The interface between the blood circulation and the neural tissue features unique characteristics that are encompassed by the term 'blood-brain barrier' (BBB). The main functions of this barrier, namely maintenance of brain homeostasis, regulation of influx and efflux transport, and protection from harm, are determined by its specialized multicellular structure. Every constituent cell type makes an indispensable contribution to the BBB's integrity. But if one member of the BBB fails, and as a result the barrier breaks down, there can be dramatic consequences and neuroinflammation and neurodegeneration can occur. In this Review, we highlight recently gained mechanistic insights into the development and maintenance of the BBB. We then discuss how BBB disruption can cause or contribute to neurological disease. Finally, we examine how this knowledge can be used to explore new possibilities for BBB repair.

Development, maintenance and disruption of the blood-brain barrier

Epilepsy is the third most common chronic brain disorder, and is characterized by an enduring predisposition to generate seizures. Despite progress in pharmacological and surgical treatments of epilepsy, relatively little is known about the processes leading to the generation of individual seizures, and about the mechanisms whereby a healthy brain is rendered epileptic. These gaps in our knowledge hamper the development of better preventive treatments and cures for the approximately 30% of epilepsy cases that prove resistant to current therapies. Here, we focus on the rapidly growing body of evidence that supports the involvement of inflammatory mediators-released by brain cells and peripheral immune cells-in both the origin of individual seizures and the epileptogenic process. We first describe aspects of brain inflammation and immunity, before exploring the evidence from clinical and experimental studies for a relationship between inflammation and epilepsy. Subsequently, we discuss how seizures cause inflammation, and whether such inflammation, in turn, influences the occurrence and severity of seizures, and seizure-related neuronal death. Further insight into the complex role of inflammation in the generation and exacerbation of epilepsy should yield new molecular targets for the design of antiepileptic drugs, which might not only inhibit the symptoms of this disorder, but also prevent or abrogate disease pathogenesis.

/pdf/the-role-of-inflammation-in-epilepsy-4xfw1i0fyo.pdf

The role of inflammation in epilepsy

Traumatic brain injury (TBI) is the leading cause of death in young adults and children. The treatment of TBI in the acute phase has improved substantially; however, the prevention and management of long-term complications remain a challenge. Blood-brain barrier (BBB) breakdown has often been documented in patients with TBI, but the role of such vascular pathology in neurological dysfunction has only recently been explored. Animal studies have demonstrated that BBB breakdown is involved in the initiation of transcriptional changes in the neurovascular network that ultimately lead to delayed neuronal dysfunction and degeneration. Brain imaging data have confirmed the high incidence of BBB breakdown in patients with TBI and suggest that such pathology could be used as a biomarker in the clinic and in drug trials. Here, we review the neurological consequences of TBI, focusing on the long-term complications of such injuries. We present the clinical evidence for involvement of BBB breakdown in TBI and examine the primary and secondary mechanisms that underlie such pathology. We go on to consider the consequences of BBB injury, before analyzing potential mechanisms linking vascular pathology to neuronal dysfunction and degeneration, and exploring possible targets for treatment. Finally, we highlight areas for future basic research and clinical studies into TBI.

/pdf/blood-brain-barrier-breakdown-as-a-therapeutic-target-in-2ip3gaif14.pdf

Blood–brain barrier breakdown as a therapeutic target in traumatic brain injury

https://www.cogsci.ucsd.edu/~mboyle/COGS163/pdf-files/W5-AR-Glia%20and%20epilepsy-%20excitability%20and%20inflammation-TINS-2013.pdf

Glia and epilepsy: excitability and inflammation

The blood-brain barrier (BBB) is formed by tightly connected cerebrovascular endothelial cells, but its normal function also depends on paracrine interactions between the brain endothelium and closely located glia. There is a growing consensus that brain injury, whether it is ischemic, hemorrhagic, or traumatic, leads to dysfunction of the BBB. Changes in BBB function observed after injury are thought to contribute to the loss of neural tissue and to affect the response to neuroprotective drugs. New discoveries suggest that considering the entire gliovascular unit, rather than the BBB alone, will expand our understanding of the cellular and molecular responses to traumatic brain injury (TBI). This review will address the BBB breakdown in TBI, the role of blood-borne factors in affecting the function of the gliovascular unit, changes in BBB permeability and post-traumatic edema formation, and the major pathophysiological factors associated with TBI that may contribute to post-traumatic dysfunction of the BBB. The key role of neuroinflammation and the possible effect of injury on transport mechanisms at the BBB will also be described. Finally, the potential role of the BBB as a target for therapeutic intervention through restoration of normal BBB function after injury and/or by harnessing the cerebrovascular endothelium to produce neurotrophic growth factors will be discussed.

/pdf/blood-brain-barrier-pathophysiology-in-traumatic-brain-10i5i3tt5a.pdf

Blood-brain barrier pathophysiology in traumatic brain injury.

Brain injury may result in the development of epilepsy, one of the most common neurological disorders. We previously demonstrated that albumin is critical in the generation of epilepsy after blood-brain barrier (BBB) compromise. Here, we identify TGF-beta pathway activation as the underlying mechanism. We demonstrate that direct activation of the TGF-beta pathway by TGF-beta1 results in epileptiform activity similar to that after exposure to albumin. Coimmunoprecipitation revealed binding of albumin to TGF-beta receptor II, and Smad2 phosphorylation confirmed downstream activation of this pathway. Transcriptome profiling demonstrated similar expression patterns after BBB breakdown, albumin, and TGF-beta1 exposure, including modulation of genes associated with the TGF-beta pathway, early astrocytic activation, inflammation, and reduced inhibitory transmission. Importantly, TGF-beta pathway blockers suppressed most albumin-induced transcriptional changes and prevented the generation of epileptiform activity. Our present data identifies the TGF-beta pathway as a novel putative epileptogenic signaling cascade and therapeutic target for the prevention of injury-induced epilepsy.

https://www.jneurosci.org/content/jneuro/29/28/8927.full.pdf

Alexander J Lakhter

Papers

Transcriptome Profiling Reveals TGF-β Signaling Involvement in Epileptogenesis