Angiotensin II–mediated vascular brain inflammation emerged as a novel pathophysiological mechanism in neurogenic hypertension. However, the precise underlying mechanisms and functional consequence...

Circulating Angiotensin II Gains Access to the Hypothalamus and Brain Stem During Hypertension via Breakdown of the Blood–Brain Barrier

We form coronas of serum proteins on gold nanorods (NRs) coated with cetyltrimethylammonium bromide (CTAB). These coronas can be exploited for their ability to hold small molecular therapeutics at ...

Exploiting the protein corona around gold nanorods for loading and triggered release.

Fit for purpose application of currently existing animal models in the discovery of novel epilepsy therapies.

The blood-brain barrier (BBB) is a dynamic, highly selective barrier primarily formed by endothelial cells connected by tight junctions that separate the circulating blood from the brain extracellular fluid. The endothelial cells lining the brain microvessels are under the inductive influence of neighboring cell types, including astrocytes and pericytes. In addition to the anatomical characteristics of the BBB, various specific transport systems, enzymes and receptors regulate molecular and cellular traffic across the BBB. While the intact BBB prevents many macromolecules and immune cells from entering the brain, following epileptogenic brain insults the BBB changes its properties. Among BBB alterations, albumin extravasation and diapedesis of leucocytes from blood into brain parenchyma occur, inducing or contributing to epileptogenesis. Furthermore, seizures themselves may modulate BBB functions, permitting albumin extravasation, leading to activation of astrocytes and the innate immune system, and eventually modifications of neuronal networks. BBB alterations following seizures are not necessarily associated with enhanced drug penetration into the brain. Increased expression of multidrug efflux transporters such as P-glycoprotein likely act as a ‘second line defense’ mechanism to protect the brain from toxins. A better understanding of the complex alterations in BBB structure and function following seizures and in epilepsy may lead to novel therapeutic interventions allowing the prevention and treatment of epilepsy as well as other detrimental neuro-psychiatric sequelae of brain injury.

https://www.mdpi.com/1422-0067/21/2/591/pdf

Structural, Molecular, and Functional Alterations of the Blood-Brain Barrier during Epileptogenesis and Epilepsy: A Cause, Consequence, or Both?

Bromodomain and extraterminal (BET) bromodomain (BRD) proteins are epigenetic readers that bind to acetylated lysine residues on chromatin, acting as co-activators or co-repressors of gene expression. BRD2 and BRD4, members of the BET family, are significantly increased in glioblastoma multiforme (GBM), the most common primary adult brain cancer. OTX015 (MK-8628), a novel BRD2/3/4 inhibitor, is under evaluation in dose-finding studies in solid tumors, including GBM. We investigated the pharmacologic characteristics of OTX015 as a single agent and combined with targeted therapy or conventional chemotherapies in glioblastoma cell lines. OTX015 displayed higher antiproliferative effects compared to its analog JQ1, with GI50 values of approximately 0.2 µM. In addition, C-MYC and CDKN1A mRNA levels increased transiently after 4 h-exposure to OTX015, while BRD2, SESN3, HEXIM-1, HIST2H2BE, and HIST1H2BK were rapidly upregulated and sustained after 24 h. Studies in three additional GBM cell lines supported the antiproliferative effects of OTX015. In U87MG cells, OTX015 showed synergistic to additive activity when administered concomitant to or before SN38, temozolomide or everolimus. Single agent oral OTX015 significantly increased survival in mice bearing orthotopic or heterotopic U87MG xenografts. OTX015 combined simultaneously with temozolomide improved mice survival over either single agent. The passage of OTX015 across the blood-brain barrier was demonstrated with OTX015 tumor levels 7 to 15-fold higher than in normal tissues, along with preferential binding of OTX015 to tumor tissue. The significant antitumor effects seen with OTX015 in GBM xenograft models highlight its therapeutic potential in GBM patients, alone or combined with conventional chemotherapies.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.30256

OTX015 (MK-8628), a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone and in combination with conventional therapies in glioblastoma models.

