Exam 3 - Rochet (CNS/MS Drugs) Flashcards
3 main parts of brain
hindbrain
midgrain
forebrain
main parts of hindbrain
medulla
pons, cerebellum
main parts of midbrain
substantia nigra (SN)
main parts of forebrain
cerebral cortex
basal ganglia (minus SN)
limbic system
diencephalon
what makes up limbic system
hippocampus
amygdala
what makes up basal ganglia
striatum
globus pallidus
subthalamic nucleus
what makes up the diencephalon
thalamus
hypothalamus
is it in the hindbrain, midbrain, forebrain?
medulla
hindbrain
is it in the hindbrain, midbrain, forebrain?
substantia nigra
midbrain
is it in the hindbrain, midbrain, forebrain?
pons, cerebellum
hindbrain
is it in the hindbrain, midbrain, forebrain?
cerebral cortex
forebrain
is it in the hindbrain, midbrain, forebrain?
basal ganglia
forebrain
is it in the hindbrain, midbrain, forebrain?
limbic system
forebrain
is it in the hindbrain, midbrain, forebrain?
diencephalon
forebrain
is it in the hindbrain, midbrain, forebrain?
hippocampus
in limbic system — therefore in FOREBRAIN
is it in the hindbrain, midbrain, forebrain?
amygdala
in limbic system — therefore in FOREBRAIN
is it in the hindbrain, midbrain, forebrain?
hypothalamus
in diencephalon — therefore in FOREBRAIN
is it in the hindbrain, midbrain, forebrain?
thalamus
in diencephalon — therefore in FOREBRAIN
what is the overall function of medulla
autonomic functions
what is overall function of pons
a “bridge”
relays signal from forebrain to cerebellum
Pons: relays signal from ______ to _______
from forebrain to cerebellum
main function of cerebellum
“little brain”
governs motor coordination for producing SMOOTH movements
Medulla does conscious or non-conscious actions?
NON-conscious/autonomice
reflexes, respiration, cardiac function etc…
_________ undergoes neurodegeneration in spinocerebellar ataxias
cerebellum
Substantia Nigra: Pars Compacta
provides _____ to basal ganglia (supplies _______ to the ______
provides INPUT
supplies DOPAMINE to STRIATUM
what are the two parts of substantia nigra
pars COMPACTA
or pars RETICULATA
Substantia Nigra: Pars Reticulata
has ______ function
relays signal from _________ to ______
OUTPUT function
from basal ganglia; to thalamus
Pars Compacta or Pars Reticulata?
has input function
compacta
Pars Compacta or Pars Reticulata?
has output function
reticulata
Pars Compacta or Pars Reticulata?
provides signal to basal ganglia
compacta
Pars Compacta or Pars Reticulata?
provides signal to thalamus
reticulata
Pars Compacta or Pars Reticulata?
supplies dopamine to striatum
compacta
Pars Compacta or Pars Reticulata?
involved with voluntary motor control
compacta (b/c dopamine)
main function of cortex
processing/interpreting information (executive function)
other name for cortex
cerebrum
main role of basal ganglia
voluntary motor control
some cognitive functions
main role of limbic system
emotions and memory
emotions - amygdala; memory - hippocampus
what is the role of amygdala
emotions
what is the role of hippocampus
memory
main role of diencephalon
relay station to AND from cortex
regulating internal homeostasis, emotions, hormonal control, and direct regulation
(relaying - thalamus; hypothalamus does the rest (aka lots of regulation)
main role of thalamus
relay station to AND from cortex
main role of hypothalamus
regulating internal homeostasis, emotions, hormonal control, and direct regulation
Decisions are made in “______________” about how to interpret and act on the incoming sensory information
cortico-thalamic loops
Schizophrenia is considered a disease of the _______
frontal cortex
damage to the cortex can affect what things?
movement, speech, personality
T or F: when there is damage to the cortex, drugs are not typically available to treat these deficiencies
True!!
exception is Schizophrenia tho
Afferent or Efferent Neuron Tracts?
transmit signals from cortex to periphery
efferent
Afferent or Efferent Neuron Tracts?
transmit signals from periphery to cortex
afferent
brain is surrounded by layers of membranes collectively known as the ______
meninges
3 main layes of meninges
dura
arachnoid
pia
Dura, Arachnoid, Pia layer of meninges?
us closest to bone
dura
dura = hard next to bone
Dura, Arachnoid, Pia layer of meninges?
is closest to brain
pia
Dura, Arachnoid, Pia layer of meninges?
is the middle layer
arachnoid
Dura, Arachnoid, Pia layer of meninges?
is the outer layer
dura
Dura, Arachnoid, Pia layer of meninges?
is the inner layer
pia
what fills the space b/w arachnoid and pia layers?
