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Oxygen, glucose, and white blood cells are molecules that are able
to pass through this barrier. Red blood cells cannot.
Blood Brain Barrier
The blood-brain barrier (abbreviated BBB)
is composed of endothelial cells packed
tightly in brain capillaries that more greatly
restrict passage of substances from the
bloodstream than do endothelial cells in
capillaries elsewhere in the body. Processes
from astrocytes surround the epithelial cells
of the BBB providing biochemical support to
the epithelial cells. The BBB should not be
confused with the blood-cerebrospinal fluid
barrier, a function of the choroid plexus.
History of the BBB
The existence of such a barrier was first noticed in experiments by Paul Ehrlich
in the late-19th century. Ehrlich was a bacteriologist who was studying staining,
used for many studies to make fine structures visible. Some of these dyes,
notably the aniline dyes that were then popular, would stain all of the organs of
an animal except the brain when injected. At the time, Ehrlich attributed this to
the brain simply not picking up as much of the dye.
However, in a later experiment in 1913, Edwin Goldmann (one of Ehrlich's
students) injected the dye into the spinal fluid of the brain directly. He found that
in this case the brain would become dyed, but the rest of the body remained
dye-free. This clearly demonstrated the existence of some sort of barrier
between the two sections of the body. At the time, it was thought that the blood
vessels themselves were responsible for the barrier, as there was no obvious
membrane that could be found. It was not until the introduction of the scanning
electron microscope to the medical research fields in the 1960s that this could
be demonstrated. The concept of the blood-brain (then termed
hematoencephalic) barrier was proposed by Lina Stern in 1921 [3].
What is the purpose of the BBB?
The blood-brain barrier protects the brain from the many chemicals flowing
around the body. Many bodily functions are controlled by hormones, which are
detected by receptors on the plasma membranes of targeted cells throughout
the body. The secretion of many hormones are controlled by the brain, but these
hormones generally do not penetrate the brain from the blood, so in order to
control the rate of hormone secretion effectively, there are specialized sites
where neurons can "sample" the composition of the circulating blood. At these
sites, the blood-brain barrier is 'leaky'; these sites include three important
'circumventricular organs', the subfornical organ, the area postrema and the
organum vasculosum of the lamina terminalis (OVLT).
The blood-brain barrier is an effective way to protect the brain from common
infections. Thus infections of the brain are very rare; however, as antibodies are
too large to cross the blood-brain barrier, when infections of the brain do occur
they can be very serious and difficult to treat.
How does the BBB affect the design of
therapeutic agents?
http://www.clinicaloptions.com/HIV/Man
agement%20Series/NeuroAIDS/Animati
on/Blood%20Brain%20Barrier.aspx
Neurotransmitters found in the
CNS
HO
O Me HO NH2
Me HO NH2 (Small Peptides)
N
H3 C O Me
HO HO
Acetylcholine Endorphins
Noradrenaline Dopamine
O O
HO NH2 HN HO
NH2
HO OH
N NH2 O
N NH2
H
Histamine gamma-aminobutyric acid Glutamate
Serotonin (GABA)
(5-Hydroxytryptamine)
5-HT
Its a balancing act!!
Current models of CNS diseases often
attribute the physiological cause of the
disease to an imbalance of
neurotransmitters.
Acetylcholine
All ACh receptors in the CNS are nicotinergic. The
stimulating effect of nicotine is due to the
influence of these receptors.
HO
Dopamine
HO NH2 HO NH2
NH2
Tyrosine Dopa
HO
CO2H
hydroxylase HO
CO2H
Decarboxylase HO
Epinephrine
Norepinephrine (Adrenaline)
(Noradrenaline)
HO NH2
HO
Dopamine
HO NH2 HO NH2
NH2
Tyrosine Dopa
HO
CO2H
hydroxylase HO
CO2H
Decarboxylase HO
Epinephrine
Norepinephrine (Adrenaline)
(Noradrenaline)
Wait a minute!
If dopamine is too polar to cross the
BBB, how can L-DOPA cross it?
HO NH3+
+
HO NH3 Polar groups Mostly protonated
Polar groups Mostly protonated to the corresponding
HO O
HO
to the corresponding O ammonium salt
ammonium salt H
Dopamine L-DOPA
Polar group
Answer!
L-DOPA is transported across the BBB by an
amino acid transport system (same one used
for tyrosine and phenylalanine)
Once across, L-DOPA is decarboxylated to
dopamine by Dopa Decarboxylase.
