title: Oxygen-glucose deprivation (OGD) and interleukin-1 (IL-1) differentially modulate cathepsin B/L mediated generation of neuroprotective perlecan LG3 by neurons.
abstract: Brain extracellular matrix (ECM) is highly degraded after cerebral ischemia. The perlecan c-terminal fragment LG3 is generated at increased levels by proteolytic processing as long as 3 days after ischemia. It has previously been shown that oxygen-glucose deprivation (OGD), reperfusion and interleukin-1 α (IL-1α) stimulate brain cells to yield increased levels of LG3. This LG3, in turn, is neuroprotective against OGD, and may therefore represent one of the brain's defenses against ischemic injury. Here, we investigate whether, in neurons, this increased LG3 is the result of increased perlecan generation and cellular release, increased protease release (to generate LG3 from previous extracellularly deposited perlecan) or both. We found that pre-synthesized perlecan may be exocytosed by neurons during OGD and de novo synthesis of perlecan is increased during reperfusion, even 24 h after OGD. Furthermore, while cathepsin L activity was seen to be marginally important to generate LG3 during normoxic conditions, cathepsin B activity was found to be important to generate increased levels of LG3 following OGD and reperfusion. On the other hand, IL-1α treatment raised levels of cathepsin L in neuronal media, and both cathepsin L and cathepsin B were demonstrated to be important for increasing LG3 levels after IL-1α treatment.
authors.affiliation: Department of Molecular and Cellular Medicine, Texas A&M College of Medicine, College Station, TX, USA.
authors.forename: Maxim G
authors.initials: MG
authors.lastname: Saini
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Bix
mesh_terms: D000818:Animals; D002401:Cathepsin B / Q000378:metabolism*; D056668:Cathepsin L / Q000378:metabolism*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology; D005089:Exocytosis; D005947:Glucose / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism
chemical_list: D019812:Heparan Sulfate Proteoglycans; D007375:Interleukin-1; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C071927:perlecan; D002401:Cathepsin B; C533915:Ctsb protein, mouse; D056668:Cathepsin L; C534278:Ctsl protein, mouse; D005947:Glucose; D010100:Oxygen