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Pharmacology > Pharmacology of the blood-brain barrier > Flashcards

Pharmacology of the blood-brain barrier Flashcards

1
Q

What is the blood-brain barrier?

A

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

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2
Q

The Blood Brain Barrier: Bottleneck in Brain Drug Development

A
  • 98 % of small molecule drugs do not cross the BBB
  • 100 % of large molecule drugs do not cross the BBB
  • 1 % of drug companies have a BBB drug targeting program
  • 1 % of academic neuroscience programs emphasize BBB transport biology
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3
Q

What is the blood-brain barrier?

A

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

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4
Q

Structure - different barriers

A
  • neurovascular unit (blood brain barrier)
  • Chloroid plexus (blood CSF barrier)
  • Meninges (arachnoid barrier)
  • Neuroependyma (fetal CSF brain barrier)
  • adult ependyma (free exchange)
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5
Q

Structure - circumventricular organs

A
  • The circumventricular organs are characterized by extensive vasculature and fenestrated capillaries which lead to a “leaky” BBB.
  • sensory organs: area postrema (AP), subfornical organ (SFO) and vascular organ of lamina terminalis
  • secretory organs: posterior pituitary, pineal gland, choroid plexus and median eminence
  • choroid plexus: CSF production and filtration
  • pineal gland: Melatonin release
  • median eminence: release of CRH, TRH, GnRH
  • area postrema: trigger of vomiting
  • subfornical organ: fluid balance
  • vascular organ of lamina terminalis: fever regulation
  • posterioir pituitary: Oxytocin and ADH release
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6
Q

Structure - brain vasculature

A
  • 600 km vessels in human brain
  • each neuron has its own capillary (by number)
  • by far the largest barrier interface in the brain
  • vessel composition differs between arterioles, capillaries and venues
    1. Penetrating artery: Basement membrane, Astrocytic end foot, VSMC, Endothelial cell, Pia, Neuronal projection, Virchow-Robin space
    2. vascular tree: penetrating artery, astrocyte, neuron, VSMC, arteriole, pre-capillary arteriole, pericyte, capillary, pericyte
    3. Arteriole: endothelial cell, VSMC
    4. Capillary: Pericyte, endothelial cell
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7
Q

Structure - brain vasculatur 2

A
  • 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

peripheral capillary: fenestration, pinocytotic vesicle, intracellular cleft, nucleus, pericyte, endothelial cell, mitochondriium, capillary lumen

cerebral capillary: nucleus, pericyte, endothelial cell, mitochondria, capillary lumen, astrocyte, neuron, tight junction

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8
Q

Structure - neurovascular unit

A

Central players of the neurovascular unit:
* endothelial cells
* pericytes / smooth muscle cells
* astrocytes
* neurons
Extended parts:
* microglia
* blood cells

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9
Q

Structure - pericytes

A
  • 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)
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10
Q

Structure - astrocytes

A
  • 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
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11
Q

Structure - endothelial cells

A
  • 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
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12
Q

Structure - tight junctions

A

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: <800 Da)

Occludin:
* N-Terminus important for tight junction formation
* serves as anchor
Adaptor proteins: Tethering of junctional transmembrane proteins to the cytoskeleton (actin filaments)
* Zonula occludens proteins (ZO-1, 2 und 3)
* Cingulin, MUPP1, MAGI

Junctional adhesion molecules (JAMs)
* JAM1 mainly expressed in endothelial and epithelial cells

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13
Q

Barrier dysfunction in diseases

A
  1. BBB breakdown, accumulation of blood-derived neurotoxic molecules
  2. Aberrant angiogenesis
  3. Disrupted phagocytosis, accumulation of neurotoxins
  4. CBF dysfunction and reductions
  5. Increased leukocyte trafficking and loss of immune privilege
  6. Compromised stem cell activity
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14
Q

Blood brain barrier leakage

A
  • accumulation of neurotoxic serum proteins
  • accumulation of iron→ROS production
  • antibodies could lead to autoimmune diseases
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15
Q

Diseases linked to BBB dysfunction

A
  • stroke
  • epilepsy
  • AD
  • Familial ALS
  • PD
  • MS
  • Natalizumab-PML with IRIS
  • NMO
  • primary CNS vasculitis
  • secondary CNS vasculitis
  • VZV vasculopathy
  • cerebral malaria
  • primary CNS lymphoma
  • glioblastoma
  • PRES
  • TBI
  • migraine
  • diabetes
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16
Q

Strategies to overcome the barrier

A
  • route of administration (transcranial, intracerebroventricular, intracerebral injection, transnasal)
  • increasing lipid solubility of small molecules (drawback→increased uptake in other organs (e.g. liver) and decreased plasma levels)
  • use of drug precursors or modified drugs that are substrates of transporters (e.g. L-Dopa)
  • efflux-inhibition (inhibition of P-gp, etc.)
  • temporary damage to BBB, e.g. osmotic opening, solvents, ultrasound (drawback: entry of plasma proteins!)
  • molecular „trojan horses“ (Transferrin (Tf-R)-Ab, Insulin-receptor (IR)-Ab)
  • viral vectors (rAAVs)
17
Q

Strategies to overcome the barrier - lipophilicity

A

Which factors define the permeation of a substance?
* the distribution coefficient between octanol and water (Ko/w) is a measure of lipophilicity
* Ko/w can be predicted from structure
* substances with high Ko/w generally display high permeability into the CNS
there are exceptions from the rule:
* Paroxetin, a selective serotonin-reuptake inhibitor is used as an antidepressant
*despite being highly lipophilic, paroxetin displays only low cerebral uptake

