A Tribute to Nick Short

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Nick was the driving force behind WikiVet and all that it stood for, and it is thanks to his vision, innovative approach and tireless enthusiasm and belief, that WikiVet is available as a free resource to veterinary professionals around the world today. Nick’s dedication and passion for veterinary education were truly inspirational and his very many friends, colleagues and students across the world have lost a true gem. He was an exceptional human being: gentle, good-natured, charming, generous and kind: he has left many legacies which will ensure that he will be remembered for many years.

Our thoughts are with his friends and family at this heartbreaking time. A book of remembrance has been set up for anyone that would like to leave a message of condolence for Nick and his family have asked that anyone who wishes to do so make a donation to BipolarUK, a charity that was close to Nick’s heart.

Blood Brain Barrier - Anatomy & Physiology

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Structure and Function

The Blood Brain Barrier refers to the mechanisms in place around the microvasculature of the brain to ensure optimal neural functioning. Endothelial cells are the structural basis of the blood brain barrier and are joined by tight cellular junctions formed by the transmembrane proteins the occludins and the claudins. These junctions form a physical barrier are impermeable to proteins and also restrict the passage of non-lipid soluble molecules. Oxygen and carbon dioxide can diffuse across the endothelial cells. Within the BBB, most molecules use carrier systems to cross the endothelial cells as the tight junctions prevent molecules from crossing via the paracellular route (between cells). Larger hydrophilic molecules can be transported across the endothelial cells from the lumen of the blood vessels into the interstitial fluid by a variety of ways such as the specific receptor mediated endocytosis or transcytosis or the less specific adsorptive mediated transcytosis. The endothelial cells possess transporters for glucose, amino acids, purine bases, nucleosides, choline and other substances. The properties of the BBB are induced and probably maintained by molecules secreted by astrocytes. The astrocyte endfeet (perivascular endfeet) surround the endothelial cells and have K+ channels and aquaporins and so are likely to be involved in ion and water volume regulation within the neural environment. As well as the transporters mentioned, there are also efflux pumps present, such as p-glycoprotein, responsible for transporting potentially toxic molecules back into the lumen of the blood vessels. Along with this 'physical barrier', a 'metabolic barrier' also exists which involves the presence of intracellular and extracellular enzymes. Peptidases and nucleotidases are capable of metabolizing peptides and ATP where as the intracellular enzymes such monoamine oxidase and cytochrome P450 can break down neuroactive and potentially toxic compounds. The BBB prevents circulating antibodies reaching the central nervous system (CNS) and thus is a component of the immunological privilege manifest by the CNS. The BBB is not considered to affect the movement of inflammatory cells into the CNS; activated lymphocytes can enter the normal CNS.

Inflammatory responses in the CNS are different to elsewhere in the body. Injections of lipopolysaccaride, which would result in massive influx of granulocytes (polymorphonuclear leukocytes (PML)) in peripheral tissue result in no influx into the brain substance, however influx into CSF does occur.
The blood brain barrier is not well developed and the endothelium is 'leaky' in the regions of the circumventricular organs such as the pars nervosa of the pituitary gland (posterior pituitary) and the hypothalamus, as these regions may be involved in homeostatic regulation, which requires the detection of concentrations of certain blood constituents.

Defects of the Blood Brain Barrier

VASOGENIC OEDEMA

This BBB defect causes the BBB to break down in many pathological situations, e.g around brain tumours and when there is inflammation in the CNS. When this happens protein rich fluid spreads through the extracellular space of the brain, and is termed vasogenic oedema and since there are no lymphatic channels in the CNS, the excess fluid flows down pressure gradients, making its way to white matter and eventually to the ventricles. The presence of protein rich fluid causes astrocytes and microglial cells to react, causing astrocyte hypertrophy, swelling and upregulate many molecules. Microglia express MHC-2 molecules and take up plasma proteins. The presence of extra fluid in the extracellular space results in an increase in brain volume.

CYTOTOXIC OEDEMA

It is important to distinguish the brain swelling which results from the presence of plasma in the extracellular space from the brain swelling that occurs as a consequence of cell swelling. Accumulation of fluid within cells, cytotoxic oedema is a common manifestation of many neurotoxic situations. It usually affects specific cells, or even parts of cells with the location being a reflection of the metabolic process being blocked by the neurotoxin:

  • Hexochlorophene and tri-ethyl tin cause fluid to accumulate in myelin sheaths
  • Cyanide caused swelling of axons
  • Interfering with energy generation causes swelling of astrocytes.



The distinction between cytotoxic and vasogenic oedema is important clinically when one is trying to decrease brain volume using hyperosmolar agents since one can only decrease brain volume with these agents when the BBB is intact.



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