The Blood Brain Barrier Flashcards
Neural factors regulating cerebral blood flow
- sympathetic nerve stimulation to main cerebral arteries, producing vasoconstriction to control blood supply (operating only if high arterial BP)
- parasympathetic (facial nerve) stimulation producing slight vasodilation to increase blood supply
- central cortical neurones releasing vasoconstrictor neurotransmitters (eg: catecholamines)
- dopaminergic neurones producing vasoconstriction (localised effect related to increased brain activity)
Chemical factors regulating cerebral blood flow
-Carbon dioxide (indirect action), pH, nitric oxide, potassium ions, adenosine and anoxia are vasodilators
Fluid compartments of the brain
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CSF production
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Differences between peripheral capillaries and blood brain barrier capillaries
- peripheral capillaries have sparse pericyte coverage whilst BBB capillaries have dense pericyte coverage
- BBB capillaries are covered with end-feet from astrocytes
- astrocytes produce growth factors and differentiation factors
Syncope
FAINTING
- common manifestation of reduced blood supply to brain
- causes include hypotension, postural changes, vaso-vagal attack, sudden pain, emotional shock etc-> results in temporary interruption/reduction of brain blood flow
Cerebral blood flow regulation
- mechanisms affecting total cerebral blood flow
- mechanisms relating activity to requirement in specific brain regions by altered localised blood flow
Total cerebral blood flow autoregulation range
Between mean arterial pressure of ~60-160 mmHg
The process of cerebral blood flow autoregulation
- Arteries and arterioles dilate or contract to maintain blood flow, depending on BP/arterial pressure
- Stretch-sensitive cerebral vascular smooth muscle contracts at high BP and relaxes at lower BP
The clinical importance of the blood-brain barrier
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Antihistamines and the BBB
- First generation antihistamines (H1 receptor blockers) were hydrophobic and could cross the BBB by simple diffusion (could get into the brain)
- Histamine is important in wakefulness and alertness so the first generation antihistamines made people drowsy (now used as sleep aids)
- Modification led to second generation antihistamines which were polar (typically with a hydrophilic attachment)->do not readily cross the BBB so do not induce drowsiness
BBB vs Parkinson’s disease treatment
- Parkinson’s treatment involves pharmacologically raising dopamine levels in the brain
- Peripheral dopamine administration does not work because dopamine is very hydrophilic so cannot cross the BBB to get into brain
- L-DOPA used as similar to amino acid and can cross BBB via amino acid transporter
- Once in the brain, L-DOPA is converted to dopamine by DOPA decarboxylase (allows dopamine to get into the brain)
- However, there is lots of DOPA decarboxylase in the peripheral circulation, so most of circulating L-DOPA is converted to dopamine outside of the CNS-> less L-DOPA available to access the brain
- Problem solved by co-administration with Carbidopa (DOPA decarboxylase inhibitor)
- Carbidopa inhibits DOPA decarboxylase in peripheral circulation but can’t cross BBB, so does not inhibit DOPA decarboxylase in the brain (ensures enough L-DOPA available for brain)
Circumventricular organs
- In areas close to venticles, the capillaries lack BBB properties
- Capillaries here are fenestrated (leaky to access blood) but ventricular ependymal lining close to these areas are tighter to compensate->limits exchange between circumventricular organs and CSF
- Function: involved in secreting into circulation or to sample plasma composition
- CVOs must have leaky, fenestrated vessels for particular functions
- Example CVO’s include median eminence, area postrema, pineal body, OVLT, neurohypophysis, subfornical organ, subcommissural organ etc
Lipophilic molecules and the BBB
- cross BBB so can access/be removed from CNS directly via simple diffusion down concentration gradient
- reason why many anaesthetics are lipophilic gases
- examples include: oxygen, carbon dioxide, alcohol etc
Hydrophilic molecules and the BBB
- need specific transport mechanisms for hydrophilic substances to enter the CNS and brain ECF
- Examples include: water via aquaporin channels (AQP1, AQP4), glucose via GLUT1 transporter proteins expressed on endothelial cells in brain and BBB, amino acids via 3 different transporters and electrolytes via specific transporter systems
Role of the BBB
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Reduction of cerebral blood flow
- Cerebral blood flow reduced by > 50%, oxygen delivery is insufficient and function is significantly impaired
- If total cerebral blood flow is interrupted for ~4 seconds, unconsciousness results, with irreversible brain damage occurring after a couple of minutes
Blood flow to the brain
- Blood flow high at ~55ml per 100g tissue per min
- ~15% of cardiac output
- ~20% oxygen consumption
- brain only ~2% of body weight
Glucose supply to the brain
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Hypoglycaemia and brain function
-glucose concentration below 2mM-> results in unconsciousness, coma and ultimately death
Autoregulation of cerebral blood flow when MAP <60mmHg
-insufficient blood supply leads to compromised brain function
Autoregulation of cerebral blood flow when MAP >160mmHg
-increased blood flow leads to swelling of brain tissue which is not accommodated by the closed cranium, increasing intracranial pressure->DANGEROUS
Regulation of local cerebral blood flow
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Pattern of vascularisation in CNS tissues
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Dopaminergic neurones in the regulation of cerebral blood flow
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The effect of carbon dioxide on cerebral blood flow
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Local changes to cerebral blood flow
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CSF production
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CSF composition
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CSF functions
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Importance of the BBB
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Properties of peripheral capillaries
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CNS capillaries
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Interendothelial junctions
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Example CVO’s
- neurohypophysis and median eminence secrete hormones
- area postrema samples plasma for toxins and will induce vomiting
- other organs involved in sensing electrolytes and regulating water intake
