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Liposomal Encapsulated FSC231, a PICK1 Inhibitor, Prevents the Ischemia/Reperfusion-Induced Degradation of

Lindsay M Achzet1, Fanny Astruc-Diaz2, Phillip H Beske2

  • 1Department of Pharmaceutical Sciences, Washington State University Health Sciences, Spokane, WA 99202, USA.

Pharmaceutics
|May 5, 2021
PubMed

Insights

A new study shows that blocking protein-interacting with C kinase-1 (PICK1) with FSC231 prevents the loss of GluA2 AMPA receptors after stroke. This finding offers a potential therapeutic target for stroke recovery.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Ischemic stroke causes neuronal death via excitotoxicity, partly due to intracellular calcium overload.
  • Calcium-permeable AMPA receptors (AMPARs) lacking the GluA2 subunit contribute to this calcium cytotoxicity.
  • Protein-interacting with C kinase-1 (PICK1) mediates the degradation of GluA2 AMPAR subunits following oxygen-glucose deprivation/reperfusion (OGD/R).

Purpose of the Study:

  • To investigate if the PICK1 inhibitor FSC231 can prevent the OGD/R-induced degradation of the GluA2 AMPAR subunit.

Main Methods:

  • An acute rodent hippocampal slice model was used.
  • Slices were subjected to oxygen-glucose deprivation/reperfusion (OGD/R).
  • The effect of FSC231 pretreatment on PICK1-GluA2 association and GluA2 protein levels was assessed.

Main Results:

  • Pretreatment with FSC231 inhibited the OGD/R-induced association between PICK1 and GluA2.
  • FSC231 treatment during OGD/R successfully preserved total GluA2 AMPAR subunit protein levels.
  • The interaction between GluA2 and PICK1 is a key factor in reducing GluA2 levels during ischemic/reperfusion injury.

Conclusions:

  • Blocking the PICK1-GluA2 interaction with FSC231 protects against OGD/R-induced GluA2 degradation.
  • Targeting the PICK1-GluA2 pathway represents a promising therapeutic strategy for stroke.
  • Further research into PICK1 inhibitors may lead to novel stroke treatments.
Keywords:
AMPA receptorFSC231drug delivery systemischemic/reperfusion injuryliposomeprotein interacting with C kinase 1 (PICK1)

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