This is an example of a prodrug, that is, a
molecule that is a precursor to the drug and is
converted to the actual drug at an appropriate
place in the body.
In actual practice, L-DOPA is almost always
coadminstered together with an inhibitor of
aromatic L-amino acid decarboxylase, so it
doesnt get converted to dopamine before it
crosses the BBB.
The inhibitor commonly used is carbidopa,
which does not cross the BBB itself.
The inhibitor also prevents undesirable side
effects of dopamine release into the PNS,
including nausea.
HO NH3+ H
HO N
NH2
HO O H3C CO2H
O HO
H
L-DOPA Carbidopa
SINEMET
(CARBIDOPA-LEVODOPA)
DESCRIPTION
SINEMET* (Carbidopa-Levodopa) is a combination of
carbidopa and levodopa for the treatment of
Parkinson's disease and syndrome.
http://www.learningcommons.umn.edu/n
euro/mod6/carb.html
Endorphin
HO
5-Hydroxytryptamine, or 5-HT
N
H
HO
5-Hydroxytryptamine, or 5-HT
N
H
In the central nervous system, serotonin is believed to play an important role in the regulation
of body temperature, mood, sleep, vomiting, sexuality, and appetite. Low levels of serotonin
have been associated with several disorders, namely clinical depression, obsessive-
compulsive disorder (OCD), migraine, irritable bowel syndrome, tinnitus, fibromyalgia, bipolar
disorder, and anxiety disorders.[citation needed] If neurons of the brainstem that make
serotoninserotonergic neuronsare abnormal, there is a risk of sudden infant death
syndrome (SIDS) in an infant.[1]
Understanding Serotonin
http://www.abilify.com/abilify/channels/s
ch_content.jsp?BV_UseBVCookie=Yes
&channelName=Schizophrenia%2fSch_
Brain_Sch_Abilify&referrer=null
Historical: Drugs to treat
schizophrenia
http://www.pbs.org/wgbh/aso/databank/
entries/dh52dr.html
HN
N NH2
Histamine
Histamine is a biogenic amine chemical involved in local immune responses as
well as regulating physiological function in the gut and acting as a
neurotransmitter (Marieb, 2001, p.414). New evidence also indicates that
histamine plays a role in chemotaxis of white blood cells.
Sexual response:
Research has shown that histamine is released as part of the
human orgasm from mast cells in the genitals, and the
histamine release has been connected to the sex flush among
women. If this response is lacking while a woman also has
trouble achieving orgasm, this may be a sign of histapenia. In
such cases, a doctor may prescribe diet supplements with
folic acid and niacin (which used in conjunction can increase
blood histamine levels and histamine release), or L-histidine.
Conversely, men with high histamine levels may suffer from
premature ejaculations.
Antibodies and the Immune Response
http://pennhealth.com/health_info/anima
tionplayer/allergies.html
Antihistamines to Antipsychotics?
In the late 1930s, such dicyclic antihistamines as
phenbenzamine, diphenhydramine, and mepyramine were
in wide clinical use. The antihistamines' most striking
clinical side-effect was CNS depression -- drowsiness.
N
H3C NMe2
O CH2 N O
CH2 N
NMe2 NMe2
S
S
N
N
H3C NMe2
Cl NMe2
Promethazine
(Phenargan) Chlorpromazine
(currently used as an anti-emetic)
Antihistamines to Antipsychotics?
http://ajp.psychiatryonline.org/cgi/conten
t/full/160/10/1895?etoc
S
S
N
N
H3C NMe2
Cl NMe2
Promethazine
(Phenargan) Chlorpromazine
(currently used as an anti-emetic)
Antihistamines to Antipsychotics?
Chlorpromazine was the first antipsychotic drug,
used during the 1950s and 1960s. Used as
chlorpromazine hydrochloride and sold under the
tradenames Largactil and Thorazine, it has
sedative, hypotensive and antiemetic properties as
well as anticholinergic and antidopaminergic
effects. It also has anxiolytic (alleviation of anxiety)
properties. Today, chlorpromazine is considered a
typical antipsychotic.
S
S
N
N
H3C NMe2
Cl NMe2
Promethazine
(Phenargan) Chlorpromazine
(currently used as an anti-emetic)
Antihistamines to Antipsychotics?
The drug had been developed by Laboratoires Rhe-Poulenc in 1950
but they sold the rights in 1952 to Smith-Kline & French (today's
GlaxoSmithKline). The drug was being sold as an antiemetic when its
other use was noted. Smith-Kline was quick to encourage clinical trials
and in 1954 the drug was approved in the US for psychiatric treatment.
