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Isolation Of Cerebral Capillaries From Fresh Human Brain Tissue, Anika M. S. Hartz, Julia A. Schulz, Brent S. Sokola, Stephanie E. Edelmann, Andrew N. Shen, Ralf G. Rempe, Yu Zhong, Nader El Seblani, Bjoern Bauer

Sanders-Brown Center on Aging Faculty Publications

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 …

Temporal And Spatial Effects Of Shock Overpressure On Blood-Brain Barrier Permeability In Blast-Induced Traumatic Brain Injury, Matthew Joseph Kuriakose

Dissertations

Exposure to shock waves is the leading cause of traumatic brain injury (TBI) in military personnel and blast-induced TBI (bTBI) is considered the signature wound in recent conflicts in Iraq and Afghanistan. Many researchers attempt to replicate field-relevant shock waves in laboratory settings through the use of gas-driven shock tubes in order to investigate the generation and propagation of shock waves and also explore possible mechanisms of bTBI. Among several injury mechanisms of bTBI, damage to the blood-brain barrier (BBB) has been identified as a potential candidate and has been the focus of several clinical and experimental investigations aimed to …

Preventing P-Gp Ubiquitination Lowers Aβ Brain Levels In An Alzheimer's Disease Mouse Model, Anika M. S. Hartz, Yu Zhong, Andrew N. Shen, Erin L. Abner, Björn Bauer

Sanders-Brown Center on Aging Faculty Publications

One characteristic of Alzheimer’s disease (AD) is excessive accumulation of amyloid-β (Aβ) in the brain. Aβ brain accumulation is, in part, due to a reduction in Aβ clearance from the brain across the blood-brain barrier. One key element that contributes to Ab brain clearance is P-glycoprotein (P-gp) that transports Aβ from brain to blood. In AD, P-gp protein expression and transport activity levels are significantly reduced, which impairs Aβ brain clearance. The mechanism responsible for reduced P-gp expression and activity levels is poorly understood. We recently demonstrated that Aβ₄₀ triggers P-gp degradation through the ubiquitin-proteasome pathway. Consistent with these …

Matrix Metalloproteinase-Mediated Blood-Brain Barrier Dysfunction In Epilepsy, Ralf G. Rempe, Anika M. S. Hartz, Emma L. B. Soldner, Brent S. Sokola, Satya R. Alluri, Erin L. Abner, Richard J. Kryscio, Anton Pekcec, Juli Schlichtiger, Björn Bauer

Pharmaceutical Sciences Faculty Publications

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 …

High-Intensity Focused Ultrasound: Past, Present, And Future In Neurosurgery, Syed A. Quadri,, Muhammad Waqas, Inamullah Khan, Muhammad Adnan Khan, Sajid S. Suriya, Mudassir Farooqui, Brian Fiani

Section of Neurosurgery

Since Lynn and colleagues first described the use of focused ultrasound (FUS) waves for intracranial ablation in 1942, many strides have been made toward the treatment of several brain pathologies using this novel technology. In the modern era of minimal invasiveness, high-intensity focused ultrasound (HIFU) promises therapeutic utility for multiple neurosurgical applications, including treatment of tumors, stroke, epilepsy, and functional disorders. Although the use of HIFU as a potential therapeutic modality in the brain has been under study for several decades, relatively few neuroscientists, neurologists, or even neurosurgeons are familiar with it. In this extensive review, the authors intend to …

Dual Lox/Cox Inhibition: A Novel Strategy To Prevent Neurovascular Leakage In Epilepsy, Brent S. Sokola

Theses and Dissertations--Pharmacy

Epilepsy affects 3.4 million patients in the USA and is characterized by recurring seizures. The blood-brain barrier is leaky in epilepsy and may contribute to seizure progression but the mechanisms which cause this leakage are not fully understood. We hypothesized that seizures trigger LOX- and COX-mediated blood-brain barrier leakage and that dual LOX/COX inhibition prevents barrier leakage in vivo. To test this hypothesis, we administered either the dual LOX/COX inhibitor licofelone or a combination of the 5-LOX inhibitor zileuton and the COX-2 inhibitor celecoxib to rats that experienced status epilepticus (SE). Serum and brain capillaries were isolated 48 hours …

Effects Of Hiv-1 Tat And Drugs Of Abuse On Antiretroviral Penetration Inside Different Cns Cell Types, Sulay H. Patel

Theses and Dissertations

Human immunodeficiency (HIV) infection can result in neurocognitive deficits in about one-half of infected individuals. Despite excellent systemic effectiveness, restricted antiretroviral penetration across the blood-brain barrier (BBB) is a major limitation in fighting HIV infection within the central nervous system (CNS). Drug abuse exacerbates cognitive impairment and pathologic CNS changes in HIV-infected individuals. This work investigates the effects of the HIV-1 protein, Tat, and drugs of abuse on factors affecting drug penetration into the brain.

Firstly, an in vitro model of the blood-brain barrier was built to study effects of HIV-1 Tat and methamphetamine (Meth) on integrity and function of …

Investigation Of The Ms2 Bacteriophage Capsid As An Mri-Capable, Brain-Targeted Nanoparticle Platform, Stephanie M. Curley

Legacy Theses & Dissertations (2009 - 2024)

Novel methods are needed to traverse the blood-brain barrier (BBB) and deliver drugs to specific targets in the brain. To this end, MS2 bacteriophage was explored as a multifunctional transport and targeting vector. The MS2 capsid exterior was modified with two different targeting moieties for delivery across the BBB and targeting specific regions of interest in the brain. Successful modification of MS2 capsids with a brain targeting peptide and NMDAR2D-targeting antibody was confirmed by immunoblotting and fluorescence detection. To measure transport efficiency of MS2 particles across an in vitro BBB model, a highly sensitive RT-qPCR protocol was developed and implemented. …

The Response Of Pericytes To Microvascular Ischemia, Robert Gordon Underly

MUSC Theses and Dissertations

The goal of this research is to investigate the role of pericytes during ischemia, and more specifically, to investigate their cell-specific proteolytic contributions that lead to the degeneration of the blood-brain barrier (BBB). BBB degeneration represents a pathological hallmark of ischemic stroke and is a major factor in limiting the window for pharmacological treatments by increasing the likelihood for hemorrhagic transformation. By understanding cell-specific proteolytic contributions to BBB degeneration during ischemia, novel biomarkers to predict the severity of the injury as well as new targets to reduce the extent of damage from stroke could be discovered. Pericytes are a cell …