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Mechanisms of Neuronal Death (Excitotoxicity (Raised intracellular Ca2+…
Mechanisms of Neuronal Death
Necrosis
occurs after severe insults
Ischaemia
i.e. Non physiological causes
NMDAR activation enhances intracellular Ca2+
#
Inflammation
cytoplasm and mitochondria swelling
Loss of PM integrity
Activating NOS increasing mitochondrial Ca2+
Superoxide generation + formation of peroxynitrite
Cellular damage (to DNA)
activation of poly-ADP-ribose polymerase
Mitochondrial Ca2+ accumulation + oxidative damage
PTP activation > cell death
Apoptosis
Mild excitotoxic insults
physiological stimuli
NMDAR activation by ambient glutamate concentrations
Mitochondrias Ca2+ increased
free radicals produced
Mitochondria may release cytochrome C (+ other cell death mediators
Relatively preserved ATP production
Excitotoxicity
Actiation of AMPA
depolarises cell (removes Mg2+ block of NMDA)
permits Ca2+ entry
opens voltage-dependent Ca2+ channels
inhibits glutamate uptake (increased extracellular concentration)
formation of ROS enhanced
Reactive Oxygen Species
Glutamate = ubiquitous neurotransmitter
highly toxic to neurons
activates NMDA, AMPA and metabotropic receptos
Mitochondria + ER normally monitor Ca levels
mitochondrial stores overloaded
reduced ATP synthesis
decreased energy for membrane pumps
Raised intracellular Ca2
+
glutamate release from nerve terminals
activation of proteases + lipases
membrane damage
activation of NOS
generates free radicals
damages biomolecules