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Neuro B1 - WLB > Week 1 - Drewes > Flashcards

Week 1 - Drewes Flashcards

1
Q

What are the majory pathways for energy metabolism in the brain?

A
  1. Glycolysis

2. TCA (Kreb’s Cycle) and Oxidative Phosphorylation

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2
Q

What is the role of brain glycogen?

A

Energy substrate held in reserve, but is also dynamically involved in higher functions such as memory.

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3
Q

What are the key regulatory sites in brain glucose metabolism?

A
  • Hexokinase (Glucose –> Glucose-6-P)
  • Phosphofructokinase (Fructose-6-P –> Fructose-1,6,-P)
  • Pyruvate kinase
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4
Q

For each mole of glucose consumed by the brain, how much is converted to lactate under aerobic conditions? Under anaerobic (stroke) conditions?

A

O2 consumption/6 = Glucose equivalent of O2 consumption
(To oxidize 1 glucose, you need 6 oxygen due to 1:6 molar ratio)

Glucose utilization - Glucose equivalent of O2 consumption = LACTATE

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5
Q

Are there alternative pathways of glucose metabolism?

A
  • Pentose Phosphate Pathway

- Glycogen synthesis/breakdown

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6
Q

How is brain metabolism of any substrate measured?

A

Using 2-Deoxyglucose (or other substrates) as a marker when radioactively labeled and in tracer concentrations you can measure substrate in different regions and monitor the substrate utilization.

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7
Q

Is the arteriovenous difference of a substance sufficient to determine the rate of consumption?

A

Yes, for glucose you can use the: Cerebral Metabolic Rate for Glucose (CMR-G = (A-V)F/W) to measure rate of consumption.

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8
Q

Is cerebral blood flow related to metabolism? To local brain functional activity?

A

Yes, cerebral blood flow is linked to metabolism and the neurovascular unit.

Neuron stimulates adjacent Astrocyte –> PLA2 –> PGE2 (Prostaglandin) –> Capillary dilates!

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9
Q

What substrates can replace glucose? Under what circumstances does this occur?

A

Acetoacetate & D-3-Hydroxybutyrate

  • Starvation, Fasting, or Extreme Ketogenic diet in Adults
  • Lactation in Neonates (suckling)
  • Hibernation
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10
Q

How is metabolism altered under pathological states such as hypoxia, ischemia, hypoglycemia, hyperammonemia, depression, etc.?

A

Hypoxia - same/higher CMRG, decreased CMRO2
Ischemia - increased CMRG, decreased CMRO2
Hypoglycemia - decreased CMRG, same CMRO2(?)
Depression - no clue!

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11
Q

What is the energy budget of the brain?

A

3/4 of Plasma glucose

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12
Q

What is the lactate shuttle?

A

Astrocyte-Neuron Lactate Shuttle (ANLS):
-Astrocytes can transport excess lactate to nearby neurons for further conversion to pyruvate or further metabolism by oxidative phosphorylation to CO2 and H2O or removed from the brain as lactate flowing in blood.

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13
Q

What are the roles of astrocytes in brain metabolism?

A

Help cycle glutamate and supply the energy used by Na+/K+ ATPase to expel Na+

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14
Q

Describe a tight junction and its components.

A
  • Where two endothelial cells come together.

- Held together by claudin, junctional adhesion molecule (JAM), and occludin.

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15
Q

What are the key features of the blood-brain barrier?

A
  • Tight junctions between endothelial cells.
  • Endothelial cell membranes are asymmetrical (Luminal-inside, Abluminal-outside).
  • Enzymatic barrier in cytoplasm
  • Basement Membrane
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16
Q

Compare the BBB to the NVU (neurovascular unit).

A
17
Q

What are the basic transporters for nutrient influx?

A
  1. GLUT1 (glucose)
  2. Monocarboxylate Transporter-1 (MCT1 - lactic acid)
  3. LAT1/MFSD2A (amino acids)
  4. ENT1/CNT2 (adenosine nucleoside)
  5. FATP1 (fatty acid)
  6. CT1 (creatine)
  7. Aquaporin Channel (H20)
18
Q

What are the major transporters for efflux of drugs?

A

P-glycoprotien, Erlotinib

19
Q

When is the BBB/NVU formed?

A

At the very beginning of development when the first vessels appear.
Mouse: embryonic brain day 12.5/21
Human: first few weeks after fertilization

20
Q

What is the link between the brain blood flow and the NVU?

A

The neurovascular unit is responsible for regulating the brain blood flow.

21
Q

What are the diseases that are linked to dysfunction of the NVU that were discussed in class?

A
  • MS
  • Alzheimer’s
  • Epilepsy
  • Glucose transporter dysfunction
  • MCT-1 deficiency
  • Rabies
  • Pathogenic infections (Meningitis, bacterial, parasitic)
  • Viral Infections (HIV)
  • Late-stage neurological trypanosomiasis (Sleeping Sickness)
  • Progressive Multifocal Leukoencephalopathy (PML)
22
Q

What are the pathways between blood and brain?

A

Transcytosis (via receptors)
Immune cell migration (via diapedesis)
Transporters

23
Q

What is the “Trojan Horse” model for drug delivery into the CNS?

A

Create drugs that bind to endothelial receptors in the NVU.

-Ex. Paclitaxel, ANG1005 (Angiochem) bind to LRP-1 allowing them to effectively cross the BBB.

24
Q

How do cells of the immune system traffic into the brain?

A

DIAPEDESIS:

  • Rolling (weak adhesion)
  • Emigration (strong adhesion)
  • Inflammatory Signals (chemokines) allow tight adhesion and passage through the brain endothelium and basal lamina
25
Q

What cells are involved in making CSF?

A

Ependymal cells of the choroid plexus produce more than two thirds of CSF.

26
Q

What transporters are essential for CSF formation?

A
  • Aquaporins
  • Na+/K+ ATPase
  • NKCC pump
27
Q

What drugs reduce CSF production?

A
  • Acetazolamide
  • Ouabain
  • Furosemide
28
Q

What drug inhibits Carbonic Anhydrase in order to reduce CSF production?

A

ACETAXOLAMIDE inhibits CA → less HCO3 in the CSF → less osmotic → less H20 flowing into the CSF

29
Q

What drug inhibits NKCC pumps in order to reduce CSF production?

A

FUROSEMIDE inhibits NKCC pumps:

  • Cl- cannot enter the CSF, therefore cannot make the CSF hyperosmotic
  • Thus H20 isn’t forced into CSF –> thus reducing edema.
30
Q

What drug inhibits Na+/K+ ATPase in order to reduce CSF production?

A

OUABAIN inhibits Na+/K+ ATPase:

-Na+ cannot enter the CSF, therefore cannot make the CSF hyperosmotic; thus reducing edema

31
Q

What is the Glymphatic System of the Brain?

A
  • “Garbage Truck of the Brain”

- Supports interstitial fluid and solute clearance from the brain.

32
Q

What does the Glymphatic System do?

A
  • Convective glymphatic fluxes of CSF and ISF propel the waste products of neuron metabolism into the paravenous space.
  • They are then directed into lymphatic vessels and
  • Finally returned to the general circulation for clearance by the kidney and liver.
  • During sleep → brain cells shrink → increase fluid space between cells → extra fluid is forced in the paravenous space carrying its waste with it
  • 4-5x faster when you sleep!

Neuro B1 - WLB (8 decks)

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