The effect of this drug in emptying psychiatric hospitals has been
compared to that of penicillin and infectious diseases.[1] Over 100
million people were treated but the popularity of the drug fell from the
late 1960s as the severe extrapyramidal side effects and tardive
dyskinesia became more of a concern. From chlorpromazine a number
of other similar neuroleptics were developed (e.g. triflupromazine,
trifluoperazine).
S
S
N
N
H3C NMe2
Cl NMe2
Promethazine
(Phenargan) Chlorpromazine
(currently used as an anti-emetic)
Antihistamines to Antipsychotics?
Previously used as an antihistamine and antiemetic its effects on
mental state were first reported by the French doctor Henri Laborit in
1951 or 1952 (different sources) as sedation without narcosis. It
became possible to cause 'artificial hibernation' in patients, if used as a
cocktail together with pethidine and hydergine. Patients with shock,
severe trauma or burns, become, if treated so, sedated, without anxiety
and unresponsive/indifferent to painful external stimuli like minor
surgical interventions. The first published clinical trial was that of Jean
Delay and Pierre Deniker at Ste. Anne Hpital in Paris in 1952, in
which they treated 38 psychotic patients with daily injections of
chlorpromazine.[1] Drug treatment with chlorpromazine went beyond
simple sedation with patients showing improvements in thinking and
emotional behaviour. Ironically, the antipsychotic properties of
chlorpromazine appear to be unrelated to its sedative properties.
During long term therapy some tolerance to the sedative effect
develops.
Chlorpromazine substituted and eclipsed the old therapies of electro
and insulin shocks and other methods such as psychosurgical means
(lobotomy) causing permanent brain injury. Before the era of
neuroleptics, starting with chlorpromazine, positive long-term results for
psychotic patients were only 20%.
Definitions
Neuroleptic: A term that refers to the effects
of antipsychotic drugs on a patient, especially
on his or her cognition and behavior.
Neuroleptic drugs may produce a state of
apathy, lack of initiative and limited range of
emotion. In psychotic patients, neuroleptic
drugs cause a reduction in confusion and
agitation and tend to normalize psychomotor
activity.The term comes from the Greek
"lepsis" meaning a taking hold.
Definitions
Extrapyramidal side effects: Physical
symptoms, including tremor, slurred
speech, akathesia, dystonia, anxiety,
distress, paranoia, and bradyphrenia,
that are primarily associated with
improper dosing of or unusual reactions
to neuroleptic (anti-psychotic)
medications.
Reward pathways in the CNS
The most important reward pathway in brain is the mesolimbic
dopamine system. This circuit (VTA-NAc) is a key detector of a
rewarding stimulus. Under normal conditions, the circuit controls
an individuals responses to natural rewards, such as food, sex,
and social interactions, and is therefore an important
determinant of motivation and incentive drive. In simplistic
terms, activation of the pathway tells the individual to repeat
what it just did to get that reward. It also tells the memory
centers in the brain to pay particular attention to all features of
that rewarding experience, so it can be repeated in the future.
Not surprisingly, it is a very old pathway from an evolutionary
point of view. The use of dopamine neurons to mediate
behavioral responses to natural rewards is seen in worms and
flies, which evolved 1-2 billion years ago.
http://www3.utsouthwestern.edu/molpsych/pa
ths_b02.htm
Norepinephrine Reuptake
Inhibitors as Antidepressants
Norepinephrine reuptake inhibitors (NRIs), also known as
noradrenaline reuptake inhibitors (NARIs), are compounds that elevate
the extracellular level of the neurotransmitter norepinephrine in the central
nervous system by inhibiting its reuptake from the synaptic cleft into the
presynaptic neuronal terminal. The drugs inhibit the class of
neurotransmitter transporters known as norepinephrine transporters. They
have virtually no action at other monoamine transporters.
Depression
http://www.healthcentral.com/depression/intro
duction-5003-109.html
http://www.healthcentral.com/depression/intro
duction-5003-109.html
http://www.healthscout.com/animation/68/10/
main.html
http://www.insidecymbalta.com/patient_resou
rces/neuro_animation.jsp
Norepinephrin Reuptake Inhibitors for Depression
H3C
OH
O
HO NHCH3
CH3
N
H
HO
Atomoxetine Epinephrine
(Strattera, Eli Lilly & Co.)
