Lecture 25: Ischemia Reperfusion Flashcards
1
Q
Describe energy metabolism in the brain
A
- Human brain expensive/inefficient in terms of energy usage.
- Only 2% body weight but uses 20% energy consumed.
- ATP consumption per gm/min used in signaling = energy used by leg muscle to complete a marathon.
- Approx. 75% used for signaling, rest 25% used for maintaining essential cellular activity.
- Metabolic rates higher in gray matter than in white matter.
2
Q
Describe substrates for cerebral energy metabolism
A
- Energy rich substrates enter brain from blood via blood brain barrier
- Endothelial cells of BBB and brain cells have transporters for uptake of glucose and monocarboxylic acids
- Transporters unique to diff cell types, determine specific substrate(s) used by them
- Altered during development and under pathological conditions
- Cerebral metabolic rate increases during early development and plateaus after maturation
3
Q
Describe brain energy metabolism
A
- Glucose, glycogen, monocarboxylic acids (lactate) and ketone bodies (acetoacetate and beta hydroxy butyrate).
- Respiratory quotient (CO2 produced/O2 consumed) shows that carbohydrate oxidation main source of energy in brain.
- Glucose essential for brain, most imp energy source for adult brain
- Lactate imp during immediate post natal period
- Ketone bodies used during suckling due to high fat content of milk
- Glycogen actively utilized by nerve cells (2% of total metabolic rate compared to glucose).
4
Q
Describe regulation of cerebral metabolic rate
A
- Continuous cerebral circulation is required to sustain brain function.
- Both excitatory and inhibitory neurons consume equivalent energy.
- Oxygen concentration in cerebral venous blood is lower than in cerebral arterial blood.
- High extraction of O2 by brain cells (50-70%). Glucose extracted only 10%.
- See Slide 7
5
Q
What are the 5 main metabolic pathways?
A
- Glycolysis
- Glycogenolysis
- Pentose phosphate shunt
- Malate Aspartate shuttle
- TCA cycle
6
Q
I don’t totally follow what’s being described, but describe that experimental models slide.
A
- Primary neuronal cultures or co-cultures
- Excitatory - Cerebellar granule neurons (glutamate)
- Inhibitory - Cortical neurons (GABA)
- Cell lines
- Brain
– Isolated organelles: Synaptosomes, Mitochondria, Cytosol
– Brain slice cultures - Surgical methods performed in live animals
– Middle cerebral artery occlusion – focal ischemia
– Carotid artery occlusion – global occlusion - In vivo imaging techniques (humans)
7
Q
Describe Metabolic Studies in Brain: Imaging and Spectroscopy
A
- Global imaging of whole brain: brain metabolic rates with assays of arterio-venous differences.
- Glucose and oxygen primary fuels.
- Various analogs used
- Useful technique, but effect averages out across various brain structures. Changes in small structures not detectable
8
Q
Describe Local Rates of Glucose and O2 Utilization
A
- PET Imaging (Positron Emission Tomography)
- Uses analogs of glucose (2-deoxy glucose, in experimental animals) and 2-fluoro-deoxy glucose (in humans)
- Rely on quantitative intracellular trapping of the major phosphorylated metabolite DG-6phosphate, which enables assays of the hexokinase reaction in all regions of the brain in conscious individuals.
9
Q
Describe Magnetic Resonance Spectroscopy (MRS)
A
- Utilizes glucose labeled with radioactive (3H, 14C, 11 C) or stable isotope (13C)
- Allows assessment of glucose metabolites as they are formed in different pathways.
- Method – NMR spectra obtained. Each very characteristic and unique
- Used to determine metabolism of precursors via specific neuronal and glial pathways.
10
Q
Summarize what the hell we just covered so far…I guess.
A
- Brain energy metabolism has several unique features:
– High metabolic rate
– Limited intrinsic energy stores
– Critical dependence on circulation to provide glucose and other fuels - In vivo imaging techniques useful for studying brain metabolism in humans
11
Q
What are lifestyle results of Ischemia and Brain Infarction
A
- According to WHO, 15 million people have a stroke each year, 6 million of whom die.
- Survivors have severe and permanent disabilities.
- 2nd leading cause of death and disability worldwide.
- No good treatments available
- Outcome depends on which particular part of the brain and which cell types affected
12
Q
What are two types of ischemia?
A
- Focal cerebral ischemia: focal disruption of blood flow to a part of the brain (e.g., due to occlusion of an artery by an embolus).
- Global cerebral ischemia: Transient impairment of blood flow to whole brain (e.g., during cardiac arrest).
13
Q
Describe focal ischemia
A
- Accounts for majority of strokes
- Occurs when an artery supplying a brain region is occluded by an embolus, thrombus or platelet plug
- Ischemic stroke is an emergency
- The area of infarction typically less than the entire distribution of the occluded artery
- Due to collateral circulation
- Injury depends on duration and degree of vascular occlusion and the magnitude of collateral blood supply
- Ischemic core or umbra…Injury grows over time – electrophysiological, molecular, metabolic, and perfusion disturbances in the area
- Rim/area surrounding core is penumbra. An area of reduced cerebral flow, impaired protein synthesis, preserved energy metabolism.
- Prompt restoration of perfusion in penumbra by injection of thrombolytic agents key to minimizing damage in this region.
- In acute phase, focus is on saving penumbra
- Window of opportunity short
- If adequate blood supply not established within 3 hours necrosis extends to penumbra (area of reversible damage).
- See Slides 19-21
14
Q
Describe global ischemia
A
- Transient loss of blood flow to the entire brain as in cardiac arrest followed by resuscitation.
- Neurons more sensitive than glial cells
- Neurons present within same vascular position and juxtaposed to each other may be selectively vulnerable or resistant to insult.
- Selective loss of vulnerable neuronal populations
- Hippocampal pyramidal cells of CA 1 region, pyramidal neocortical neurons (layer 3, 5 and 6), Purkinje cells and striatal neurons have highest vulnerability
- CA3 in hippocampus and granule cells in dentate gyrus resistant
- See Slides 23-24
15
Q
Describe the biochemistry of ischemia
A
- Disruption of blood flow
- Reduction or absence of O2 and glucose supply to brain
- Impaired energy metabolism
- Reduction in ATP levels
- Ion pump dysfunction (pumps need ATP)
- Disruption of ion gradients
- Membrane depolarization
- Opening of voltage-gated channels
- Cascade of subsequent signaling events
- Cell death in a given brain region
