Liposomal encapsulated FSC231, a PICK1 inhibitor, prevents the ischemia/reperfusion-induced degradation of GluA2-containing AMPA receptors

Lindsay M. Achzet, Fanny Astruc-Diaz, Phillip H. Beske, Nicholas R. Natale, Travis T. Denton, Darrell A. Jackson

Research output: Contribution to journalArticlepeer-review

Abstract

Strokes remain one of the leading causes of disability within the United States. Despite an enormous amount of research effort within the scientific community, very few therapeutics are available for stroke patients. Cytotoxic accumulation of intracellular calcium is a well-studied phenomenon that occurs following ischemic stroke. This intracellular calcium overload results from excessive release of the excitatory neurotransmitter glutamate, a process known as excitotoxicity. Calcium-permeable AMPA receptors (AMPARs), lacking the GluA2 subunit, contribute to calcium cytotoxicity and subsequent neuronal death. The internalization and subsequent degradation of GluA2 AMPAR subunits following oxygen-glucose deprivation/reperfusion (OGD/R) is, at least in part, mediated by protein-interacting with C kinase-1 (PICK1). The purpose of the present study is to evaluate whether treatment with a PICK1 inhibitor, FSC231, prevents the OGD/R-induced degradation of the GluA2 AMPAR subunit. Utilizing an acute rodent hippocampal slice model system, we determined that pretreatment with FSC231 prevented the OGD/R-induced association of PICK1-GluA2. FSC231 treatment during OGD/R rescues total GluA2 AMPAR subunit protein levels. This suggests that the interaction between GluA2 and PICK1 serves as an important step in the ischemic/reperfusion-induced reduction in total GluA2 levels.

Original languageEnglish
Article number636
JournalPharmaceutics
Volume13
Issue number5
DOIs
StatePublished - 2021

Keywords

  • AMPA receptor
  • Drug delivery system
  • FSC231
  • Ischemic/reperfusion injury
  • Liposome
  • Protein interacting with C kinase 1 (PICK1)

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