Abstract
Recent studies have demonstrated that adiponectin (APN) attenuates cerebral ischemic/reperfusion via globular adiponectin (gAD). However, the therapeutic role of gAD in cerebral ischemic injury in type 1 diabetes mellitus (T1DM) remains unclear. Our results showed that gAD improved neurological scores and reduced the infarct volumes in the 8-week T1DM (T1DM-8W) mice, but not in the 2-week T1DM (T1DM-2W) mice. Moreover, the ischemic penumbra APN levels increased and peaked in T1DM-2W mice, and reduced to normal in T1DM-8W mice, while the APN receptor 1 (AdipoR1) expression change was the opposite. Administration of rosiglitazone in T1DM-2W mice up-regulated the expression of AdipoR1 and restored the neuroprotection of gAD, while intracerebroventricular injection of AdipoR1 small interfering RNA (siRNA) in T1DM-8W mice reversed it. Furthermore, the expression of p-PERK, p-IRE1 and GRP78 were increased whereas the expressions of CHOP and cleaved caspase-12 as well as the number of apoptotic neurons were decreased after gAD treatment in T1DM-8W mice. These beneficial effects of gAD were reversed by pretreatment with AdipoR1 siRNA. These results demonstrated a dynamic dysfunction of APN/AdipoR1 accompanying T1DM progression. Interventions bolstering AdipoR1 expression during early stages and gAD supplementation during advanced stages may potentially reduce the cerebral ischemic injury in diabetic patients.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adiponectin / genetics
-
Adiponectin / metabolism
-
Adiponectin / pharmacology*
-
Animals
-
Apoptosis / drug effects
-
Brain Ischemia / complications
-
Brain Ischemia / drug therapy*
-
Brain Ischemia / genetics
-
Brain Ischemia / metabolism
-
Caspase 12 / genetics
-
Caspase 12 / metabolism
-
Diabetes Mellitus, Experimental / complications
-
Diabetes Mellitus, Experimental / drug therapy*
-
Diabetes Mellitus, Experimental / genetics
-
Diabetes Mellitus, Experimental / metabolism
-
Diabetes Mellitus, Type 1 / drug therapy
-
Diabetes Mellitus, Type 1 / genetics
-
Diabetes Mellitus, Type 1 / metabolism
-
Diabetes Mellitus, Type 1 / pathology
-
Endoplasmic Reticulum Chaperone BiP
-
Gene Expression Regulation
-
Heat-Shock Proteins / genetics
-
Heat-Shock Proteins / metabolism
-
Humans
-
Hypoglycemic Agents / pharmacology
-
Injections, Intraventricular
-
Male
-
Membrane Proteins / genetics
-
Membrane Proteins / metabolism
-
Mice
-
Mice, Inbred C57BL
-
Neurons / drug effects
-
Neurons / metabolism
-
Neurons / pathology
-
Neuroprotective Agents / pharmacology
-
Protein Serine-Threonine Kinases / genetics
-
Protein Serine-Threonine Kinases / metabolism
-
RNA, Small Interfering / administration & dosage
-
RNA, Small Interfering / genetics
-
RNA, Small Interfering / metabolism
-
Receptors, Adiponectin / agonists
-
Receptors, Adiponectin / antagonists & inhibitors
-
Receptors, Adiponectin / genetics*
-
Receptors, Adiponectin / metabolism
-
Reperfusion Injury / complications
-
Reperfusion Injury / drug therapy*
-
Reperfusion Injury / genetics
-
Reperfusion Injury / metabolism
-
Rosiglitazone
-
Signal Transduction
-
Thiazolidinediones / pharmacology
-
Transcription Factor CHOP / genetics
-
Transcription Factor CHOP / metabolism
-
eIF-2 Kinase / genetics
-
eIF-2 Kinase / metabolism
Substances
-
Adiponectin
-
Adipoq protein, mouse
-
Ddit3 protein, mouse
-
Endoplasmic Reticulum Chaperone BiP
-
HSPA5 protein, human
-
Heat-Shock Proteins
-
Hspa5 protein, mouse
-
Hypoglycemic Agents
-
Membrane Proteins
-
Neuroprotective Agents
-
RNA, Small Interfering
-
Receptors, Adiponectin
-
Thiazolidinediones
-
adiponectin receptor 1, mouse
-
Rosiglitazone
-
Transcription Factor CHOP
-
Ern2 protein, mouse
-
PERK kinase
-
Protein Serine-Threonine Kinases
-
eIF-2 Kinase
-
Casp12 protein, mouse
-
Caspase 12