Term
| Neural dysfunction may occur at what type/location of neural tissue? |
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Definition
disorders act to alter both the complex neuron network and action potential conduction at the single neuron level
excess or deficiency of neurotransmitter type
Ex) Parkinson's disease - insufficient dopaminergic transmission
Ex) schizophrenia - too much dopaminergic transmission in certain regions
Ex) depression - not enough NE or serotonin
Ex) epilepsy - too much excitatory transmission or too little inhibitory transmission
blockage of nociception involves inhibition of CNS pain pathways or inhibition of peripheral sensory fibers |
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Term
| Steps in synaptic transmission |
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Definition
1) neurotransmitters (NT) are synthesized in the axon terminal or transported down the axon (from cell body) pre-synthesized via microtubule transport system
2) action potentials are compreised of Na influx followed by K efflux (involves diffusion through voltage-gated channels)
3) Ca channels sense the action potential (voltage-gated) and then open; these Ca channels are high0voltage activated type
4) Ca moves in via diffusion (Ca extracellular concentration higher)
5) vesicles have Ca sensing proteins on surface; vesicles fuse with cell membrane
6) NT release into synapse through exocytosis
7) post synaptic NT receptor can be ionotropic (ligand gated ion channel) or metabotropic (linked to ion channels via G-proteins)
8) the action of the NT causes ion channels on the postsynaptic membrane to open or close
9) EXCITATORY = DEPOLARIZATION or INHIBITORY = HYPERPOLARIZATION postsynaptic potential occurs
10) vesicle associated proteins are recycled |
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Term
| 3 criteria for neurotransmitters |
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Definition
1) stored in the presynaptic terminal
2) released from the presynaptic terminal after depolarization
3) receptors are present on the postsynaptic cell (another neuron or an effector cell) |
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Term
| what are the effects of glutamate and gamma-amino butyric acid (GABA) on post synaptic potential? |
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Definition
glutamate is excitatory
GABA is inhibitory |
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Term
| potential sites and mechanisms of drug action/steps at which drugs can alter synaptic transmission |
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Definition
action potential inhibited
Ex) Na channel blockers
altered synthesis
Ex) administration of levodopa increases dopamine synthesis
vesicle storage depleted
Ex) reserpine inhibits VMAT
decreased metabolism of neurotransmitters
Ex) inhibitors of monoamine oxidase
increased NT release from vesicles
Ex) amantadine is thought to increase dopamine release from vesicles
inhibitors of reuptake pump increase synaptic concentration of NE and serotonin
Ex) SSRIs, tricyclic antidepressants
inhibition of synaptic degradation
Ex) acetylcholinesterase inhibitors
agonists and antagonists at receptors
Ex) some anti-epilepsy drugs |
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Term
| comparison of BBB capillaries to peripheral capillaries |
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Definition
Periphery:
capillary endothelial cells have gaps (termed fenestrae) between them
they use intracellular pinocytotic vesicles to facilitate the transcapillary transport of fluid and soluble molecule
CNS vessles:
sealed by tight functions between the endothelial cells
cells have fewer pinocytotic vesicles and are surrounded by pericytes and astroglial processes
capillary endothelial cells in the CNS have more mitochondria than those in systemic vessels; these mitochondria may reflect the energy requirements necessary for CNS ednothelial cells to transport certain molecules against a concentration gradient |
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Term
| cause of Parkinson's disease |
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Definition
loss of dopaminergic neurotransmission in the basal ganglia
the primary deficit in PD is loss of the neurons in the substantia nigra that privide dopaminergic input to the striatum (nigrostriatal pathway)
in PD, there is degeneration of the pars compacta in the substantia nigra resulting in OVER ACTIVITY IN THE INDIRECT PATHWAY (inhibits movement) AND DECREASED ACTIVITY OF THE DIRECT PATHWAY (inhibits movement) |
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Term
| what does activation of the direct and indirect pathways in PD result in? |
