The blood-brain barrier (BBB) is a physical barrier that prevents entry of large and potentially toxic molecules into the brain, thus separating the central nervous system and systemic circulation. It is formed by tight junctions between brain endothelial cells, which selectively prevent the diffusion of hydrophilic molecules and pathogens such as bacteria from entering the brain parenchyma.
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As well as protecting the brain from potentially damaging molecules and plasma fluctuations, the BBB also serves a homeostatic purpose, supplying the brain with nutrients (via selective transporters) and aiding removal of waste products. By maintaining a stable environment, the blood-brain barrier helps ensure synaptic transmission.
BBB Anatomy and Physiology
Various components make up the blood-brain barrier in addition to brain endothelial cells: pericytes; astrocyte end feet; microglia; and a basement membrane made from structural proteins such as the extracellular matrix proteins collagen and laminin. Aquaporins enable the transport of water across the blood-brain barrier; these proteins may play a key role in cerebral edema, which can result from brain damage, hemorrhage or other injury. Whilst the tight junctions of the BBB are responsible for keeping bacteria out of the brain, they also prevent entry of antibodies and antibiotics; infections of the brain are thus quite difficult to remedy. Cancers of the brain are also hard to treat with chemotherapeutics, which are not normally brain penetrant and are often transported out of cells by multidrug transporters. For example, P-glycoprotein transports drugs out of the target cell, so inhibition of this transporter is of particular interest in reversing multidrug resistance.
Inflammation, caused by an infection or virus, can have a detrimental effect on the integrity of the blood-brain barrier, making it more permeable to immune cell infiltration. Increased permeability may precede or follow disease development. Ischemic stroke precedes a breakdown in the BBB. Meningitis is characterized by inflammation of the membranes that surround and protect the brain and spinal cord, while the entry of T lymphocytes through the BBB in multiple sclerosis (MS) results in demyelination. Disruption of the blood brain barrier has been associated with numerous neurological disorders including Alzheimer's disease (AD) and Parkinson's disease (PD), where breakdown of the barrier is thought to encourage disease progression. Disruption of the BBB induces loss of dopaminergic neurons, which may contribute to the pathogenesis of PD, and expression of the influx transporter of Aβ (RAGE) is increased in AD models.
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Potent, selective LRRK2 inhibitor
Tocris is the first to launch GSK2578215A, licensed from GlaxoSmithKline, for the study of Parkinson's Disease.