Atomoxetine is classified as a norepinephrine reuptake inhibitor, and is approved
for use in children, adolescents, and adults.
OH
O
HO NHCH3
CH3
N
H
HO
Atomoxetine Epinephrine
(Strattera, Eli Lilly & Co.)
O O
HO
Epinephrine
(Adrenaline) Viloxazine
S
N
N
NMe2
Cl NMe2
Chlorpromazine Imipramine
(anti-psychotic) (anti-depressant)
Historical
Imipramine was, in the late 1950s, the first tricyclic
antidepressant to be developed (by Ciba-Geigy). Initially, it
was tried against psychotic disorders (e.g. schizophrenia),
but proved insufficient.
During the clinical studies its antidepressant qualities,
unsurpassed until the advent of SSRIs, became evident.
Subsequently it was extensively used as standard
antidepressant and later served as a prototypical drug for
the development of the later released tricyclics.
It is not as commonly used today but sometimes used to
treat major depression as a second-line treatment.
S
N
N
NMe2
Cl NMe2
Chlorpromazine Imipramine
(anti-psychotic) (anti-depressant)
Tricyclic Antidepressants
The tricyclic antidepressants share the
common structural feature of fused 6-7-6
membered rings, as shown below.
N N
Cl
Clomipramine Me Desipramine H
N
Amitriptyline Me (Novartis) N
(Elavil, etc.) N
Me Me
Me
Imipramine Me Nortryptyline Me
N N
Me Me
Tricyclic antidepressants
Tricyclic antidepressants are a class of antidepressant drugs first used
in the 1950s. They are named after the drugs' molecular structure, which
contains three rings of atoms (compare tetracyclic antidepressant). The
term 'tricyclic antidepressant' is sometimes abbreviated to TCA.
The exact mechanism of action is not well understood, however it is
generally thought that tricylic antidepressants work by inhibiting the re-
uptake of the neurotransmitters norepinephrine, dopamine, or serotonin
by nerve cells. Tricyclics may also possess an affinity for muscarinic and
histamine H1 receptors to varying degrees. Although the pharmacologic
effect occurs immediately, often the patient's symptoms do not respond
for 2 to 4 weeks.[1]
Tricyclic antidepressants are used in numerous applications; mainly
indicated for the treatment of clinical depression, pain, nocturnal enuresis,
and ADHD, but they have also been used successfully for headache,
bulimia nervosa, interstitial cystitis, irritable bowel syndrome, narcolepsy,
persistent hiccups, pathological crying or laughing, smoking cessation, as
an adjunct in schizophrenia, and in ciguatera poisoning.[1]
Definitions
Narcolepsy is a neurological condition most characterized by
Excessive Daytime Sleepiness (EDS). A narcoleptic will most likely
experience disturbed nocturnal sleep, confused with insomnia, and
disorder of REM or rapid eye movement sleep. It is a type of
dyssomnia. A person with narcolepsy is likely to become drowsy or to
fall asleep, often at inappropriate times and places.
While the cause of narcolepsy has not yet been determined, scientists
have discovered conditions that may increase an individual's risk of
having the disorder. Specifically, there appears to be a strong link
between narcoleptic individuals and certain genetic conditions. One
factor that may predispose an individual to narcolepsy involves an area
of Chromosome 6 known as the HLA (human leukocyte antigen)
complex.
Certain variations in the HLA complex are thought to increase the risk
of an auto-immune response to protein producing neurons in the brain.
The protein produced, called hypocretin or orexin, is responsible for
controlling appetite and sleep patterns. Individuals with narcolepsy
often have reduced numbers of these protein-producing neurons in
their brains.
Attention Deficit Hyperactivity
Disorder (ADHD)
Attention-Deficit/Hyperactivity Disorder (ADHD) (sometimes referred to as
ADD when only inattentiveness and distractibility are problematic) is a
neurological disorder initially appearing in childhood which manifests itself with
symptoms such as hyperactivity, forgetfulness, poor impulse control, and
distractibility.
Research suggests that ADHD arises from a combination of various
genes, many of which affect dopamine transporters.[27] Suspect genes
include the 10-repeat allele of the DAT1 gene,[28] the 7-repeat allele of
the DRD4 gene,[28] and the dopamine beta hydroxylase gene (DBH
TaqI).[29] Additionally, SPECT scans found people with ADHD to have
reduced blood circulation,[30] and a significantly higher concentration of
dopamine transporters in the striatum which is in charge of planning
ahead.