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Definition
the direct and indirect pathways are neuronal pathways that connect the striatum with the thalamus
the direct pathway results in excitatory input to the cerebral cortex
the indirect pathway results in inhibitory input to the cerebral cortex |
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Term
| disinhibition: inhibition of an inhibitory input results in ( ) in a neuron circuit |
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Definition
| excitation (action potential production) |
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Term
| steps to synaptic dopamine transmission |
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Definition
1) tyrosine from the diet (or from conversion of phenylalanine to tyrosine in the liver) is transported into the cytoplasm by a symporter
2) tyrosine is converted to L-DOPA catalyzed by tyrosine hydroxylase; rate limiting step in all catecholamine synthesis
3) L-DOPA is converted to dopamine catalyzed by aromatic amino acid decarboxylase
4) DA is packaged into intracellular vesicles by vesicular monoamine transporter (VMAT), an antiporter, dependent on hydrogen ion gradient
5) an action potential comes down the nerve terminal resulting in Ca influx and then DA release into the synapse
6) DA binds to postsynaptic and presynaptic dopamine receptors
7) DA can reenter the neuron (reuptake) via a dopamine transporter, a symporter requiring Na gradient
8) DA can be transported back into the vesicle or can be degraded by MAO and catechol-O-methyl transferase |
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Term
| classification of dopamine receptors |
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Definition
D1 Receptor Family = EXCITATORY (neuron depolarization)
Subtypes = D1
cause and increase in cAMP
D2 Receptor Family = INHIBITORY (hyperpolarization)
Subtypes = D2
cause a decrease in cAMP |
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Term
| location of dopamine receptors in the brain |
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Definition
the D1 and D2 subtypes are involved in motor coordination (important for PD treatment) located in the striatum
D2 subtype receptors can be located presynaptically (autoreceptors) and regulate release and synthesis of dopamine (via down regulation of TH enzyme activity) |
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Term
| nigrostriatal pathway in Parkinson's disease |
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Definition
[image]
dopaminergic neurons originating in the substantia nigra normally modulate output from the corpus striatum
the GABA neurons have dopamine receptors and acetylcholine receptors
in PD there is a selective loss of dopaminertic neurons
the final result of dopaminergic loss is decreased output to the motor cortex
the GABAergic neurons in striatum may have D1 subtype (excitatory) or D2 subtype (inhibitory) receptors
the D1 receptors activate the direct pathway
the D2 receptors inhibit the indirect pathway |
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Term
| the direct pathway is controlled by the ( ) subtype receptor |
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Definition
|
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Term
| the indirect pathway is controlled by the ( ) subtype receptor |
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Definition
|
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Term
| final effect of the indirect pathway |
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Definition
inhibition of movement
in the normal brain the indirect pathway is inhibited (dopamine activates the D2 receptor; activation of D2 turns off the indirect pathway = movement)
in PD the indirect pathway becomes overactive because there is loss of DA binding to D2 receptor in the striatum |
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Term
| final effect of the direct pathway on the cortex |
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Definition
stimulation of movement
in the normal brain dopamine activates the D1 (excitatory) which turns on the direct pathway
in PD the direct pathway is under active because of loss of DA binding to D1 in the striatum |
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Term
| pathophysiology of PD: direct and indirect pathways in a normal brain and PD brain |
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Definition
[image]
normal:
dopamine inhibits the indirect pathway and stimulates the direct pathway, yielding a balance that allows purposeful movement
both direct and indirect pathway neurons in the putamen (striatum) receive inputs from the substantia nigra (SNc) dopaminergic system