CSF - cerebrospinal fluid
blood enters brain via the ________
carotid artery
once carotid artery enters the brain… it branches into what things?
4 arteries total…
opthalmic artery;
anterior, middle, and posterior cerebral arteries
CNS consists of ______ and _____ cells
neurons;
glial cells
which is more abundant?
neurons or glial cells
glial cells
3 main glial cells
astrocytes
Oligodendrocytes
Microglia
Role of Astrocytes
provide neurons w/ _________ & _______
remove excess __________
support the _________
provide growth factors and anti-oxidants
remove excess GLUTAMATE
support BLOOD BRAIN BARRIER
Role of Oligodendrocytes
produce myelin sheath that insulates axons
Role of Microglia
Clear debris!!
also provide growth factors
(if too many microglia => inflammation)
why is it good astrocytes remove excess glutamate
too much glutamate can damage neurons
Astrocytes, Oligodendrocytes, or Microglia?
remove debris
Microglia
Astrocytes, Oligodendrocytes, or Microglia?
remove excess glutamate
astrocytes
Astrocytes, Oligodendrocytes, or Microglia?
make myelin sheath for axon insulation
oligodendrocytes
Astrocytes, Oligodendrocytes, or Microglia?
support blood brain barrier
astrocytes
Astrocytes, Oligodendrocytes, or Microglia?
provide growth factors
astrocytes (mainly)
also microglia
Astrocytes, Oligodendrocytes, or Microglia?
provide anti-oxidants
astroyctes
Blood Brain Barrier:
stabilized by ________ in the ______ cell layer of blood vessels in the brain
tight junctions
in endothelial cell layer
Neurotransmission is triggered by ______ of the neuron
electrical depolarization (shocking…)
Neurotransmission occurs when a influx of ______ changes polarity of membrane
Na+ ions…
T or F:
smaller axon diameter leads to faster firing
false!
bigger diameter = faster firing
depolarizing neurons = excitatory or inhibitory?
excitatory
polarizing neurons = excitatory or inhibitory?
inhibitory
T or F: action potentials for a SINGLE neuron are always the same magnitude
true!
“all or none” type thing
bundle of axons aka _______
nerve fiber
currents carrier by a nerve fiber are higher because of the result of ________
summation
what is EPSP
excitatory postsynaptic potential
______ neurotransmitters will induce EPSP
excitatory…
Excitatory neurotransmitters act on (chronotropic or ionotrpic?) receptor allowing ____ ions to cross the membrane
ionotropic; Na+
Inhibitory neurotransmitters induce _________ by allowing ____ ions to cross the membrane
hyperpolarizing; Cl- ions
T or F: IPSP can decrease the magnitude of a subsequent EPSP
true!
if lots of hyperpolarizing (hella negative), it can prevent a action potential the next time (aka like refractory period)
what are the common amino acid neurotransmitters
GABA
Glycine
Glutamate
what are the common non-amino acid neurotransmitters
Ach
DA (dopamine)
NE
Serotonin (5-HT)
GABA:
is a excitatory or inhibitory neurotransmitter?
inhibitory
GABA:
decrease neuronal excitability by doing what?
increasing the influx of Cl- ions into the neuron
what are types of GABA receptors?
GABA-A and GABA-B
drugs that normally interact with GABA pathways are known as CNS ________
depressants
what drug classes are known to be related to the GABA pathway
- Sedative hypnotics (BZDs, Barbituates)
- Anticonvusalnts
- Anxiolytics
______ is similar to GABA but it works in the spinal cord
glycine
glycine is similar to GABA but it works in the _______
spinal cord
GABA-A receptor is a ______
and
GABA-B receptor is a _______
A: ion channel
B: GPCR
GABA-A or GABA B receptor is more relevant in seizures
A!
Glutamate:
is a excitatory or inhibitory neurotransmitter?
excitatory
Excess glutamate leads to neuronal damage by allowing excessive _____ into neuron
Ca2+ influx
what are the glutamate receptors?
AMPA/NMDA
mGluR
Glutamate receptors are ______tropic or ______tropic
metabotropic
or
ionotropic
Ach receptors are?
muscarinic (mAchR)
or
nicotinic (nAchR)
what parts of the brain does Ach have an effect?
basal forebrain!!
Pons, Cortex, Basal Ganglia
Ach
is a excitatory or inhibitory neurotransmitter?
excitatory
Glutamate works in what parts of the brain?
throughout the whole brain
GABA works in what parts of the brain?
throughout the whole brain
Ach or DA?
works in basal forebrain
Ach
Ach or DA?
works in midbrain
DA
Dopamine Drug Targets
D1 - D5 GPCR receptors
and
DAT (dopamine transporter)
DA neurons arise from where?
