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Neuro Pharmacology > Cell Death > Flashcards

Cell Death Flashcards

1
Q

What are the biologically programmed theories of aging?

A
  1. Programmed Senescence
  2. Endocrine Senescence
  3. Immune Senescence
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2
Q

What are the Accumulation of errors/ damage theories of aging?

A
  1. Wear and tear theory
  2. Rate of living theory
  3. Environmental exposures theory
  4. Failure of repair & neurogenesis theory
  5. Free radical theory.
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3
Q

What is the programmed Senescence theory?

A
  1. Genetics regulate a “program”
  2. After spawning - Massive corticosteroid release - rapid deterioration and death of male and female salmon.
  3. “hayflick’s limits”
  4. Telomerase theory -shorten each time cell divides.
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4
Q

What are “Hayflick’s Limits”?

A
  1. Fibroblasts die after about 50 cell divisions.
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5
Q

What is the Endocrine Homeostasis Theory?

A
  1. Decreased HT/Pituitary/Ovarian function leads to sexual senescence in females.
  2. Decreases in additional hormones follows.
  3. Becomes harder to maintain homeostasis
    - Produce less hormones
    - Target organs less responsive
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6
Q

What is the Immune Homeostasis Theory?

A

Changes in the immune system lead to increased vulnerability to infectious diseases, that over time leads to senescence.

  • Decreased T cells
  • Increased autoimmune shit
  • Involution of thymus
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7
Q

What is the Accumulation of Damage and Errors Theory?

A
  1. Cell functions depend on oxygen/glucose utilization. Accumulating cellular debris causes “wear and tear”
  2. Live fast, die young theory
  3. Failure of one physiological system starts chain.
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8
Q

What is the Rate of Living Theory?

A
  1. All cells have a metabolic “bank account” (calories)
  2. Once cells have consumed systems begin to fail.
  3. Greater an organisms rate of oxygen basal metabolism shorter its lifespan
  4. supported by caloric restriction studies.
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9
Q

Failure of Neurogenesis Theory?

A
  1. In some parts of brain (Hippocampus, olfactory bulb)
  2. occurs throughout lifespan
  3. crucial for synaptic plasticity, learning, and memory.
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10
Q

Failure of Endogenous Repair Mechanisms Theory?

A
  1. We are often exposed to dangerous things in environment.
  2. Neurotrophic support, DNA repair, and anti-oxidants can neutralize such effects of exposures.
  3. Neurotrophic signaling pathways get “turned off” at some stage of CNS development, but can be “turned on” in response to trauma or toxicity to CNS.
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11
Q

Oxidative Stress/Free radical Theory?

A
  1. Highly reactive free radicals contain an unpaired electron
  2. Molecules cause significant damage to any cellular membrane
  3. Slow, but persistent accumulating damage to DNA
  4. Mitochondria can be the “death switch” for neurons.
  5. Endogenous anti-oxidants can offset some oxidative stress.
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12
Q

What are the two types of cell death in the CNS?

A

Appropriate

Inappropriate.

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13
Q

What is appropriate cell death?

A
  1. Regulated by cells specific genetic program
  2. Cells die by APOPTOSIS
  3. Occurs as a part of normal brain development
  4. Induced by Neurotrophic Factor Withdrawal
  5. Requires multiple genes and synthesis of new proteins.
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14
Q

What is inappropriate cell death?

A
  1. Apoptotic (active) or Necrotic (passive)
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15
Q

What is the active portion of Inappropriate cell death?

A
  1. Apoptosis occurs following exposure to a mild cellular stressor, and neurons actively die.
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16
Q

what is the passive portion of Inappropriate cell death?

A
  1. Necrosis occurs when cells are placed in toxic environments and passively die (Low O2, High temp, trauma, toxicants, disease)
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17
Q

What is Apoptosis?

A

“Cell Suicide”

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18
Q

What is the intrinsic pathway of apoptosis?

A
  1. Starts w/ mitochondrial impairment, and increases activity of pro-apoptotic proteins such as B-Cell lymphoma2-associated protein X (BAX) and BCL-associated death promoter (BAD).
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19
Q

What does BAX and BAD do?

A
  1. Increase mitochondrial membrane permeability and cause release of additional apoptotic factors, that then activate proteolytic enzymes including the Capases and Calpains which degrade cellular constituents.
20
Q

What is the extrinsic pathway of apoptosis?

A
  1. Starts w/ death signals that bind to plasma membrane receptors initiating a different cascade.
21
Q

What do Microglia do?

A

Scavenge what is left of cells but these cells can also cause secondary brain damage.

22
Q

What is the difference between Microglia and Necrosis?

A
  1. Microglia engulf cellular components

2. Necrosis everything explodes.

23
Q

What is necrosis?

A
  1. Severe disruption of cellular homeostasis leads to “passive” cell death.
  2. Can be induced by extracellular stuff
  3. Cellular SWELLING is followed by rupture of all cell membranes.
  4. Cellular constituents are “dumped” into the areas surrounding dying cells, causing secondary damage to innocent “by-stander” cells.
  5. Necrosis is associated w/ robust inflammation and microglial infiltration into the area of cell death.
24
Q

What is characteristic of ROS?

A
  1. Essential for life, cellular metabolism of oxygen can also generate toxic free radical species that contain highly reactive unpaired electrons (ROS)
  2. In neurons Ca must be buffered appropriately
  3. Ca overload leads to mitochondrial dysfunction, oxidative stress, ROS generation, cell death, and inflammation.
  4. Neuorns particularly vulnerable b/c
    - High metabolic demand
    - Little capacity to make or store energy
25
Q

Why is mitochondrial production of ATP essential for normal neuronal function?