PD:
direct pathway inhibited and indirect pathway activated, both leading to reduced movement
degeneration of dopaminergic neurons in the substantia nigra (SNc) results in understimulation of the direct pathway and underinhibition of the indirect pathway
decreased direct pathway activation
increased indirect pathway activation |
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|
Term
|
Definition
1) intestinal absorption and CNS entry requires amino acid transporters
2) extensive gut and first pass metabolism
3) converted to dopamine in the peripheral tissues and CNS
4) dopamine cannot enter CNS
Problem:
levodopa is converted to dopamine in intestinal mucosa and other peripheral tissue sites by AMINO ACID DECARBOXYLASE
competition with dietary AAs
undergoes first pass metabolism |
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Term
| drugs that get levodopa into the CNS and allow convertion to DA and prevent DA metabolism |
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Definition
[image]
1) amino acid decarboxylase inhibitors (carbidopa (DOES NOT CROSS BBB!)) prevent conversion of levodopa to DA; COMT inhibitors (entacapone/tolcapone) prevent conversion of levodopa to 3-O-methyldopa in the periphery
2) in the CNS AAD is not inhibited (this allows conversion of levodopa to dopamine where it is needed ); MAO-B inhibitors (selegiline/rasagiline) prevent degradation of DA to DOPAC; COMT inhibitors (tolcapone) prevent degradation of DA to 3MT; thus increasing Da concentration in the nigrostriatal pathway |
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Term
| transport of levodopa to site of action |
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Definition
[image]
1) the precursor of DA (levodopa) is absorbed in the duodenum via an AA transporter; the AA transporter is also needed for CNS entry
2) levodopa can be decarboxylated by aromatic decarboxylase (clocked by carbidopa); once inside the CNS, levodopa is converted to dA (this is not blocked since carbidopa does not cross the BBB)
3) levodopa can be methylated by COMT (blocked by tolcapone); any levodopa that is converted to 3-O-methyldopa will compete with levodopa for transport across the BBB
4) DA can be metabolized to DOPAC by MAO (blocked by selegiline); selegiline may also decrease free radical generation through reducing hydrogen peroxide production
5) amantadine increases dopamine release from nerve terminals;
6) pergolide and other agonists can act directly on receptors in the striatum |
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|
Term
|
Definition
administered with levodopa
inhibits conversion of levodopa to dopamine
carbidopa and dopamine do NOT cross BBB
reduces peripheral side effects
when levodopa is given without carbidopa most of the levodopa is converted to dopamine which causes peripheral side effects
without carbidopa nausea and vomiting occur because dopamine stimulates the chemoreceptor trigger zone and more NE synthesis in the periphery causes cardiac side effects (tachycardia and occasionally atrial fibrillation) |
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Term
|
Definition
inhibits action of COMT in periphery and CNS
risk of acute HEPATIC FAILURE
prevents degradation of levodopa
physician should monitor liver enzymes |
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|
Term
|
Definition
inhibits action of COMT ONLY in the periphery
does not cross BBB
NO HEPATIC FAILURE association
COMT is ubiquitous and also metabolizes NE, so in priciple inhibition of this enzyme can also increase NE levels (same applies to tolcapone) |
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Term
| MOA of selegiline and rasagiline |
|
Definition
inhibit MAO-B (irreversible)
blocks conversion of dopamine to DOPAC and H2O2; thought to decrease free radical generation (PD progression)
MOA-A and MAO-B are both in the periphery; MAO-B is predominant in the brain
these 2 drugs have specificity for MAO-B therefore, they do not interfere with metabolism of ingested sympathomimetic amines such as tyramine in wines, aged cheese or smoked meats (MAO-A is free to metabolizetyramine
selegiline is metabolized to methamphetamine and amphetamine |
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|
Term
|
Definition
mechanism uncertain
thought to INCREASE SYNAPTIC DA by enhancing vesicle release and/or inhibiting DA reuptake |
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Term
| peripheral and central side effects of levodopa |
|
Definition
peripheral:
stimulation of the chemoreceptor trigger zone (not BBB protected) and cardiac arrhythmias (beta-adrenergic stimulation); reduced by inhibiting conversion to dopamine
