World Surgery Forum

Contents

1. What is Blood Brain barrier?
2. What is a Neurovascular Unit?
3. Anatomy of Blood Brain Barrier
1. Cellular Components of Blood Brain Barrier
4. Function of Blood Brain Barrier
5. What are Circumventricular Organs?
6. Pathological States involving Blood Brain Barrier Breakdown
7. Blood Brain Barrier and Drug Delivery: Getting Drugs Across Blood Brain Barrier
8. Blood Brain Barrier Video

What is Blood Brain barrier?

• To maintain normal brain function, the neural environment must be preserved within a narrow homeostatic range
• This requires a tight regulation of transportation of cells, molecules and ions between the blood and the brain. 
• Such tight regulation is maintained by a unique anatomical and physiological barrier, called the Blood Brain Barrier.

What is a Neurovascular Unit?

• The term Blood Brain Barrier does not adequately encompass the wide range of morphological features and functional characteristics
• For this reason the term Neurovascular unit (Neuwelt,2004) is being used increasingly 
• It comprises of:  

-Endothelial cells
-Pericytes
-Microglia
-Astrocytes
-Basement membrane 

-Tight junction

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Anatomy and Physiology of Blood Brain Barrier

Sites of Blood Brain Barrier

• Blood-brain barrier (BBB) with Endothelium,Pericytes and Astrocyte foot processes
• Blood-CSF barrier (BCSFB) with the choroid plexus epithelium
• The arachnoid epithelium separating the blood from the subarachnoid CSF.

Cellular Components of Blood Brain Barrier

Endothelium: It has 3 structural features

• Tight intracellular junctions without fenestrations
• Less Pinocytic Intracellular Vesicles: Relative lack of vesicular transport 
• Abundant Mitochondria

Pericytes

• Reside adjacent to capillaries
• Have smooth muscle like properties
• Control cerebral blood flow by regulation of capillary diameter through actin

Astroglial Process or Astrocyte end feet : ensheath >95% of vessel surface

Physiology of Blood Brain Barrier

Mechanisms of transport of molecules across Blood brain barrier

1. Diffusion
2. Paracellular transport
3. Transport protein
4. Receptor mediated transcytosis
5. Adsorptive transcytosis
6. Efflux proteins

Functions of Blood Brain Barrier

Barrier function

1. Paracellular Barrier : Endothelial tight junctions restrict the free movement of H2O soluble compounds
2. Transcellular barrier : Low level of endocytosis and transcytosis
3. Enzymatic Barrier : Complex set of enzymes to degrade various compounds (eg acetylcholinesterase, monoamineoxidase)
4. Efflux Transporters : Cerebral Endothelium has large number of efflux transporters eg- ABC, ATP binding  cassette transporters

Carrier function

1. Nutrients to brain : Glucose and Amino acids require specific transporter proteins
2. Small lipid molecules diffuse freely
3. Diffusion of O2 and CO2 passively 
4. Removal of metabolites

What are Circumventricular Organs?

• Areas of brain where BBB is weak
• Leaky regions are isolated from the rest of the brain by specialized ependymal cells called Tanycytes, along the ventricular surface close to midline

Sensory Circumventricular organs

1. Area postrema
2. Vascular organ of the lamina terminalis
3. Subfornical organ (SFO)

Secretory Circumventricular organs

1. Posterior Pituitary gland
2. Pineal gland
3. Median eminence
4. Subcommissural organ

Pathological States involving Blood Brain Barrier Breakdown

Trauma

• Bradykinin is produced
• Stimulates release of IL6 from Astrocytes
• Leads to opening of BBB

Stroke

• Astrocytes secrete TGF Beta which downregulates brain endothelial expression of fibrinolytic enzyme tPA and anticoagulant thrombomodulin
• Proteolysis of vascular basement membrane
• Induction of Aquaporin 4 mRNA 

Infectious or Inflammatory Process

• Eg Meningitis, Encephalitis, Sepsis
• Bacterial lipopolysaccharides affect permeability of BBB tight junctions
• This mediated by production of free radicals, IL6, IL 1 Beta
• Interferon Beta prevents BBB disruption

Multiple Sclerosis

• Breakdown of BBB
• Downregulation of laminin in the basement membrane
• Selective loss of Claudin 1/3

HIV

• BBB tight junction disruption

Alzheimer’s Disease

• Upregulation of GLUT 1 transporter
• Altered Agrin levels
• Upregulation of Aquaporin 4 expression
• Accumulation of Amyloid beta due to decrease level of p-glycoprotein transporter expression
• Alteration in BBB-  Changes in basal lamina and Amyloid Beta clearance
• Parkinson’s Disease
• Dysfunction of the BBB by reduced  efficacy of P-glycoprotein

Epilepsy

• Transient BBB opening in epileptogenic foci
• Upregulated expression of P Glycoprotein in astrocytes and endothelium

Brain tumours

• Breakdown of BBB
• Downregulation of tight junctions

Blood Brain Barrier and Drug Delivery: Getting Drugs Across Blood Brain Barrier

An intact BBB is a major obstacle for the development of drugs for CNS disorders.

 

Approximately 98% of small molecule drugs and all large molecule neurotherapeutics, e.g., recombinant peptides, proteins, anti-sense-agents and genetic vectors, are normally excluded from the brain (Pardridge, 2007) 

Most psychiatric drugs are small molecules, lipid soluble compounds which are capable of crossing BBB

There is currently no way large enzymes can be delivered to the brain using gene therapy – for the disease for which gene and enzyme involved are known eg Alzheimer's disease, Parkinson’s disease, Huntington’s disease

Keywords: Blood Brain barrier, Neurovascular Unit, Anatomy of Blood Brain Barrier, Cellular Components of Blood Brain Barrier, Function of Blood Brain Barrier, Circumventricular Organs,  Blood Brain Barrier Breakdown, Blood Brain Barrier and Drug Delivery, Getting Drugs Across Blood Brain Barrier, Blood Brain Barrier Video

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6/24/2020 12:02:00 PM