Neuroprotective mechanism of NMDAR activation

PI3-Kinase Cascade
The PI3-Kinase/Akt pathway is activated by NMDARs in many neurons.
Akt goes onto inhibit/downregulate glycogen synthase Kinase 3 beta (GSK3-beta) (which plays a role in apoptotic signalling pathways), Bcl-2 (Beta-cell lymphoma-2) associated death promotor (BAD) (also involved in apoptosis) and p53, which is known to be involved in a number of pro-apoptotic pathways including Bcl-2 associated X-protein (BAX).
  • In laymens, it prevents the combining of BAD/BAX with other proteins so they cannot form the active complexes.

Antioxidant defences

The balance of reactive oxygen species (ROS) production and neutralisation is important to protect against cellular damage and death.  NMDAR activity seems to play a role in the regulation of a cell’s vulnerability to oxidative stress: neurons with higher NMDAR activity withstand oxidative damage more than electrically quiet neurons.  Conversely, if NMDAR activity is blocked, cells become highly vulnerable to oxidative damage.

The proposed mechanism behind this is that synaptic activity exerts changes in the thioredoxin-peroxiredoxin system. (Thioredoxin reduces (chemically) hyperoxidised peroxiredoxins (antioxidant enzymes)- freeing them to reduce ROS.)  Synaptic activity also promotes a series of gene-expression changes that boost anti-oxidant defenses e.g. inhibition of thioredoxin inhibitor TXNIP (a FOXO target gene).

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