VTA and SN
```
VTA = ventral tegmental area
(SN = substanta nigra)
~~~
Drugs that block DAT lead to (decrease or increase) in DA?
increase!!
what drugs block DAT
amphetamine and cocaine = more dopamine = euphoria = addiction
DA Receptors:
D1 like is G___ coupled
D2 like is G____ coupled
D1: Gs
D2: Gi
NE works where in the brain?
Pons
drug targets for NE
adrenergic receptors (alpha and beta)
and
NET (NE transporter)
NET inhibitors are used to treat _______
depression
D2 receptor antagonists are used as _______ drugs
Antipsychotics
Drug targets for 5-HT
GPCRs and
Gated Ion channel and
SERT (serotonin transporter)
5-HT axons arise from a group of cell bodies in the brain stem called __________
Raphe Nuclei
5-HT(2A) antagonists are known as _______
atypical antipsychotics
5-HT(1D) agonists are used for ______
migraines
SERT uptake inhibitors are used for ______
depression (SNRIs??)
5-HT(2A) agonists are known as ________
hallucinogenic
(2A - antag used as antipsych…
2A- agonist used to create hallucinogens…)
what is Charcot’s Triad used for?
its the 3 key signs of MS
what makes up Charcot’s Triad?
1 - Nystagmus
2 - intention tremor
3 - telegraphic speech
what is nystagmus
uncontrolled eye movement
what the common symptoms of MS
Rochet lists 10…
- Visual problems
- Numbness/Tingling
- fatigue/motor weakness
- Problems walking/gait problems
- pain
- spasticity
- dizziness/vertigo
- Sexual dysfunction
- Bladder problems/Constipation
- Emotional/Cognitive changes/depression
Viral/bacterial infections may increase risk of MS by activating _________ cells
autoreactive immune
What evidence supports the idea that viral/bacterial infections can lead to MS (autoreactive immune cells cause it)
- increased ______ synthesis in CNS of MS pts
- increased ______ to certain viruses
- epidemiological data suggests that _____ infection increases MS risk
IgG;
antibody titers
childhood
EBV and MS:
- sequence similarities b/w EBV and self peptides –> activation of ___________ (aka _________)
activating autoreactive T or B Cells; molecular mimicry
Genetic Influences in MS:
Risk is ______ in twins/siblings and _____ in children/half siblings
higher; lower
Genes linked to MS encode the following immune related proteins:
- MHC/HLA______
- interleukin ____ receptor
- interleukin ____ receptor
- MHC/HLA: DR15/Dr6
2(alpha)
7(alpha)
List the Clinical Forms of MS:
RRMS (relapsing remitting) SPMS (secondary progressive) PPMS (primary progressive) CIS (clinically isolated syndrome) Marbug Variant
SPMS:
has less ________ but does have progressive _____
less inflammation
progressive decline
RRMS or PPMS:
which one has later onset
PPMS (primary progressive)
probs bc RRMS has inflammatory episodes surpass symptomatic threshold
what is CIS
clinically isolated syndrome;
initial episode of neurologic syndrome > 24 h
involves inflamm. and demyelination in optic nerve/cerebrum,cerebellum, brainstem, or spinal cord
what is Marburg Variant of MS
aggressive MS — hella inflammation; may resemble brain tumor
MS consists of what 2 phases
autoimmune and degenerative
MS Autoimmune Phase:
_____ cells present CNS antigens and activate ____ cell responses in the peripheral ________ tissue
Dendritic cells
T cells
lymphoid
MS Autoimmune Phase:
activated B and T cells proliferate and infiltrate CNS (it involves _______ mediated binding and penetration of _____)
involves alpha-4 integrin
penetrate BBB (blood brain barrier)
MS Autoimmune Phase:
after re-encountering their specific antigen in CNS, B cells mature into ________ and release ______ to target the antigen on expressing cells
mature into PLASMA CELLS
release IgG antibodies
CD8 T Cells or CD4 T Cells?
interact with target ligands on oligodendrocytes
CD8 T cells
CD8 T Cells or CD4 T Cells?
interact with target ligands on microglia
CD4 T cells
CD8 T Cells or CD4 T Cells?
interact with MHC Class I molecules
CD8 T cells
MS Autoimmune Phase:
T cells being activated leads to what things?
cytokine release + macrophage stimulation –> damage to myelin sheath
what cytokines are released by T cells
IFN- gamma
TNA-alpha
perforin
granzyme
MS Autoimmune Phase:
antibodies trigger activation of ________ on oligodendrocytes that result in _____ formation/cell damage
activated COMPLEMENT
result in PORE
MS Autoimmune Phase:
Macrophages get recruited to the _________ and release _______ that will harm _________
to the inflamm. lesion
release toxins
harm oligodendrocytes
Node of Ranvier have ____ channels
vs
Myelin sheath have _____ channels
Ranvier: Na+ Channels
Myelin: K+ Channels
T or F: Action potentials travel faster if myelin sheath isn’t there
False…. need the sheath for insulation (duh why demyleination is bad..)
