from Truven Health Market Scan administrative claims database. The patients included in the study had to be ≥ 18 years of age. The presence of IBD was based on at least 2 claims of International Classification of Diseases (ICD-9 or 10) diagnosis codes. The IBD diagnosis index date had to precede the MS diagnosis index date for inclusion in the study. The diagnosis of multiple sclerosis (MS) was defined as having at least 2 claims for the disease (ICD 9, 340 and ICD 10 codes, G35) and at least one prescription claim for any of the drugs that were defined as MS therapy. RESULTS: Patients with IBD had 1.32 times the risk of MS incidence compared to healthy controls (adjusted incidence rate ratio (IRR): 1.32; 95% CI: 1.03 - 1.71; p = .0312). Patients with IBD exposed to anti-TNF-α therapies had a 43% increase in the incidence of MS compared to those with IBD without exposure (adjusted incidence rate: 1.43; 95% CI: .062 - 3.32; p = .3989). Among CD patients treated anti-TNF-α medications an increase in the incidence of MS, compared to CD patients not exposed to such medications was observed (IRR = 2.62; 95% CI: 1.00 to 6.83; p = 0.049), statistically significant. After adjusting for age/gender, patients with CD using anti-TNF-α agents had an increase of incidence in MS (adjusted IRR: 2.24; 95% CI: 0.85 - 5.94; p = .1035) but it was not statistically significant. CONCLUSIONS: Use of anti-TNF-α drugs in CD was associated with a statistically significant increase in the incidence of MS but this effect was lost when controlled for age/gender.

Can a diagnosis of multiple sclerosis be made without ruling out neuromyelitis optica spectrum disorder ?

BACKGROUND: The symptoms of multiple sclerosis (MS) can overlap with neuromyelitis optica spectrum disorder (NMOSD). Although testing is available for aquaporin 4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies, screening for NMOSD is recommended but not mandatory to establish a diagnosis of MS. METHODS AND RESULTS: We queried 319,994 individuals who filed claims for MS and NMOSD in a Truven Health Analytics (THA) database and had at least one year of uninterrupted health insurance coverage. Of this cohort, 2001 (0.62%) were diagnosed as having NMOSD after an initial diagnosis of MS, based on ICD 9/10 codes. Since THA only offers claims-based data, we initiated an individual patient-based data search at our medical center to screen for potential misdiagnoses. We identified 4/54 (7.4%) NMOSD cases that were initially diagnosed as having MS. CONCLUSIONS: The results from our small study have significant implications--symptoms, clinical presentation or classic radiological findings perhaps cannot reliably separate MS from NMOSD. If our study findings can be replicated, guidelines to diagnose MS ought to recommend that NMOSD be excluded first despite typical clinical and radiological findings pointing to MS.

Isolation of Cerebral Capillaries from Fresh Human Brain Tissue.

Understanding blood-brain barrier function under physiological and pathophysiological conditions is critical for the development of new therapeutic strategies that hold the promise to enhance brain drug delivery, improve brain protection, and treat brain disorders. However, studying the human blood-brain barrier function is challenging. Thus, there is a critical need for appropriate models. In this regard, brain capillaries isolated from human brain tissue represent a unique tool to study barrier function as close to the human in vivo situation as possible. Here, we describe an optimized protocol to isolate capillaries from human brain tissue at a high yield and with consistent quality and purity. Capillaries are isolated from fresh human brain tissue using mechanical homogenization, density-gradient centrifugation, and filtration. After the isolation, the human brain capillaries can be used for various applications including leakage assays, live cell imaging, and immune-based assays to study protein expression and function, enzyme activity, or intracellular signaling. Isolated human brain capillaries are a unique model to elucidate the regulation of the human blood-brain barrier function. This model can provide insights into central nervous system (CNS) pathogenesis, which will help the development of therapeutic strategies for treating CNS disorders.

Ketogenic diet enhances neurovascular function with altered gut microbiome in young healthy mice.

Neurovascular integrity, including cerebral blood flow (CBF) and blood-brain barrier (BBB) function, plays a major role in determining cognitive capability. Recent studies suggest that neurovascular integrity could be regulated by the gut microbiome. The purpose of the study was to identify if ketogenic diet (KD) intervention would alter gut microbiome and enhance neurovascular functions, and thus reduce risk for neurodegeneration in young healthy mice (12-14 weeks old). Here we show that with 16 weeks of KD, mice had significant increases in CBF and P-glycoprotein transports on BBB to facilitate clearance of amyloid-beta, a hallmark of Alzheimer's disease (AD). These neurovascular enhancements were associated with reduced mechanistic target of rapamycin (mTOR) and increased endothelial nitric oxide synthase (eNOS) protein expressions. KD also increased the relative abundance of putatively beneficial gut microbiota (Akkermansia muciniphila and Lactobacillus), and reduced that of putatively pro-inflammatory taxa (Desulfovibrio and Turicibacter). We also observed that KD reduced blood glucose levels and body weight, and increased blood ketone levels, which might be associated with gut microbiome alteration. Our findings suggest that KD intervention started in the early stage may enhance brain vascular function, increase beneficial gut microbiota, improve metabolic profile, and reduce risk for AD.