GalR3 activation promotes adult neural stem cell survival in response to a diabetic milieu.
Type 2 diabetes impairs adult neurogenesis which could play a role in the CNS complications of this serious disease. The goal of this study was to determine the potential role of galanin in protecting adult neural stem cells (NSCs) from glucolipotoxicity and to analyze whether apoptosis and the unfolded protein response were involved in the galanin-mediated effect. We also studied the regulation of galanin and its receptor subtypes under diabetes in NSCs in vitro and in the subventricular zone (SVZ) in vivo. The viability of mouse SVZ-derived NSCs and the involvement of apoptosis (Bcl-2, cleaved caspase-3) and unfolded protein response [C/EBP homologous protein (CHOP) Glucose-regulated protein 78/immunoglobulin heavy-chain binding protein (GRP78/BiP), spliced X-box binding protein 1 (XBP1), c-Jun N-terminal kinases (JNK) phosphorylation] were assessed in the presence of glucolipotoxic conditions after 24 h. The effect of diabetes on the regulation of galanin and its receptor subtypes was assessed on NSCs in vitro and in SVZ tissues isolated from normal and type 2 diabetes ob/ob mice. We show increased NSC viability following galanin receptor (GalR)3 activation. This protective effect correlated with decreased apoptosis and CHOP levels. We also report how galanin and its receptors are regulated by diabetes in vitro and in vivo. This study shows GalR3-mediated neuroprotection, supporting a potential future therapeutic development, based on GalR3 activation, for the treatment of brain disorders.
Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset, Stockholm, Sweden.
Shiva
S
Mansouri
Swapnali
S
Barde
Henrik
H
Ortsäter
Mohamed
M
Eweida
Vladimer
V
Darsalia
Ulo
U
Langel
Ake
A
Sjöholm
Tomas
T
Hökfelt
Cesare
C
Patrone
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D003470:Culture Media; D004268:DNA-Binding Proteins / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005227:Fatty Acids / Q000494:pharmacology; D019004:Galanin / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000473:pathology* / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D060888:Real-Time Polymerase Chain Reaction; D044093:Receptor, Galanin, Type 3 / Q000187:drug effects / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D013936:Thymidine / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects / Q000502:physiology; D000071717:X-Box Binding Protein 1
D003470:Culture Media; D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D005227:Fatty Acids; C000717248:Hspa5 protein, mouse; D012333:RNA, Messenger; D044093:Receptor, Galanin, Type 3; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D051742:Transcription Factor CHOP; D019004:Galanin; D000255:Adenosine Triphosphate; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose; D013936:Thymidine
GalR3; diabetes; galanin; neural stem cells; neuroprotection