Blood brain barrier

BLOOD BRAIN BARRIER

1. BLOOD BRAIN BARRIER Dr Himanshu Soni __ __

2. Introduction 1882, Paul Ehrlich – first demonstration using intravascular dye injection. Brain and spinal cord were not stained !! However, some areas did get stained : pineal gland, posterior pituitary, tuber cinerum , optic recess, area postrema . First time concept – Blood Brain Barrier __

3. 1898 – Lewandowsky coined the term “blood brain barrier”; demonstrated neurotoxic agents affected when directly injected, but not when IV 70 years later, Reese and Colleagues – localised barrier to capillary endothelial cells __

4. Formation Complex system consists of Specialised basal membrane Pericytes Astrocytic feet Endothelial cells Brain endothelial cells Continuous tight junctions No detectable transendothelial pathways such as vesicles __

5. Formation __

6. “tight” junctions Composed of dimer subunits – transmembrane proteins : Occludin (first discovered but not essential) Claudin (essential protein) Junctional adhesion molecule (JAM) or ESAM Anchored to endothelial cells by proten complexes Zone occluding – 1 (ZO – 1), ZO – 2, ZO – 3 Adherens junctiions containing specific integral membrane proteins VE cadherins __

7. “tight” junctions __

8. “basal membrane” Continuous basal membrane outside the endothelial lining __

9. “ glia limitans ” Astrocytic feet Astrocytic foot processes release specific factors & are necessary for development of BBB. Contain water channels ( aquaporin – 4) that allow water uptake and contribute to brain swelling __

10. “transport carriers” Carriers for glucose and essential amino acids facilitate their movement since brain cannot synthesize them. Secondary transport systems – for efflux of small molecules and nonessential amino acids from the brain to the blood. Sodium ion transporters on luminal membrane and Na-K- ATPase on anti-luminal membrane account for Na movement. Large number of endothelial mitochondria provide energy. __

11. “transport carriers” __

12. Development Early 1920s, immature BBB in newborn – false!! Recent studies no difference in permeability detected between newborn and adult BBB capillaries. No difference in updake of glucose, AA, purines , choline , nucleosides observed Conclusion – newborn BBB has restrictive properties similar to that of the adult. __

13. Permeability Molecular weights >60k Da – donot pass L-DOPA – readilly cross Plasma protein bound compounds – do not pass Size and lipid solubility ! Highly lipid soluble Alcohol, nicotine Antibiotics – many does, others dont ! __

14. __

15. Water Moves freely in and out of the brain as osmolarity changes Clinically useful – poorly permeable compounds like mannitol can osmotically dehydrate the brain and reduce ICP. Gases CO2, O2, volatile anesthetics diffuse rapidly The rate at which their concentration equilibrate with plasmy is limited primarily by the cerebral blood flow rate __

16. Glucose Brain endothelium – rich in GLUT – 1 transporter They carry glucose across BBB. Glut – 1 deficiency Severe learning difficulties Low CSF glucose and not plasma, identifies ! __

17. Amino acids Essential AA need to be supplied to the brain hence they rapidly enter, with precursor of dopamine, L-DOPA They enter via Leucine -preferring or L-type transport proteins. They compete for entry, hence, elevation of levels of one AA will inhibit uptake of others. Important in conditions like Phenylketonuria (PKU). Small neutral amino acids – alanine , glycine , proline and GABA are markedly restricted in entry These are non-essential and are transported by alanine-prefering or A-type transporter. __

18. Functions The blood-brain barrier (BBB) protects the neural tissue from variations in blood composition and toxins.  E xtracellular concentrations of hormones, amino acids and potassium undergo frequent fluctuations, especially after meals, exercise or stressful times.  Since many of these molecules regulate neuronal excitability, a similar change in the composition of interstitial fluid in the CNS can lead to uncontrolled brain activity.  Blood borne infections of the brain are rare. BBB becomes permeable during inflammation, allowing macrophages to move across. Antibodies are too large to cross BBB. Certain Biochemical poisons are too large to pass BBB, for e.g. Botulinum toxin can affect peripheral nerves but not CNS. __

19. Absent BBB BBB lacking areas – The chemoreceptor trigger zone in the area postrema in the floor of the fourth ventricle, subfornical organ in the anterior wall of the third ventricle, the median eminence of the hypothalamus, choroid plexus, organum vasculosum lamina terminalis , and the pineal and posterior pituitary glands. These areas are collectively known as the circum-ventricular organs Many are involved in hormonal control __

20. Absent BBB __

21. Their capillaries have fenestrations instead of tight junctions. Many drugs produce nausea and vomiting as a prominent side effect because the lack of a BBB allows unfettered access directly from the blood stream to the area postrema and chemoreceptor trigger zone. __

22. Clinical Significance Mannitol – osmotic dehydrant ! L-DOPA – in Parkinson’s disease Glut-1 deficiency – severe learning diff. PKU – reduce brain uptake of other AA Botulinum – does not affect CNS Alcohol, Nicotine – readily affect CNS Gases – conc. Primarily depend on Blood flow. __

23. P-GLYCOPROTEINS Are ATP driven pumps, on endochelial cells Pump out hydrophobic compounds, from endothelium back to the blood, hence limit their permeability. E.g. Cyclosporin A, vinblastine Hence, confer multi-drug resistance to cancer cells __

24. “enzymatic BBB” Most blood neurotransmitters donot enter the brain because of low lipid solubility. L-DOPA, precursor of dopamine, has high affinity for L-type transporter and enters brain more easily then predicted based on its lipid-solubility. But the penetration of L-DOPA is limited by presence of L-DOPA decarboxylase and MonoAmine Oxydase in the endothelium. This “enzymatic BBB” limits passage of L-DOPA into brain and hence larger doses are required in Parkinson’s disease. __

25. MonoAmine Oxidase – inactivates neurotransmitters released by neuronal activity. The monoamine uptake is present on the anti-luminal side. Several other neurotransmitter-metabolizing enzymes such as cholinesterases , GABA transaminases , aminopeptidases , endopeptidases are contained in endothelial cells. In addition, drug and toxin metabolising enzymes are present too, thus enzymatic BBB protects from circulating NT and toxins. __

26. Compromised BBB in Diseases Tumors , encephalitis, multiple sclerosis, stroke Decrease production of claudin Tumors secrete VEGF and others, inducine formation of new leaky capillaries Ultimately cause compromised BBB and brain edema . __

27. DRUG DELIVERY For drugs which have low lipid solubility or no transporters /carriers, can be facilitated by Direct delivery into the CSF – meningitis, cancers Vasoactive compounds – bradykinin , histimine they can alter BBB permeability in pathological conditions and bot in normal people. can be used to deliver chemotherapeutics. Synthesize lipid soluble drugs. For e.g. Heroin and morphine are similar, but heroin has two acetyl groups, hence more soluble and more rapid onset. __

28. KERNICTERUS Indirect bilirubin enters the brain across BBB easily causing higher concentrations in the extracellular spaces and causing kernicterus . MENINGITIS Caused by Pneumococcus , hemophilus Disrupts BBB, increase penetration to toxins Antibiotics used to treat may aggravate CNS inclammation by releasing toxins from the cell walls like LPS. __

29. MULTIPLE SCLEROSIS It is suggested that, primarily this is a disease of weakened BBB, exposing the myelin in the brain or the spinal cord to the macrophages. Oxidative stress plays an important role in breakdown of BBB, anti-oxidants like lipoic acid may be able to stabilise. __

30. DEVIC’S DISEASE Neuromyelitis Optica Has high levels of antibodies against protein – aquaporin-4. Thus disrupting BBB and causing effects similar to multiple sclerosis. SLEEPING SICKNESS Late Neurological Trypanosomiasis The protozoa is found in the brain tissue, thought to cross through choroid plexus __

31. PML Progressive multifocal leucoencephalopathy A demyelinating disease of the CNS caused by the reactivation of a latent papavovirus ( the JC polyoma virus) It crosses the BBB. Seen in immunocompromised patients, usually AIDS. __

32. HIV ENCEPHALITIS HIV laden macrophages in the blood, crosses the BBB thereby releasing the virus in the parenchyma. The virus then attacts the attention of microglia and activates the inflammatory cascade. __

33. Thank you __