central:
PSYCHIATRIC effects (hallucinations, confusion, schizophrenia-like) due to excessive dopamine stimulation in mesolimbic system
MOVEMENT disorders - too much dopamine in the CNS can cause over-activity of the direct pathway and not enought activity of the indirect pathway
dystonia (abnormal muscle tone)
dyskinesia (increased involuntary movement) |
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Term
| benefits of dopamine receptor agonists |
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Definition
do not require functioning dopaminergic neurons in SN
associated with less motor fluctuations
longer duration of action
do not require conversion by AAD in CNS
no competition for absorption in small intestine |
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|
Term
| the therapeutic activity of dopamine receptor agonists in on the ( ) subtype receptors |
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Definition
| D2 = inhibits the indirect pathway |
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|
Term
|
Definition
dopamine receptor agonist
ergot alkaloid
strong D2 agonist with some D1 antagonist activity
side effects from D2 ACTIVATION OUTISDE BASAL GANGLIA (CTZ, pituitary, mesolimbic)
inhibits prolactin secretion from the anterior pituitary (anti-psychotics have opposite effect)
mental disturbances (hallucinations, delusions, confusion) mediated through mesolimbic system
may also cause orthostatic hypotension |
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|
Term
|
Definition
dopamine receptor agonist
ergot alkaloid
D1 and D2 agonist activity
WITHDRAWN due to heart valve damage |
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Term
| MOA of ropinirole and pramipexole |
|
Definition
dopamine receptor agonists
D2 and D3 receptor agonists
NONERGOT AGENTS
more selective for dopamine receptors compared to ergot alkaloids |
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Term
|
Definition
dopamine receptor agonist
less selective dopamine receptor agonist
used to treat "FREEZING" OR "OFF" EPISODES IN PD
potent CTZ ACTIVATION
non-ergotamine agonist |
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|
Term
MOA of anticholinergic drugs for PD
benztropine, diphenhydramine, trihexyphenidyl |
|
Definition
cholinergic input at the striatum activates the indirect pathway (inhibitory input to the cortex, disables movement)
anticholinergic drugs reduce indirect pathway activity
SIDE EFFECTS from parasympathetic blockage: constipation, dryness of mouth, urinary retention, blurred vision, exacerbate forms of glaucoma |
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Term
| pathological features of Alzheimer's disease |
|
Definition
atrophy (shrinkage) of the cerebral cortex with enlarged ventricles and loss of cortical and sub-cortical neurons is observed in advanced AD
loss of cholinergic neurons originating the basal forebrain
loss of cholinergic neurons in the hippocampus (functions in memory formation) that originate from the basal forebrain (provides cholinergic innervation throughout the cortex and hippocampus)
presence of beta-amyloid plaques and neurofibrillary tangles
a few amyloid plaques and NFTs are seen in normal brain with no cognitive impairment; however, beta-amyloid plaques and NFTs are at much higher concentration in the brains of AD patients
inflammation (cytokines, glial cells) associated with plaques
not an initiating event in AD, but inflammation is detected around areas of plaque formation |
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Term
| the AMYLOID HYPOTHESIS of AD pathogenesis |
|
Definition
beta-amyloid aggregation -> plaques and NFTs -> neuronal dysfunction/loss -> dementia
abnormal protease digestion of amyloid precursor protein (APP) causes production of beta-amyloid protein
plaques and NFTs begin to form
NFTs are comprised of polymerized tau protein
a contributing factor to tau polymerization is its hyperphosphorylation
these lesions are associated with neuron death especially those of the cholinergic type
evidence:
1) natural mutations in APP associated with early onset AD
2) genetic mouse models also support this hypothesis (mutations in the APP gene cause similar brain pathology)
3) experimental evidence shows that in these mouse models antibodies directed aginast beta-amyloid protine can reduce brain lesion development |
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|
Term
| structure and enzymatic processing of amyloid precursor protein (APP) |
|
Definition
[image]
(A)
the APP protein and the different sites where the enzymes (called secretases)c cut APP
APP is a transmembrane protein whose normal physiologic function is not entirely clear