A
  1. If glucose or oxygen availability is reduced, mitochondria lose the ability to make ATP, and calcium buffering systems fail.
  2. If no ATP glutamate sticks in the synapse and keeps signaling. Stroke - blood flow and oxygen to mitochondria is impaired.
26
Q

What does accumulation of ROS cause?

A

Damage to DNA, Lipids, and Proteins in a feed-forward manner.

27
Q

What are the Lipid Peroxidation Products?

A
  1. Malondialdehyde (MDA) and 4-Hydroxynonenal (4-HNE)

2. Damage cellular membranes, increasing vulnerability to further damage.

28
Q

What is the Fenton Reaction?

A
  1. Fe catalyzes H2O2 to Hydroxyl Radical
29
Q

What does Superoxide Dismutatse convert Superoxide Radical to?

A
  1. H2O2
30
Q

What does adding Argining to Superoxide Radical do?

A
  1. Peroxynitrite Radical
31
Q

What does Catalse do to H2O2?

A

H2O + O2

32
Q

What does Glutathione Peroxidase do to H2O2?

A

H2O

33
Q

What is Excitotoxicity?

A

Calcium overload toxicity

  • most well studied type of cell death
  • Many in vitro and in vivo studies
  • Occurs in the brain following ischemia (global or focal) or traumatic brain injury (TBI)
34
Q

What does delayed excitotoxicity lead to?

A
  1. Inflammation in the CNS and a delayed increase in apoptosis - A lot of necrosis comes out of this.
35
Q

What does Failure of Glutamate and Ca buffering lead to?

A

Necrosis

  1. Mg leaves, NMDA receptor activated, opening of Ca channels through depolarization.
  2. Glutamate released in the synapse would be taken up through EEAT in normal cells
  3. Failure of ATP that doesnt happen and keeps interacting w/ receptors and more and more Ca goes into cell
  4. Ca lead to stuff that will chew the cell up.
36
Q

What are the Calcium Buffering Systems?

A
  1. ATP-Dependent Ca uptake pumps.
  2. Cytosolic Calcium Sensors (Calmodulin)
  3. Cytosolic Calcium Binding Proteins (Calbindin)
37
Q

What is Ischemic Stroke?

A
  1. Lack of blood flow reduces tissue oxygenation (ischemia) and deprives neurons of glucose, their only source of energy.
  2. If a neuron has no glucose, mitochondria can’t make ATP.
  3. Ca, and GLU buffering systems fail.
  4. Energy failure causes disruption of Ca homeostasis, leading to excitotoxicity, free radicals
  5. Uncontrolled NT release
  6. Anti-Platelet drugs and daily aspirin used prophylactically.
38
Q

what is the association b/w Stroke and Excitotoxicity?

A

Decreased O2, Glucose and ATP

  1. Increased Glutamate release and NMDAr agonism
    - Increased Ca influx
    - Decreased EAAT activity due to lack of ATP
  2. Increased ACh release and alpha 7 nAChR agonism
    - Increased Ca influx.
  3. Ca dependent activation of Lipases, DNAases, and Proteases.
  4. Increased Free radical production due to mitochondrial impairment.
39
Q

What are pharmacological strategies in neurodegeneration?

A
  1. “neuroprotection” versus “neurorestoration”
  2. Neuroprotection is relatively easy to study
  3. Neurorestoration is a great idea
  4. Brain tries to mount a defense to age/trauma
  5. Injury can produce growth inhibitory molecules.
40
Q

What are NMDA receptor antagonists for neurodegeneration?

A

MK801 (Dizocilpine), many others

  1. Sounds easy, but a very difficult target
  2. Memantine (Namenda)
41
Q

Can Alpha 7 nAChR antagonists be used for neurodegeneration?

A

YES

42
Q

What are the Calcium Channel Antagonists used for neurodegeneration?

A

Pre- and Post-synaptic stabilization

  1. Nifedipine, Nimodipine
  2. Increased activity/expression of Ca binding proteins.
43
Q

What are the Anti-oxidants/free radical scavangers used for neurodegeneration?

A
  1. Mitochondrial stabilizers
  2. Vit A,C,E selenium
  3. Estrogen
  4. Melatonin (direct and indirect)
  5. Red beans, Lycopene, Blueberries, Curcumin
  6. Catechins (Flavinoids; green tea, chocolate)
  7. Resveratrol (Red wine)
44
Q

What are the anti inflammatory drugs used for neurodegenration?

A
  1. IBU, COX inhibitors, Microglia inhibitors.
  2. COX1 appears to be a target.
  3. No efficacy for COX2 inhibitors in AD.
45
Q

What neurotrophic factors are used for neurodegeneration?

A
  1. GDNF - PD (DA selectivity)
  2. NGF - AD (ACh selectivity)
  3. Pluripotent neuronal stem cells.
46
Q

What omega 2 FA are used?

A
  1. DHA and EPA
  2. Anti-oxidants + GPCR modulators
  3. Predatory fish have high levels, but could be problematic due to mercury, PCB, etc.
  4. Pleitrophic compounds DHA and EPA are plant products that come from algae and are passed up the food chain.
47
Q

What is Crypthecondinium Cohnii?

A
  1. Is a marine algae and a naturally high producer of DHA
  2. DSM’s flagship orducts, life’s DHA is found over 98% of U.S. infant formulas.
  3. DHA treatment initiated following mFPI significantly reduces brain inflammation.

Neuro Pharmacology (9 decks)

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