Lecture 36: Ischemia Reperfusion Flashcards
What percentage of the brain is used for signaling, and what percentage is used for maintaining cellular activity?
Signaling: 75%
Cellular activity: 25%
Are metabolic rates higher in gray or white matter?
Gray matter - neurons
Blood brain barrier
Site of entry for energy rich substrates; transporters fo uptake of glucose, monocarboxylic acids
What is the preferred energy source of the brain?
Glucose
What energy sources can be used secondarily under low glucose conditions?
Glycogen, lactate, ketone bodies
Primary neuronal cultures/co-cultures
Neurons taken up from brain; can be excitatory (glutamate) or inhibitory (GABA)
Cell lines
Immortalized, can divide due to tumor component
Samples of brain
Organelles or brain slice cultures
Surgical methods in live animals
Focal ischemia or global ischemia produced
In vivo imaging techniques
Humans; PET scans - analogs of glucose fluorescently tagged and observed in brain regions
Magnetic Resonance Spectroscopy (MRS)
Utilizes glucose labeled with radioactive isotope and obtain NMR spectra
Focal cerebral ischemia
Focal disruption of blood flow to a part of the brain due to occlusion of artery (region supplied by artery is deprived of circulation)
Global cerebral ischemia
Transient impairment of blood flow to the whole brain
What steps are taken to minimize damage to penumbra during focal ischemia?
Thrombolytic agents injected to minimize damage, during acute phase; necrosis will occur after 3 hours
What cells/neurons have the highest vulnerability to injury during global ischemia?
Hippocampal pyramidal cells of CA 1 region, pyramidal neocortical neurons (layers 3,5,6), Purkinje cells and striatal neurons
What cells/neurons are most resistant to injury during global ischemia?
CA3 cells in hippocampus, granule cells in dentate gyrus
What is the most significant consequence of ischemia injury?
Disruption of ion gradients due to impaired energy metabolism/low ATP
The influx of what ion causes overactivation of neurotransmitters and eventually activates cytotoxic pathways?
Ca2+
What harmful molecules form as a result of Ca2+ overloading?
Free radicals (NOS/RNS/ROS)
What happens to the blood brain barrier following reperfusion injury?
It becomes damaged, leaky; hemorrhage may occur; edema occurs
What is the cause of ischemic apoptosis?
Programmed cell death due to deprivation of growth factors, oxidative stress, exposure to inflammatory cytokines, damage to mitochondria
What molecules activate caspases to cause apoptosis? What is this pathway called?
FAS ligand and TNF alpha; Extrinsic Pathway
What occurs in the intrinsic pathway?
Excess Ca2+ influx disrupts homeostasis, altered calcineurin promotes apoptosis; release of cytochrome c activates caspase-3 to signal apoptosis
What are some neuroprotective strategies to treat stroke?
Thrombolytics, NMDA antagonists, GABA agonists, caspase inhibitors, omega-3 fatty acids, heat shock response, antioxidants, growth factors
Thrombolytics
Infuse TPA which re-establishes circulation, but some risk of fatal edema or hemorrhage
DHA/Omega-3 fatty acid
Beneficial in patients with coronary disease, cancer, rheumatoid arthritis; protective in ischemia; precursor of NPD1 which acts against apoptosis
