The metabolite GLP‐1 (9‐36) is neuroprotective and anti‐inflammatory in cellular models of neurodegeneration
Abstract Glucagon‐like peptide‐1 (GLP‐1) is best known for its insulinotropic action following food intake. Its metabolite, GLP‐1 (9‐36), was assumed biologically inactive because of low GLP‐1 receptor (GLP‐1R) affinity and non‐insulinotropic properties; however, recent studies contradict this assumption. Increased use of FDA approved GLP‐1 analogues for treating metabolic disorders and neurodegenerative diseases raises interest in GLP‐1 (9‐36)’s biological role. We use human SH‐SY5Y neuroblastoma cells and a GLP‐1R over‐expressing variety (#9), in both undifferentiated and differentiated states, to evaluate the neurotrophic/neuroprotective effects of GLP‐1 (9‐36) against toxic glutamate exposure and other oxidative stress models (via the MTS, LDH or ROS assays). In addition, we examine GLP‐1 (9‐36)’s signaling pathways, including cyclic‐adenosine monophosphate (cAMP), protein kinase‐A (PKA), and 5’ adenosine monophosphate‐activated protein kinase (AMPK) via the use of ELISA, pharmacological inhibitors, or GLP‐1R antagonist. Human HMC3 and mouse IMG microglial cell lines were used to study the anti‐inflammatory effects of GLP‐1 (9‐36) against lipopolysaccharide (LPS) (via ELISA). Finally, we applied GLP‐1 (9‐36) to primary dissociation cultures challenged with α‐synuclein or amyloid‐β and assessed survival and morphology via immunochemistry. We demonstrate evidence of GLP‐1R, cAMP, PKA, and AMPK‐mediated neurotrophic and neuroprotective effects of GLP‐1 (9‐36). The metabolite significantly reduced IL‐6 and TNF‐α levels in HMC3 and IMG microglial cells, respectively. Lastly, we show mild but significant effects of GLP‐1 (9‐36) in primary neuron cultures challenged with α‐synuclein or amyloid‐β. These studies enhance understanding of GLP‐1 (9‐36)’s effects on the nervous system and its potential as a primary or complementary treatment in pathological contexts..
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:159 |
|---|---|
| Enthalten in: |
Journal of Neurochemistry - 159(2021), 5, Seite 867-886 |
| Beteiligte Personen: |
Li, Yazhou [VerfasserIn] |
|---|
| Anmerkungen: |
Copyright © 2021 International Society for Neurochemistry |
|---|
| Umfang: |
20 |
|---|
| doi: |
10.1111/jnc.15521 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
WLY009035699 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | WLY009035699 | ||
| 003 | DE-627 | ||
| 005 | 20231111175853.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 230217s2021 xx |||||o 00| ||und c | ||
| 024 | 7 | |a 10.1111/jnc.15521 |2 doi | |
| 028 | 5 | 2 | |a 2023-11-11_JNC_2021_159_5.zip.xml |
| 035 | |a (DE-627)WLY009035699 | ||
| 035 | |a (WILEY)JNC15521 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 100 | 1 | |a Li, Yazhou |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a The metabolite GLP‐1 (9‐36) is neuroprotective and anti‐inflammatory in cellular models of neurodegeneration |
| 264 | 1 | |c 2021 | |
| 300 | |a 20 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Copyright © 2021 International Society for Neurochemistry | ||
| 520 | |a Abstract Glucagon‐like peptide‐1 (GLP‐1) is best known for its insulinotropic action following food intake. Its metabolite, GLP‐1 (9‐36), was assumed biologically inactive because of low GLP‐1 receptor (GLP‐1R) affinity and non‐insulinotropic properties; however, recent studies contradict this assumption. Increased use of FDA approved GLP‐1 analogues for treating metabolic disorders and neurodegenerative diseases raises interest in GLP‐1 (9‐36)’s biological role. We use human SH‐SY5Y neuroblastoma cells and a GLP‐1R over‐expressing variety (#9), in both undifferentiated and differentiated states, to evaluate the neurotrophic/neuroprotective effects of GLP‐1 (9‐36) against toxic glutamate exposure and other oxidative stress models (via the MTS, LDH or ROS assays). In addition, we examine GLP‐1 (9‐36)’s signaling pathways, including cyclic‐adenosine monophosphate (cAMP), protein kinase‐A (PKA), and 5’ adenosine monophosphate‐activated protein kinase (AMPK) via the use of ELISA, pharmacological inhibitors, or GLP‐1R antagonist. Human HMC3 and mouse IMG microglial cell lines were used to study the anti‐inflammatory effects of GLP‐1 (9‐36) against lipopolysaccharide (LPS) (via ELISA). Finally, we applied GLP‐1 (9‐36) to primary dissociation cultures challenged with α‐synuclein or amyloid‐β and assessed survival and morphology via immunochemistry. We demonstrate evidence of GLP‐1R, cAMP, PKA, and AMPK‐mediated neurotrophic and neuroprotective effects of GLP‐1 (9‐36). The metabolite significantly reduced IL‐6 and TNF‐α levels in HMC3 and IMG microglial cells, respectively. Lastly, we show mild but significant effects of GLP‐1 (9‐36) in primary neuron cultures challenged with α‐synuclein or amyloid‐β. These studies enhance understanding of GLP‐1 (9‐36)’s effects on the nervous system and its potential as a primary or complementary treatment in pathological contexts. | ||
| 700 | 1 | |a Glotfelty, Elliot J. |4 aut | |
| 700 | 1 | |a Karlsson, Tobias |4 aut | |
| 700 | 1 | |a Fortuno, Lowella V. |4 aut | |
| 700 | 1 | |a Harvey, Brandon K. |4 aut | |
| 700 | 1 | |a Greig, Nigel H. |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of Neurochemistry |g 159(2021), 5, Seite 867-886 |w (DE-627)WLY009026568 |x 14714159 |7 nnns |
| 773 | 1 | 8 | |g volume:159 |g year:2021 |g number:5 |g pages:867-886 |g extent:20 |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_WLY | ||
| 951 | |a AR | ||
| 952 | |d 159 |j 2021 |e 5 |h 867-886 |g 20 | ||