Psych/Nuero Final: Cav MS, ALS, MG

CNS

Multiple Sclerosis (MS): autoimmune, inflammatory disease of __

relapsing-remitting

4 Different Types of MS:

1. ____-____ (most common!!, unpredictable attacks which may or may not leave permanent deficits followed by periods of remission)

primary progessive

4 Different Types of MS:

2. ____ ____ (steady increase in disability without attacks)

secondary progressive

4 Different Types of MS:

3. ___ ____ (initial relapsing-remitting that suddenly begins to have decline WITHOUT periods of remission)

progressive-relapsing

4 Different Types of MS:

4. ____-___ (steady decline since onset with superimposed attacks)

cognitive

MS Symptoms

1. ___ dysfunction

vision

MS Symptoms

2. ___ problems

balance

MS Symptoms

3. ___ issues

fatigue

MS Symptoms

4. chronic ___

depression

MS Symptoms

5. ____

myelin sheath

What Happens In MS

In multiple sclerosis, the immune system attacks and destroys the ___ ___ around nerves in the CNS, leading to loss of nerve signal conduction and formation of scarred demyelinated areas called plaques.

milieu, antigen

2 Steps Required to Induce Immune Reponse in MS

1. a pro-inflammatory ___ (ie "soup") in the CNS

2. ___-drive acquired immune response

T, B

Immune Reponse in MS

1. Antigens released from the CNS are taken up and presented by dendritic cells, which then prime → ___ and ___ cells in peripheral lymphoid tissues.

clonal expansion

Immune Reponse in MS

2. After the T and B cells are primed → they rapidly multiply (___ ___) in the lymphoid tissue

CNS

Immune Reponse in MS

3. After clonal expansion in the lymphoid tissue → T and B cells infiltrate the ___

IgG, antigen

Immune Reponse in MS

4. After infiltrating CNS → B cells re-encounter their antigen, mature to plasma cells, and release large amounts of ___ antibodies, which bind to soluble or membrane-bound __ on expressed cells

brain, damage

Immune Reponse in MS

5. After infiltrating CNS → CD8+ T cells invade the ___ and encounter their specific peptide ligand which prompts direct __ to expressing cells

inflammatory cytokines, attract

Immune Reponse in MS

6. After infiltrating CNS → CD4+ T cells encounter antigens presented by microglial cells, which lead to increased production of ____ ___ that then ___ other immune cells (like macrophages)

safety

As clinical efficacy of MS Treatments increases, so does ___ concerns

1a, 1b

Interferon β-___ (Avonex, Rebif) and Interferon β-___ (Betaseron) are used in multiple sclerosis

activation, adhesion, penetration

How do IFNβ drugs work in the periphery?

1. decreases T cell ____

2. decreases T cell ___ and ___ of the BBB

presentation, cytokine

How do IFNβ drugs work in the CNS?

3. decreases antigen ___

4. promotes anti-inflammatory __ production

Th1, proliferation

How do IFNβ drugs work in the CNS?

5. decreases ___ cytokine release

6. decreases B-cell ___

damage

How do IFNβ drugs work in the CNS?

7. decreases bystander ___

Glatiramer

____ (Copaxone) is used in multiple sclerosis

BBB

Glatiramer cannot penetrate the ___

decoy

Glatiramer acetate acts in the periphery as a "___" antigen (it resembles myelin basic protein, so T cells react to it instead of attacking the actual myelin in the CNS.)

Th2

Glatiramer shifts T-cell response from pro-inflammatory Th1 cells to anti-inflammatory ___ cells

cytokines, trophic

Glatiramer

-the anti-inflammatory Th2 cells migrate into the CNS and release anti-inflammatory ____ and ___ factors (promote neuronal/glial survival)

bystander suppression

Glatiramer

-the result of peripheral Th2 cells crossing the BBB and releasing anti-inflammatory cytokines and trophic factors = "____ ____"

inflammation

"bystander suppression" refers to the reduction of ____ as a result of peripheral Th2 cells crossing the BBB and releasing anti-inflammatory cytokines and trophic factors

Teriflunomide

____ (Aubagio) is used in multiple sclerosis

DHODH, pyrimidine

Teriflunomide MOA

1. Inhibits dihydroorotate dehydrogenase (___) in mitochondria → resulting in decreased de novo ___ synthesis)

glycoproteins, phospholipids, nucleotides

Teriflunomide inhibits DHODH to decrease pyrimidine synthesis → effect = less production of ___, ___, and ___, which ultimately impairs cell function and leads to cell death.

