MolLifeSci_ss24_vl-04_blood-brain barrier_30 April.pdf

Pharmacology of the blood-brain barrier 30.04.2024 Jan Wenzel Outline 1. Introduction 2. Structure of the blood-brain barrier (BBB) 3. The diseased BBB 4. Strategies to overcome the barrier 5. BBB as target for s...

Pharmacology of the blood-brain barrier 30.04.2024 Jan Wenzel Outline 1. Introduction 2. Structure of the blood-brain barrier (BBB) 3. The diseased BBB 4. Strategies to overcome the barrier 5. BBB as target for specific diseases 6. Example: COVID-19 7. Summary Outline 1. Introduction 2. Structure of the blood-brain barrier (BBB) 3. The diseased BBB 4. Strategies to overcome the barrier 5. BBB as target for specific diseases 6. Example: COVID-19 7. Summary Introduction What is the blood-brain barrier? Paul Ehrlich: important contributions to pharmacology, e.g.: receptor theory: postulated that action of drugs are mediated via binding to the organism / cellular structures / receptors discovery of the BBB by trypan blue injection into different compartments (1885) interpreted as BBB by his student Edwin Goldmann Bentivoglio and Kristensson, 2014 Introduction Pardridge, 2005a Introduction What is the blood-brain barrier? a selective barrier between blood and CNS compartments to pathogens to small hydrophilic molecules to proteins to leukocytes a gateway between blood and CNS compartments for nutrient and oxygen supply of neurons for the regulation of blood pressure forming an interface for immune- and nervous system crosstalk Outline 1. Introduction 2. Structure of the blood-brain barrier (BBB) 3. The diseased BBB 4. Strategies to overcome the barrier 5. BBB as target for specific diseases 6. Example: COVID-19 7. Summary Structure – overview Wenzel and Schwaninger, 2016 Structure – overview Wenzel and Schwaninger, 2016 Structure – overview Different barriers Neuwelt et al., 2011 Structure – circumventricular organs CSF: cerebrospinal fluid Structure – brain vasculature Overview 600 km vessels in a human brain each neuron has its own capillary (by number) by far the largest barrier interface in the brain Wenzel and Schwaninger, 2016  Structure – brain vasculature vessel composition differs between arterioles, capillaries, and venules. VSMC: vascular smooth muscle cell Kisler et al., 2017 Structure – brain vasculature peripheral capillaries are fenestrated while cerebral capillaries are not lower transcytotic rate than peripheral endothelial cells different barrier properties: ~30 Ω/cm2, brain capillaries ~1500-2000 Ω/cm2 increased number of mitochondria in BBB endothelial cells coverage with astrocytic endfeet highest coverage of pericytes compared to peripheral vessels Structure – neurovascular unit Central players of the neurovascular unit: endothelial cells pericytes / smooth muscle cells astrocytes neurons Extended parts: microglia blood cells Neuwelt et al., 2011 Structure – pericytes surround the endothelial cell layer embedded in between the endothelial and the parenchymal basement membrane important for function and development of the BBB influence several mechanisms in the brain (immune cell infiltration, blood flow regulation) heterogenous cell type (dependent on vessel type) VSMC: vascular smooth muscle cell Kisler et al., 2017 Structure – astrocytes direct contact to vessels, neurons, synapses, other glial cells are able to influence tightness and transport mechanisms across the BBB essential for water and ion homeostasis in the brain (special water and ion channels at their endfeet) are highly reactive after disturbance Khakh et al., 2016 Structure – endothelial cells binding partner and regulator of immune cell trafficking transport of essential molecules into the brain tissue (e.g. hormones, glucose, vitamins) build up the barrier itself by two main properties very tight intercellular junctions → no paracellular flux across the BBB low uptake frequency of luminal and parenchymal molecules → low transcytotic rate Structure – tight junctions Wenzel and Schwaninger, 2016 Structure – tight junctions Claudins: homophilic interaction leads to formation of tight junctions 24 different claudins in vertebrates, of which only Claudin-3, -5 and -12 are expressed in BBB Regulation of permeability for proteins of certain size (claudin-5 KO mice are neonatal lethal due to increased permeability in lower molecular weight range: