Blood-Brain-Barrier (BBB)

and
Cerebrospinal Fluid (CSF)
 BLOOD-BRAIN-BARRIER (BBB)

 Formed by the tight junctions between capillary

endothelial cells of the brain capillaries
(BBB)and between epithelial cells in the
choroid plexus (B-CSF-B).
o Continuous/non-fenestrated capillary.
 Astrocyte foot processes secret paracrines in
facilitating the junction

 Again astrocytes remove NTs , avoid unwanted neural excitation (epilepsy)

o Maintains the constancy of the environment of the neurons in the CNS.
o Systemic change will not cause change in the brain tissue
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CIRCUMVENTRICULAR ORGANS
No BBB, highly vascularized
These leaky regions are isolated from the rest of the brain by
specialized ependymal cells called tanycytes.
Functions
 Neurohemal organs: secreted neurohormones that enter into
the circulation.
 OVLT (osmoreceptor): Angiotensin II act on it to increase
water intake.
 Chemoreceptor zone: receptors for peptides and other
substances that trigger change in brain activity, e.g.
Vomiting induced by chemotherapy.

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Clinical correlate: disruption of blood–brain
barrier - Kernicterus

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6
 BLOOD - BRAIN - BARRIER
Importance
 Protect brain from circulating chemicals, infections
 But allow vital substances
 Disadvantage is not allowing drugs into brain tissue

Disruption of blood–brain barrier occurs in a variety of pathological situations, such as brain

tumours and bacterial Meningitis
Meningitis is an inflammation of the membranes that surround the brain and spinal cord
(meninges) ~ BBB is disrupted.and allow entry of either toxins or antibiotics into the brain

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Blood-CSF and BBB:
 Astrocytes take up excess K+ (Na+ - K+ - 2Cl-)
 Have specific transporters and carriers (glucose, aa..)
 Highly permeable to H2O, CO2, O2 and most lipophilics
 Lightly permeable to electrolytes: Na+, Cl-, K+, urea
 Slow: H+, HCO3-, diffusion of glucose but okay via GLUT1
 Almost impermeable to plasma proteins and most non-lipid-soluble large organic
molecules and drugs
Clinical correlates:
P-Glycoprotein: multidrug nonspecific transporter
o transports a large number of drugs or peptides back into the
blood which cross cerebral capillaries.
o If inhibited, proper concentration of treatment of CNS
disorders

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 Cerebrospinal fluid(CSF)
 About 500 ml is formed/day & most of it reabsorbed daily [0.35 ml/minute; is
independent of CSF pressure as well as systemic blood pressure].
o ~ 2/3rd originates as secretion from ependymal cells/choroid plexuses in the ventricles.
o The rest from meningeal and CNS blood vessels.
 The cranial cavity ~ contains 140 ml CSF, 100 ml blood and 200 ml of ECF.
 Three processes: formation, circulation and absorption (formation ~ absorption)
 Functions:
o Buoyancy/protection/’water jacket’ : Brain floats in CSF - reduces the
effective weight1400 g to ~ 50g and prevents compression/shock absorbing
o Clearing waste
o Chemical stability/hormonal transport & nutrients/prevention of ischemia

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o Facilitation of pulsatile cerebral flow
 Circulation of CSF

o The CSF flows through the ventricles (~ 40

ml), downward through the central canal of the
spinal cord, and then upward toward the brain
through the subarachnoid space (100 ml) that
completely surrounds the brain and spinal cord.

o As the CSF flows over the superior surface of the brain, it leaves the
subarachnoid space and is absorbed into the venous + lymphatic system.
o the entire volume of CSF is turned over three to four times per day.

Hydrocephalus: if one of the processes/obstruction, excessive production, interference with

absorption/ are impaired (  intracranial P.)

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Cerebrospinal Fluid Pressure
 Normal pressure is around 120 – 180 mm H2O
(~10 mm Hg in recumbent position).

Lumbar puncture: tapping of CSF from the

lumbar cistern.
CSF examination is required in many disorders of
CNS.
It is performed by inserting a needle in between the
L2 and L3 or L3 and L4 vertebrae

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CHOROID PLEXUSES
 Clusters of capillaries lined by ependymal cells
that form tissue fluid filters, which hang from
the roof of each ventricle.
 Mechanism of formation of CSF: 2 stages
 plasma is passively filtered across the
capillary endothelia.
 ions and water are secreted actively across
capillary.
 Na+ into (Cl-/HCO3- follows), K+
lateral ventricles = draws water/AQs
into CSF
 Help cleansing by removing wastes

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Brain protection
Skull(hard bone cranium)
Meanings(protective membrane)
CSF(cushing effect)
BBB

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 VENTRICLES OF THE BRAIN
 Lined by ependymal cells which help to form the choroid plexus
1.There are two lateral ventricles in the cerebral hemispheres
Choroid plexuses of the two lateral ventricles primarily secrets CSF
2. Third ventricle is located in the diencephalon
3. Fourth ventricle is located between the pons and the cerebellum

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 CSF CHEMISTRY
Constitute Lumbar CSF Blood

Na+ (mEq/L) 148 136 - 145

K+ (mEq/L) 2.9 3.5 - 5
Cl - (mEq/L) 120 - 130 100 - 106
Glucose (mg/dl) 50 – 75 70 -100
Protein (md/dl) 15 - 45 6.8 x 1000
pH 7.3 7.4

CSF: NO BLOOD CELLS AND INC NA+ & CL-

The composition of the CSF is determined by selective transport

processes of the choroid plexus and BBB

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Brain Edema
 Accumulation of fluid compresses the blood vessels, causing decreased blood
flow and destruction of brain tissue (brain concussion):
o decreases blood flow and causes brain ischemia causes arteriolar dilation
with further increase in capillary pressure, then causes more edema fluid.
o The decreased cerebral blood flow also decreases oxygen
delivery. This increases the permeability of the capillaries, allowing still
more fluid leakage.
How its treated?.
o IV infusion of concentrated mannitol solution
o Ventricular needle puncture (remove fluid from the lateral ventricles of the
brain)

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BRAIN NEUROTRANSMITTER SYSTEMS

EXCITATION OR INHIBITION
OF THE
POSTSYNAPTIC NEURON.
NEUROHORMONAL CONTROL OF BRAIN ACTIVITY
 Activation of the Brain in addition to RAS system – lasts for min.-hrs
 One system arises in the brainstem RF and sends projections to the cortex via non-specific
thalamic nuclei (Non-specific = diffuse nuclei).
 Other system consists of brainstem nuclei which release neurohormones to various brain
regions via ascending projections.

The "non-specific" or "diffuse" thalamocortical

system.
Three systems
o Norepinephrine
o Dopamine and
o Serotonin
o Acetylcholine

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Classes of Neurotransmitters
Acetylcholine
Amino acids (Glutamate, Glycine, GABA, Aspartate..)
Amines (E, NE, Dopamine, serotonin, histamine…)
Monoamines:
Tyrosine derivatives
• Dopamine, Norepinephrine, Epinephrine.
Indolamines /Tryptophan derivatives
• Serotonin: brainstem, hypothalamus, limbic system
Peptides (+ opioid peptides)
Purines (adenosine, ATP)
Gaseous NT (NO, CO, H2S)
Endocannabinoids

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Classes of receptors:
 Metabotropic receptors ( G-protein-coupled receptor):
trans membrane receptor that act through a secondary messenger.
 Ionotropic receptors (Ligand gated ion chnnles) :
ligand gated ion channel.

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The Acetylcholine System
PNS + CNS

Acetylcholine: Synthesis and Inactivation

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PNS
Acetylcholine
 All motor axons that arise from the spinal cord.
 ANS: all preganglionic + postganglionic parasympathetic fibers.
 Receptors: nicotinic + muscarinic.

• Nicotinic/nAchR: Ionotropic receptor (Na, Ca)

(NMJ, CNS, ANS)

• Muscarinic/mAChR: Metabotropic

M1: Brain
M3: Smooth muscle…
M2: Heart

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M4: Smooth muscle...
 CNS
CNS
 Primarily located on mid raphe nuclei.
 Parietal lobes (basal forebrain, ponto-mesencephalic cholinergic complex).
 Project to the cerebrum, hippocampus and thalamus.
 Learning and memory
 Sleep wake cycles
 Arousal & attention.

CC: Alzheimer’s disease (Rx: Inhibitors of Achesterase)

Mood swings, bipolar disorders, depression
Parkinson’s disease (Rx: Ach antagonists)

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 Distribution:

Cycles of sleep &

wakefulness

Learning & Memory

Alzheimer’s disease
(Loss of cholinergic neurons in the basal nucleus of

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Meynert and Ach in the cortex).
The Dopamine System

Synthesis:

Inactivation:

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Dopamine

 Usually inhibitory.
 Present in neurons of SN:
o Nigrostriatal projection
o NS to putamen and caudate nucleus.
o Inhibitory effects are on controlling factor in the voluntary motor system.
o Mesolimbic projection
o VTA to nucleus accumbens, septal area, amygdala, and the cerebral cortex.
o Plays a role in motivation , drive and cognition
o Neurons from hypothalamus to hypophysis.
o influences the secretion of certain hormones like prolactin
o Retina - role in lateral inhibition (focusing effect).
o Olfactory bulb.