JAK-STAT, cytokines

Teriflunomide MOA

2. Inhibits ___-___ signaling pathway → resulting in decreased production of pro-inflammatory ___

Dimethyl Fumarate

____ ___ (Tecfidera) is used in multiple sclerosis

TH2, bystander suppression

Dimethyl Fumarate

-MOA is similar to glatiramer → Shifts immune balance in the periphery by increasing ___ anti-inflammatory cells and decreasing pro-inflammatory T and B cells to promote ___ ___ in the CNS

CNS

Dimethyl Fumarate

-Remember glatiramer cannot cross BBB. The key difference with dimethyl fumarate is that it can enter the ___

kinase

Dimethyl Fumarate

-After entering the CNS, the drug activates ___ signaling pathway (ERK pathway) to support neuronal and glial cell survival

oxidative stress

Dimethyl Fumarate

-By activating kinase pathways, it increases anti-apoptotic and antioxidant factors, which reduces ___ ___ and inflammation in the brain.

Cladribine

____ (Mavenclad) is used in multiple sclerosis

kinases

Cladribine is activated by ___

phosphotases

Cladribine is inactivated/degraded by ___

somatic

Cladribine

-in ___ (normal body) cells, there is low kinase and high phosphatase, meaning cladribine gets inactivated/degraded and has minimal efffect

lymphocytes

Cladribine

-is preferentially activated in ___ due to higher kinase and lower phosphatase activity,

DNA

Cladribine MOA

-selectively accumulates in lymphocytes, where it disrupts ___ synthesis/repair and causes cell death.

Fingolimod, Siponimod

____ (Gilenya) and ___ (Mayzent) are used in multiple sclerosis

S1R

Fingolimod, Siponimod

-Normally, T cells are activated in lymph nodes and are signaled to leave (egress) by ___ binding to its receptor

S1P

Fingolimod, Siponimod MOA

-prevent T cell egress from lymph nodes by antagonizing ___ receptors

Mitoxantrone

____ (Novantrone) is used in multiple sclerosis

DNA

Mitoxantrone

-intercalates (ie inserts itself) into __

non-specific cytotoxic

Mitoxantrone

-In DNA, has a __-___ ___ effect ("like dropping a bomb on immune response")

T, B, macrophages

Mitoxantrone Effects in DNA:

1. ↓ proliferation of __ cells, __cells, and ___

antigen

Mitoxantrone Effects in DNA:

2. Impairs ___ presentation

pro-inflammatory cytokines

Mitoxantrone Effects in DNA:

-↓ secretion of ___-___ __

ocrelizumab, ofatumumab, ublituximab

____ (Ocrevus), ____ (Kesimpta), and ____ (Briumvi) are used in multiple sclerosis

CD20, B

Ocrelizumab, Ofatumumab, and Ublituximab bind to ___ on __ cells

depletion

Ocrelizumab, Ofatumumab, and Ublituximab bind to CD20 on B cells. This results in ___ of B cells

antibody, complement, apoptosis

Ocrelizumab, Ofatumumab, and Ublituximab deplete B cells in 3 ways:

1. ___-dependent cell-mediated cytotoxicity

2. ___-mediated cytotoxicity

3. ___ induction

Natalizumab

____ (Tysabri) is used in multiple sclerosis

T

Natalizumab

-Monoclonal antibody against α4β1 integrin on __ cells (not CD20 like the B-cell drugs)

VCAM-1

Natalizumab

-Blocks T-cell adhesion to ___ on endothelial cells

CNS

Natalizumab

-Final effect = decreased T-cell entry into the ___ (therefore decreased inflammation and myelin damage)