when APP is cut by the alph secretase a soluble fragment is formed, sAPP (it is thought that this fragment plays the normal function of this APP)
in AD APP is cut by the beta and gamma secretases which results in the 40 and 42 AA fragments (beta amyloid proteins); both fragments can form aggregates
(B)
normal path involving formation of the sAPP fragment
in AD (right side) the 40 and 42 AA fragments form
hyper-phosphorylation of tau protein is associated with AD lesions
tau polymerizes and forms filaments which in turn interferes with the microtubule transport system of neurons
beta-amyloid protein may be a causative factor in formation of NFTs
tau stabilizes microtubules, but when tau is hyper-phosphorylated it can cause NFTs
all this leads to neuron death (especially cholinergic neurons), memory loss, and dementia |
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|
Term
| site of action of acetylcholinesterase inhibitors |
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Definition
it is in the synapse where Ach is degraded by acetylcholinesterase (converted to acetate and choline)
choline is then recycled back into the presynaptic terminal
althought AChE inhibitors will increase ACh transmission in the brain, a major pitfall of this approach is it depends on the presence of functional cholinergic neurons |
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Term
| MOA and ADRs of tacrine (Cognex) |
|
Definition
AChE inhibitor
acts by inhibiting synaptic hydrolysis of acetylcholine thereby increasing brain ACh levels
increase brain cholinergic transmission and improve memory and learning ability
it is thought that AchE inhibitors do not slow the pathological process in the brain; they improve patient functioning which is dependent on presence of intact cholinergic neurons; as neurons continue to die during progression these drugs lose effectiveness
ADRs:
CHOLINERGIC SIDE EFFECTS (nausea, vomiting, diarrhea); excessive activation of the parasympathetic nervous system limits the dose
HEPATIC TOXICITY limits usage |
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Term
| MOA and ADRs of donepezil (Aricept) |
|
Definition
AChE inhibitor
acts by inhibiting synaptic hydrolysis of acetylcholine thereby increasing brain acetylcholine levels
increase brain cholinergic transmission and improve memory and learning ability
it is thought that AchE inhibitors do not slow the pathological process in the brain; they improve patient functioning which is dependent on presence of intact cholinergic neurons; as neurons continue to die during progression these drugs lose effectiveness
longer T1/2
more SELECTIVE FOR CNS AchE
ADRs:
nausea, vomiting, diarrhea (parasympathetic ADRs are less than with tacrine b/c of CNS specificity)
not associated with hepatoxicity
active and inactive metabolites |
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Term
| MOA and ADRs of rivastigmine and galantamine |
|
Definition
AChE inhibitors
act by inhibiting synaptic hydrolysis of acetylcholine thereby increasing brain acetylcholine levels
increase brain cholinergic transmission and improve memory and learning ability
it is thought that AchE inhibitors do not slow the pathological process in the brain; they improve patient functioning which is dependent on presence of intact cholinergic neurons; as neurons continue to die during progression these drugs lose effectiveness
more specific for CNS AchE
ADRs:
nausea, vomiting, diarrhea |
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|
Term
|
Definition
glutamate antagonist; NMDA receptor antagonism
for moderate to severe AD
thought to REDUCE EXCITOTOXICITY through blocking glutamate activity
NMDA receptors are ion channels that allow entry of Ca; it is thought the increase in intracellular Ca is a major contributor to the neurotoxic effects of excessive NMDA receptor activation
recent study questions the clinical efficacy |
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Term
| MOA of immunotherapy in AD |
|
Definition
immunotherapy is directed toward decreasing the formation of beta-amyloid plaques
1) immunotherapy in principle will increase removal of betta-amyloid protein; this is achieved by immunizing with the beta-amyloid protein itself or passively, through injecting anti-beta-amyloid antibodies into the patient
2) it is plausible to decrease production of amyloid protein by using inhibitors of the beta and gamma secretases |
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Term
| MOA of Active Immunotherapy in AD |
|
Definition
immunotherapy is thought to CLEAR/REMOVE PLAQUE LESIONS FROM BRAIN; cause phagocytosis of amyloid protein by microglial cells
active: injection/vaccination of beta-amyloid protein attenuates plaque formation and preserves cognitive function