The blood–brain barrier (BBB) protects the brain from harmful substances in the bloodstream, while supplying the brain with the nutrients required for proper function. The endothelial cell cerebrovasculature lining also regulates brain penetration of drugs. Because of the presence of such complex and yet delicate mechanisms of vascular protection, pharmacologic targeting of central nervous system (CNS) pathologies was and remains a challenge. In general, it is assumed that breaching the BBB will improve CNS drug delivery (Kroll & Neuwelt, 1998), but altered BBB function associated with CNS pathologies such as epilepsy is also a characteristic of pharmacokinetic drug resistance (Oby & Janigro, 2006). Therefore, the interplay between BBB function or failure, and drug delivery is more complex than originally believed.

Is there a link between leakage of the BBB, seizure-epileptic pathology, and multiple drug resistance? Several evidences have shown BBB damage and profound remodeling of the cerebrovasculature during or immediately after seizures (Marchi et al., 2006, 2007b). This has been interpreted as a vascular consequence of spontaneous seizures. It has also been repeatedly shown that BBB leakage is sufficient to promote seizures (Oby & Janigro, 2006; Marchi et al., 2007a,b; Uva et al., 2007) or epileptogenesis (Seiffert et al., 2004; van Vliet et al., 2007). Whatever the temporal or causal relationship between BBB leakage and seizures, it is clear that the epileptic brain is characterized by an abnormal blood–brain interface.

The integrity of the BBB is clinically evaluated with magnetic resonance imaging (MRI) techniques. Although T1-contrast enhancement (Gd++) is a reliable imaging method for direct testing of BBB permeability, structural changes at a cellular level and changes of the distribution of water between the extra- and intracellular compartments can be assessed by diffusion-weighted imaging (DWI) and by calculating the extent of passive water motion or diffusivity (apparent diffusion coefficient, ADC). Periictal and postictal human studies using DWI or diffusion tensor imaging (DTI) showed, in some cases, transiently decreased local diffusivity, potentially in concordance with the epileptic zone (Vincent et al., 1995; Flink & Atchison, 2003; Lang & Vincent, 2003; Vernino, 2007). Diffusion studies have also demonstrated areas of significantly increased diffusivity in patients with partial epilepsies during the interictal period (Diehl et al., 1999, 2001; Hufnagel et al., 2003; Diehl et al., 2005). These results suggest that abnormal cerebrovascular and parenchymal homeostatic mechanisms are altered in epileptics.

In human epilepsy, overexpression of drug-resistance efflux proteins at the BBB has been studied extensively in the framework of antiepileptic drug (AED) refractoriness, but additional mechanisms have also been proposed (Loscher & Potschka, 2005; Oby & Janigro, 2006). Given that the pathology of drug-resistant epilepsy often reveals morphologic and functional abnormalities of the BBB, protein extravasation, and brain edema, it is reasonable to hypothesize that the physical–chemical properties of AEDs will differently predict CNS drug delivery to the epileptic focus. For example, most AEDs are highly lipid soluble and tightly protein bound, and their permeability across an intact BBB is controlled by parameters. It is possible that altered brain water content or protein extravasation combined with overexpression of drug transporters may affect the distribution of AEDs.

We have focused our study on the consequences of BBB damage on serum protein extravasation and brain water content. Because this was induced acutely and by iatrogenic means, the results may bear specific relevance for sudden episodes of BBB disruption (BBBD), as seen in traumatic brain injury (Schmidt & Grady, 1993; Korn et al., 2005; Tomkins et al., 2008). For this pilot study we used the hydrophilic radiolabel compounds 3H-deoxy-glucose (DOG) and 3H-sucrose (SUC) and the lipophilic AEDs 14C-phenytoin (PHT) and 14C-diazepam (DIA).

/pdf/blood-brain-barrier-damage-and-brain-penetration-of-1ov6308uz7.pdf

Quinyuan Fan

Papers

Blood-brain barrier damage and brain penetration of antiepileptic drugs: role of serum proteins and brain edema.