Acute Neuronal Injury Flashcards
What two mechanisms cause acute neuronal cell death?
Excitotoxicity
Cytotoxic edema
What is the NMDA receptor permeable to?
Na
K
Ca
What two molecules are needed to open the NMDA receptor?
Glutamate and Glycine
There are trace amounts of glycine in the CNS, so presynaptic terminals do not need to release both amino acids
What binding sites are located within the pore of the NMDA receptor?
Zn
Mg
PCP - dissociative anesthetic binding site
Binding of any of these sites blocks the channel
What is the physiological importance of the Mg binding site in the NMDA channel?
Acts as a voltage gate
At resting mp, Mg will bind the site and prevent ion flow
At a depolarized mp, Mg will be forced out of its binding site and ions can flow through
Under what conditions is the NMDA channel open?
Glycine and Glutamate bound
Depolarized mp
Why doesn’t neuron volume change during normal neuronal changes in ion permeability?
Ion fluxes during physiological activity involve much less than 1% of the ions available
Active ion transport mechanisms correct any small changes
What is cytotoxic edema?
Increased intracellular volume caused by water movement from extracellular to intracellular compartments
What are the three consequences to loss of primary and secondary active transport mechanisms due to ATP depletion?
Ion concentration gradients break down, normal resting mp cannot be maintained
Glutamate reuptake transporters are no longer functional
NMDA glutamate receptors become tonically activated –intracellular Ca concentration increases
What causes calcium toxicity?
Stimulation of Ca-regulated enzymes, which cause damage when activate pathologically
Ca induced generation of free radicals which damage the cell membrane
What causes cytotoxic edema?
Greatly increased membrane permeability due to opening of voltage- and ligand-gated channels causes influx of ions
This increases the osmotic pressure inside neurons
Describe the timeline for neuronal cell death
Excitotoxicity - minutes to hours
Inflammation triggered by initial injury - hours to days
Apoptosis due to mitochondrial damage - days
What is a penumbra?
Region of tissue that surrounds the central core of tissue damaged by acute injury
Susceptible to secondary injury by glutamate and inflammatory signals released by cells in the core
