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.
Highlights
Stroke and ischemic heart disease were responsible for 15.2 million deaths in 2016
FSC231 has been utilized in studies examining pulmonary hypertension [28,29], acute liver injury [30], hyperalgesia [31,32], willed-movement in focal cerebral ischemia
FSC231 has been utilized in studies examining pulmonary hypertension [28,29], acute liver injury [30], hyperalgesia [31,32], willed-movement in focal cerebral ischemia [33], and cocaine-seeking behavior [34]
Summary
Stroke and ischemic heart disease were responsible for 15.2 million deaths in 2016. Ischemic stroke is the second leading cause of death worldwide [1]. The most prevalent form of stroke, occurs when blood flow is decreased or absent due to vessel occlusion [2]. While it is necessary to reintroduce blood flow to the infarcted area, this act results in further damage by inflammation, oxidative stress, and delayed neuronal death (DND) within vulnerable neuronal populations, including CA1 hippocampal pyramidal neurons [3,4]. Disrupting the ionic balance leads to excessive release of neurotransmitters, including glutamate, which are unable to be effectively cleared from the synapse [5].
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have