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27
CC: (+) = Parkinson’s disease
(-) = schizophrenia and psychosis
Many addictive drugs/ “reward pathway.”
Cocaine inhibits dopamine reuptake, and amphetamine promotes dopamine release and inhibits its
reuptake = both stimulate brain’s reward system/pleasure

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29
The Norepinephrine System

Norepinephrine
 Formed at Locus coeruleus (LC) and
distributed to otherl brain structures.
 Usually inhibitory (Receptors: α1, α2,
α3 and β1-3 )
 May be released into neuropile from axon varicosities filled with vesicles.
 Accounts for slow-acting & long-lasting effects following release.
o Electrical discharge of LC is proportional to the amount
of effort/attention exerted.

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Projection to Thalamus , Cortex , hippocampus , Amygdala, Hypothalamus ,
autonomic brainstem centers , Spinal cord

PGi: Nucleus Paragigantocellularis

PrH: Perirhinal Cortex

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Functions: NE >> E
• Modulator– sets brain tone.
• Suppresses irrelevant stimuli but enhances relevant stimuli.
• Modifies behavior, arousal, degree of alertness/sleep.
• SNS tone - Blood pressure regulation/ECG activity
• Decrease in Non-REM sleep (SWS) and absence in REM sleep.
• Set mood , attentiveness and affect (emotion/euphoria)
• Pain modulation.
• Hormone regulation and homeostasis
• Appetite suppression.
Amphetamines and cocaine boosting

CC: attention deficit hyperactivity disorder, narcolepsy, hypertension,

depression, pain, and appetite suppression.
Implicated in (Stress-related disorder)
Withdrawal from some drugs of abuse - panic disorder

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Inactivation:
o Reuptake into synaptic
terminal
o Uptake by effector cells
(with MAO and COMT).
o Diffusion away from site.

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Epinephrine

• Usually excitatory.

• Found in neurons of:

o Lower brainstem tegmentum.

o Locus ceruleus.

o Axons projecting rostrally to hypothalamus.

o Axons projecting to intermediolateral cell column of spinal cord.

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Synthesis:

Inactivation:

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The Serotonin System (5-HT)
 Primarily located on mid raphe nuclei.
 Mood, memory, sleep, cognitive skills.
 Projections to diencephalon, basal ganglia and cortex
and also to medulla and spinal cord – induce sleep.
o "sleep centers"
 Projections to the spinal cord inhibit transmission of
pain
o brains analgesic system.

Clinical correlates:
Depression and Anxiety

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Synthesis:

Inactivation:

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Distribution:

CC

• Certain psychotic disorders:

Depression.
• Total amnesia may occur when:
o Raphe neurons are
destroyed.
o Serotonin stores are
depleted by reserpine.

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Clinical correlates
Drugs and Neurotransmission

a. Chemical synapses are targets for

drugs (Psychoactive drugs……).
(Drugs used in the treatment of
insomnia, anxiety, depression and
schizophrenia)

b. Drugs can intercept: at presynaptic,

synaptic and postsynaptic level.

Sites of intervention

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DEPRESSION

 Reduction of norepinephrine and serotonin in locus cerulus

Which has inputs into thalamus, limbic system, and cortex

 Treatment: monoamine oxidase inhibitor that blocks the

destruction of these NTS once formed
selective serotonin reuptake inhibitors (SSRIs).
Shock therapy : allowing electrical impulse passing
through the brain area

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SUMMARY

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 THE GLUTAMATE SYSTEM
Most commonly found neurotransmitter in the
brain.
 Always excitatory.
 It is formed by the Kreb’s Cycle (alpha
ketoregulation), carried into astrocytes,
converted to glutamine and hen passed
onto glutaminergic neurons.

 Long term potentiation involved in memory and learning b causing Ca++m

influx

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GABA (GAMMA AMINOBUTYRIC ACID) SYSTEM
 The main inhibitory neurotransmitter of
the CNS and is found in the
retina.
 Formed by decarboxylation of
glutamate.
 Three types of GABA receptors

 GABA A causes hyperpolarization n (inhibition)

o Anxiolytic drugs/benzodiazepine cause increase in Cl- entry & cause soothing effects.
 GABA – B cause increase conductance of K+ into the cell (retina)

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