trial in humans was halted |
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Term
| MOA of Passive Immunotherapy in AD |
|
Definition
immunotherapy is thought to CLEAR/REMOVE PLAQUE LESIONS FROM BRAIN; cause phagocytosis of amyloid protein by microglial cells
passive: inject purified anti-beta-amyloid antibodies; bypasses the need for an active immune response which is often impaired in older patients
one problem with this approach is antibodies themselves can cause an immune response (anti-antibodies are produced); this problem is solved by "humanizing" the antibodies |
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Term
|
Definition
gamma secretase inhibitor
APP is digested by the beta and gamma secretases to produce the toxic 40 and 42 AA fragments; the beta and gamma forms of secretase are an attractive target for treatment of AD
the problem with the current beta-secretase inhibitors is that they are large and do not cross the BBB
no improvement in cognitive function was observed with this compound |
|
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Term
| MS epidemiology and etiology |
|
Definition
epidemiology:
women:men 2:1
distance from equator - incidence is lower in tropical regions
higher incidence in Northern Europeans
etiology:
concordance data indicates genetic component - HLA genes that code for MHC II
microbial infection - demyelination is observed in some viral infections; infections can precipitate MS relapses
autoimmune mechanism |
|
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Term
| protein processing they an antigen presenting cell in MS |
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Definition
antigen presenting cells may phagocytose "self" protein such as myelin protein (MBP, a protein component of the myelin sheath around nerve axons) or some other protein component of the myeline sheath or myeline prodicing cell (oligodendrocyte in the CNS; Schwann cell in the periphery)
genetic polymorphisms associated with MS have been mapped to MHC II |
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Term
| activation of T cells by antigen presenting cells in MS |
|
Definition
[image]
the APC displays the MHC II antigen complex on the cell surface
the helper T cell has a T cell receptor that binds to the MHC II antigen complex
the T cell has CD4 that binds part of the MHC II; also CD28 on the T cell binds B7 on the APC
as a result of this specific interaction the T cell becomes activated and proliferates and secretes cytokines and growth factors that activate other cells including B cells and other macrophages
In MS the interaction above occurs outside and inside the CNS; the antigen may be part of the myelin sheath thus initiating an autoimmune response against the axons |
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|
Term
| autoimmune hypothesis of MS: peripheral immune system and CNS immune system |
|
Definition
[image]
peripheral immune system:
a macrophage (APC) activates a T cells by displaying a self antigen on the cell surface
self antigen is a component of the neuron (likely oligodendrocyte or Schwann cell)
the MHC II antigen complex stimulates the T cell causing it to proliferate and release cytokines and interferons that in turn, activate other T and B cells
an important step in the pathogenesis of MS is the passage of immune cells across the BBB
there is increased BBB permeability associated with this disease
CNS immune system:
in the CNS the autoimmune response continues
astrocytes (a type of glial cell) may present self antigen to T cells in the CNS thus activating the T cell
the T cell then releases cytokines that stimulate macrophages and B cells
the stimulated macrophages attack the myelin sheath (phagocytosis of myelin components) and the B cells may produce autoantibodies
neurons throughout the CNS may be demyelinated causing action potential conduction interference |
|
|
Term
| action potential conduction in normal axons and in demyelinated axons |
|
Definition
normal:
the nodes of Ranvier contain Na and K channels which are required to produce an action potential
conduction through the myelinated areas is by a passive mechanism
when current reaches the next node another action potential is produced in that node
AP velocity along the axon in the nodes is slower than passive conduction/movement along the axon in the myelinated areas
demyelinated:
without the myelinated areas action potentials cannot "jump" from node to node b/c of leakage of current (and loss of voltage potential) across the demyelinated membrane
the myelinated areas do not normally have Na and K channels |
|
|
Term
| explanation of acute demyelination conduction block |