18
Q

Strategies to overcome the barrier - transporters
-> P-glycoprotein (P-gp)

A
  • P-gp (multi drug resistance gene 1, MDR1) was discovered in tumor cells where it is mediating resistance against cytostatic drugs
  • P-gp mediates the transport of pharmacons (e.g. paroxetin) from endothelial cells to the blood
  • P-gp is a ABC-transporter: ATP-Binding Cassette transporter
  • limited transport capacity, accumulation of high levels of pharmacons still possible
    ABC-transporters such as P-gp mediate directed transport of various substances – resulting in net efflux of pharmacons or other substances from the brain, thereby affecting bioavailability of CNS-acting drugs.
    →P-gp inhibition could lead to increased availability in the CNS.
  • there are exceptions from the rule:
  • the polar compound L-dopa can pass the BBB
19
Q

Strategies to overcome the barrier - transporters
-> P-glycoprotein (P-gp) - (lower activity) polymorphisms affect effects of antidepressants

A
  • P-gp substrates: Paroxetin, Citalopram, Venlafaxin, Amitriptylin →carriers of polymorphism show stronger effect of drug
  • no P-gp substrate: Mirtazapin
    →no difference between groups
20
Q

Strategies to overcome the barrier - transporters
-> Strategy of L-DOPA

A

1961: decreased dopamine level in the striatum of PD (parkinson ́s disease) patients
→ dopamine couldn ́t be substituted → levels not high enough in the brain
→but L-Dopa was found to be effective (Arvid Carlsson, Nobel price in 2000)
* additional peripheral administration of decarboxylase- inhibitors increases the available amount of L-dopa in the brain
Example: LAT1 (large amino acid transporter), which transports L-Dopa but not dopamine
-> also limited capacity -> L-DOPA treatment not effective after protein-rich meal

21
Q

L-DOPA and LAT1 exceptions from the rule
Which factors define the permeation of a substance?

A

*the polar compound L-dopa can pass the BBB→it is transported by solute carrier transporter (SLC, OATPs)
*SLC derive energy for transport from existing gradients, they act as:
* antiporter: simultaneous bidirectional transport
* symporter: simultaneous unidirectional transport
* uniporter: equilibrating transport

22
Q

Strategies to overcome the barrier - transporters

A

Transporters not only mediate efflux but also influx into the tissue of molecules.

BSP.: GLUT1, Pgp, LRP and RAGE

23
Q

Transporters as treatment options

A

Influencing efflux (e.g. P-gp) or influx mechanisms could be treatment options.

Influx blockade (antagonist effect) and efflux blockade (agonist effect)

24
Q

Strategies to overcome the barrier - Trojan horse

A
  • vesicle uptake and transcytosis could be used to transport drugs into the brain
  • receptor mediated uptake of peptidomimetic, monoclonal antibodies (e.g. against insulin-receptor (IR) or transferrin receptor (Tf-R))
  • antibodies coupled to peptides, recombinant peptides or siRNA (e.g. BDNF-coupled IR antibodies for stroke)
  • antibodies coupled to PEGylated liposomes -> transport of enclosed substances across the BBB (e.g. Tf-R antibodies coupled to liposomes containing tyrosine hydroxylase for the treatment of Parkinson’s)
25
Q

Strategies to overcome the barrier - rAAVs

A

Recombinant adeno-associated virus (rAAV) with modified capsid structure * changes in small peptide AA sequences results in altered tropism (1)
* uptake in endothelial cell (2), and either subsequent
* transcytosis and release of viral particles to the brain, or
* expression of therapeutic factors and secretion from endothelial cells (4)

26
Q

BBB as target for specific diseases

A

Alzheimer’s disease
ABeta (enhanced)
LRP1 (inhibited)

→RAGE inhibition or LRP1 stimulation could be effective to clear Aß

Multiple sclerosis
-> endothelial cell proteins: selectins, ICAM/VCAM
-> Immune cell proteins: P selection ligand, alpha4 integrin, LFA1
-> Natalizumab inhibits immune cell infiltration into the CNS

27
Q

COVID-19

A

up to 84 % of COVID 19 patients suffer from neurological symptoms
* imaging studies detected lesions comparable to microvascular pathology
* leakage of plasma proteins→parenchyma
1) immune cell infiltration
2) activated glial cells
3) plasma protein leakage
4) platelet aggregation

  1. Cytokine storm
  2. Immunoglobulins
  3. Complement
  4. SARS-CoV2
28
Q

NEMO loss in brain endothelial cells

A
  • induces cell death
  • induces blood-brain barrier leakage
  • induces neurological symptoms (e.g. seizures)
  • RIPK inhibition rescues symptoms

Pro cleaves NEMO -> cell death -> RIPK inhibition?

29
Q

Summary BBB

A
  • functions and anatomy of the blood-brain barrier
  • different cells of the neurovascular unit and their properties * diseased state of the BBB
  • different ways to overcome the barrier
  • the BBB as target for neurological diseases
  • example: NEMO and COVID-19

„The BBB is not simply a barrier, but a complex, interactive, ever-adapting interface that serves the needs of the CNS… and provides an array of opportunities for drug development:“ (Banks, 2016)

Pharmacology (22 decks)

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