Alemtuzumab

_____ is used in multiple sclerosis

CD52

Alemtuzumab

-Monoclonal antibody against ___ on lymphocytes (B and T cells)

complement, antibody

Alemtuzumab

-Causes lymphocyte depletion via ___-mediated cytotoxicity and

___-dependent cellular cytotoxicity

ALS

Amyotrophic Lateral Sclerosis = __

weakness, atrophy, respiration

ALS

-rapid, progressive muscle ___

-muscle ___

-spasticity

-compromised ___

sensory, cognitive, autonomic

ALS-the following are spared

-___

-___

-___

progressive, fatal

ALS is ___ and usually ___

upper, lower

ALS

-a disease of __ and ___ motor neurons (patients have varying degrees of both)

stiffness, spasticity

ALS

-upper motor neuron disease → causes ___ called ___

weakness, muscle, twitching

ALS

-lower motor neuron disease → causes ___, loss of ____ (atrophy), and muscle ___ (fasciculations)

speech, swallowing, tongue

Bulbar ALS → primarily affects muscles involved in __, ___, and __ movements

sporadic, genetic

ALS can be __ or __

infection, glutamate, free radical

Sporadic ALS Etiology

-viral ___

-autoimmunity

-excitotoxicity (____ uptake)

-___ ___ toxicity

SOD1

Genetic ALS Etiology

1. mutation in ___ (superoxidase dismutase 1, which protects from damage from the toxic free radical superoxide)

aggregates

Genetic ALS Etiology

-the mutated SOD1 ____ ("forms clumps in brain")

TARDBP, FUS, ANG

Genetic ALS Etiology

2. mutation in ___, ___, ___ (control RNA transcription an splicing)

OPTN

Genetic ALS Etiology

3. mutation in ____ (optineurin gene) that leads to apoptosis

glutamate

ALS Disease Progression-Early Stage

Astrocytes normally remove excess ___, but in ALS this system fails → leading to increased glutamate and Ca²⁺ influx → neuronal toxicity

EAAT2

ALS Disease Progression-Early Stage

___ = glutamate transporter located on astrocytes

aggregation

ALS Disease Progression-Early Stage

-Protein ___ (e.g., SOD1 mutations) leads to mitochondrial dysfunction and impaired axonal transport

toxic

ALS Disease Progression-Symptomatic Stage

-___ factors are released from activated microglia/astrocytes

muscle

ALS Disease Progression-End Stage

-involves caspase-mediated apoptosis of motor neurons with microglial phagocytosis, leading to severe __ atrophy and respiratory failure.

Riluzole

____ (Rilutek, Exservan, Tiglutik) is a glutamate antagonist used in ALS

glutamate sodium

Riluzole

1. Main mechanism = Decreases ___ release by blocking voltage-gated ___ channels → reduces neuronal firing in glutamate pathways

reuptake

Riluzole

2. Increases ___ of glutamate

receptor

Riluzole

3. Weakly blocks glutamate __

IV

Riluzole is an oral drug that has limited BBB penetration due to P-gp efflux, whereas Edaravone is given ___, and therefore better reaches the CNS

free radical scavenger

Edaravone

-MOA = ___ ___ ___ (antioxidant that neutralizes oxidative stress to neuron damage)

SOD1

Tofersen is approved for ALS who have been identified to have mutant __

oligonucleotide, RNA

Tofersen

-an antisense ___ (ASO) that targets the __ produced by mutated SOD1 genes

production

Tofersen

-blocks transcription of RNA to stop toxic SOD1 protein ___

medicare

Tofersen

-$150,000-200,000 per year, but covered under __ for qualified patients

neuromuscular

Myasthenia Gravis is an autoimmune disease where antibodies target nicotinic acetylcholine receptors at the ___ junction

respiratory

Myasthenia Gravis (MG)

-ptosis (drooping of eyelids), diplopia (double vision), difficulty speaking/swallowing, extremity weakness

-severe disease that affects all muscles including ___

acetylcholine, MuSK

Myasthenia Gravis involves antibodies against nicotinic __ receptors and/or ___

neuromuscular junctions

MuSK

-a receptor tyrosine kinase crucial for forming and maintaining ___ ___ (the connections between nerves and muscles)

agrin, acetylcholine

MuSK

-activated by ___, a nerve derived protein, and plays a key role in clustering ___ receptors and other proteins in the synapse