when there is damage in MS and a lesion has occurred, what two things migrate to the lesion?
neuronal stem cells and OPCs (oligodendrocyte progenitor cells)
what is astrogliosis
invasion/propagation of astrocytes resulting in gliotic plaques/scars (done when demyelination occurs)
Remyelination in MS:
1st Demyelination has to happen, this will cause the activation of what two cells?
microglia and astrocytes
Remyelination in MS:
when astrocytes/microglia get activated the end up releasing what? to recruit what?
pro-migratory factors and mitogens
recruit OPCs
3 possible targets/therapeutic interventions in MS
- immune system targets
(T cell binding and BBB penetration; T cell/APC interactions; Cytokines) - targeting remyelination
- targeting neurodegeneration
why is gadolinium (Gd) important to MS
when injected it penetrates the regions where the blood brain barrier is comprosmised
MS lesions are enhanced when GD is given
Guillain Barre Syndrome:
usually preceded by what?(for about 50% of pts)
GI or Respiratory infection
Guillain Barre Syndrome:
Pathophys?
autoimmune attack on peripheral nerves by circulation Abs –> leads to myelination
Tx of Guillain Barre Syndrome?
- ventilation (when resp. distress)
- Plasmapheresis (eliminate auto-Abs)
- IV immunoglobulin administration
Sx of Guillain Barre Syndrome?
weakness starts in distal muscles/lower extremities goes to upper extremities
can progress to total paralysis w/ death from respiratory failure
Progression of Guillain Barre Syndrome can peak in how long?
10 - 14 days
what drugs are used for acute MS attacks?
Methylprednisolone
Prednisone
ACTH (adrenocorticotropic hormone)
Interferon Beta Drugs:
first line or second line?
first
Interferon Beta Drugs:
act in the _______ and ______
periphery and BBB
Interferon Beta Drugs:
inhibit what?
inhibit autoreactive lymphocytes
and
inhibit BBB penetration (by decreasing matrix metalloproteinase - MMP)
Interferon Beta Drugs:
efficacious at neutralizing ________
antibodies
Glatiramer:
first line or second line
first line
MOA of Glatiramer?
synthetic polypeptide
mimics antigenic properties of myelin basic protein
inhibits T cell - APC/Dendritic interaction
MOA of Fingolimod
S1P receptor agonist (sphingosine 1 - phosphate)
Fingolimod MOA:
- stimulate ___________
- interference w/ ____________
- stimulate oligodendrocyte survival (remylenination)
- lymphocyte movement out of lymphoid organs
Fingolimoid:
first or second line?
first line
Natalizumab:
first line or second line?
second
MOA of Natalizumab?
Monoclonal Ab specific for a-4 integrin
Mitoxantrone:
first or second line
second line
MOA of Mitoxantrone
anthracenedione with CYTOTOXIC activity (reduce lymphocyte numbers)
special feature about Mitoxantrone
first cytotoxic drug licenced for SPMS
Teriflunomide:
first or second line agents
uhh…. NEW DRUG! but also used a lot so…?
MOA Teriflunomide:
CYTOTOXIC agent that inhibits dihydroorotate dehydrogenase (aka prevents de novo pyrimidine biosynthesis)
notable part of dimethyl fumarte’s structure?
its simple AF (very small..)
MOA for dimethyl fumarate
gets metabolized by esterases in GI tract, blood, tissues and activates Nrf2 mediated cellular anti-ox responses and anti-inflamm. pathyway
In Normal Circumstances,
_______ is an antagonist to Nrf2 by promoting Nrf2 ________
Keap1; ubiquitylation
Keap1 dissociates from Nrf2 when cell is exposed to _________ or _____________
electrophilic toxins or oxidative stress
for Nrf2 Pathway:
Keap 1 gets covanlently modified on key ______ residues and then Nrf2 is not ubiquitylated anymore
cysteine
for Nrf2 Pathway:
once Nrf2 is not ubiquitlyated anymore it accumulates and enters ________ to activate ________ that are regulated by _________
enters NUCLEUS
to activate gene transcription of genes
regulated by ARE (antiox response element)
what genes are under control of ARE?
enzymes for glutathione biosynthesis
and
detoxification
(aka some Phase II enzymes)
Glial cells will release _________ and _______ to create neuroprotection and regeneration
release Neurotrophin/antioxidant
Nrf2 antiox response pathway induces _______ upregulation in neurons through astrocyte-neuron communication
GSH
Firtaegrast: MOA and notable part of struc
MOA: targest a-4 integrin
small molecule