|
Definition
[image]
for a time period after demyelination the AP is blocked
the AP does not move past the area of demyelination and the demyelinated area cannot passively conduct b/c of loss of voltage potential across the membrane |
|
|
Term
| explanation of chronic demyelination and partial restoration of conduction |
|
Definition
[image]
after longer periods of demyelination the axon restores conduction
this is likely due to production of proper Na and K channels in the area of demyelination
the segment of the axon remains demyelinated (passive conduction in this area is replaced with AP conduction which is slower) |
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|
Term
| explanation of complete axon loss/degeneration in MS |
|
Definition
[image]
the axon terminal can degenerate and not recover causing permanent conduction block |
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|
Term
| MOA and ADRs of interferon-beta-1b (Betaseron) and interferon-beta-1a (Avonex, Rebif) |
|
Definition
INCREASES CD8 T SUPPRESSOR CELL FUNCTION
interferons are naturally occurring peptides with antiviral and antibacterial properties
these drug products (biologics) are in addition to interferon-beta that is already in the body (endogenous)
interferon-beta-1b is purified from genetically programmed bacteria
interferon-beta-1a is produced and purified from mammalian cells to posttranslational modifications are present making it identical to human endogenous interferon beta-1a
interferon-beta augments suppressor cell (CD8 T cells and other cells) function which decreases activation and proliferation of CD4 T cells and is thought to block autoimmune response
decreases BBB permeability thus preventing passage of the autoimmune response into the CNS where demyelination occurs
ADRs:
FLU-LIKE symptoms
INJECTION SITE REACTION
symptoms of depression
rare hepatic injury (Avonex)
antibody titers |
|
|
Term
| MOA and ADRs of glatiramer acetate (Copaxone) |
|
Definition
polypeptides containing random sequence of AAs that are found with high frequency in myelin basic protein (glutamate, alanine, lysine, and tyrosine)
reduces the number of CNS lesions
may induce immune tolerance and cause less attack on the myelin sheath
glatiramer acetate causes CD4 T cells to produce brain derived neurotrophic factor (BDNF), a CNS growth factor
binding of MHC II proteins may alter antigen presentation
ADRs:
post injection reaction (chest pain, breathing disturbance)
injection site reaction
no flu-like symptoms |
|
|
Term
| MOA and ADRs of natalizumab |
|
Definition
[image]
monoclonal antibody
HUMANIZED antibody directed against alpha4 integrin subunit
the alpha4 integrin is expressed on WBCs
alpha4 binds to vascular cell adhesion molecule (VCAM) on endothelial cells; this interaction mediates attachment of WBCs to endothelial cells in the BBB; the WBCs then migrate between endothelial cells and enter the CNS
natalizumab binds to the alpha4 integrin and blocks the interaction between alpha4 and VCAM thus preventing attachment of WBCs to endothelial cells in the BBB
ADRs:
infusion reactions (rash, shortness of breath, fever, chills, nausea)
production of anti-IgG
Associated with PML (progressive multifocal leukoencephalopathy) |
|
|
Term
| MOA and ADRs of mitoxantrone |
|
Definition
DNA-binding
inhibits topoisomerase II - causes DNA strand breaks and cross linking
suppresses the immune response by inhibiting B-cell and T-cell and macrophage proliferation
toxic to both rapidly proliferating and nonproliferating cells
used as adjunctive therapy
ADRs:
cardiotoxicity - monitor left ventricular ejection fraction (decline associated with use)
nausea, leucopenia, alopecia |
|
|
Term
| MOA and ADRs of dalfampridine |
|
Definition
potassium channel blocker
used to improve walking in MS patients
blocks voltage-dependent K channels in demyelinated areas of axons
ADRs:
seizure concern - contraindicated with history of seizure and renal impairment
drug does not significantly interfere with cardiac conduction at therapeutic doses |
|
|
Term
| MAO and ADRs of fingolimod |
|
Definition
sphingosine-phosphate receptor ligand
binds to sphingosine-phosphate receptor; interferes with lymphocyte egress
fingolimod closely resembles sphingosine
fingolimod is phosphorylated by sphingosine kinases; phosphorylated form is bioacitve and bins sphingosine-phosphate receptors
this cause downregulation of the receptor causing inhibition of the movement of lymphocytes out of lymph tissue
lymphocytes remain in the lymph tissue instead of migrating to the CNS and attacking myelinated neurons
ADRs:
bradycardia
AV block
infection risk
macular edema
hepatic effects |
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