Exendin-4 reduces ischemic brain injury in normal and aged type 2 diabetic mice and promotes microglial M2 polarization.

Darsalia V, Hua S, Larsson M, Mallard C, Nathanson D, Nyström T, Sjöholm Å, Johansson ME, Patrone C

PloS one7 Aug 2014Cited by 76 (Europe PMC)

PMID25101679PMCIDPMC4125154DOI10.1371/journal.pone.0103114PepBankPUB-25101679

Summary

Exendin-4 is a glucagon-like receptor 1 agonist clinically used against type 2 diabetes that has also shown neuroprotective effects in experimental stroke models. However, while the neuroprotective efficacy of Exendin-4 has been thoroughly investigated if the pharmacological treatment starts before stroke, the therapeutic potential of the Exendin-4 if the treatment starts acutely after stroke has not been clearly determined. Further, a comparison of the neuroprotective efficacy in normal and aged diabetic mice has not been performed. Finally, the cellular mechanisms behind the efficacy of Exendin-4 have been only partially studied. The main objective of this study was to determine the neuroprotective efficacy of Exendin-4 in normal and aged type 2 diabetic mice if the treatment started after stroke in a clinically relevant setting. Furthermore we characterized the Exendin-4 effects on stroke-induced neuroinflammation. Two-month-old healthy and 14-month-old type 2 diabetic/obese mice were subjected to middle cerebral artery occlusion. 5 or 50 µg/kg Exendin-4 was administered intraperitoneally at 1.5, 3 or 4.5 hours thereafter. The treatment was continued (0.2 µg/kg/day) for 1 week. The neuroprotective efficacy was assessed by stroke volume measurement and stereological counting of NeuN-positive neurons. Neuroinflammation was determined by gene expression analysis of M1/M2 microglia subtypes and pro-inflammatory cytokines. We show neuroprotective efficacy of 50 µg/kg Exendin-4 at 1.5 and 3 hours after stroke in both young healthy and aged diabetic/obese mice. The 5 µg/kg dose was neuroprotective at 1.5 hour only. Proinflammatory markers and M1 phenotype were not impacted by Exendin-4 treatment while M2 markers were significantly up regulated. Our results support the use of Exendin-4 to reduce stroke-damage in the prehospital/early hospitalization setting irrespectively of age/diabetes. The results indicate the polarization of microglia/macrophages towards the M2 reparative phenotype as a potential mechanism of neuroprotection.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study5

5 results from studies that gave the peptide. No result from this study comes from people.

01AnimalAnimal study (in vivo)Efficacy outcome
In young healthy and aged diabetic mice, exendin‑4 was neuroprotective when started at 1.5 or 3 hours after stroke.
In plain wordsIn mice with and without diabetes, exendin‑4 protected the brain when started at 1.5 or 3 hours after stroke.
Peptide
Exenatide (exendin-4)
Outcome
IncreaseNeuroprotection with higher dose
Study
mousen: not reported in source
Young healthy and aged diabetic/obese mice after middle cerebral artery occlusion
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
50 µg/kg initially, then 0.2 µg/kg/day · intraperitoneal · 1 weekAs given in this study (mouse).
Source sentences
Summary
We show neuroprotective efficacy of 50 µg/kg Exendin-4 at 1.5 and 3 hours after stroke in both young healthy and aged diabetic/obese mice.
3 context sentences(design, population, supporting numbers)
Summary · context
Two-month-old healthy and 14-month-old type 2 diabetic/obese mice were subjected to middle cerebral artery occlusion.
Summary · context
5 or 50 µg/kg Exendin-4 was administered intraperitoneally at 1.5, 3 or 4.5 hours thereafter.
Summary · context
The treatment was continued (0.2 µg/kg/day) for 1 week.
Show in the study text Report a problemFND-2510167901
02AnimalAnimal study (in vivo)Efficacy outcome
In the mouse stroke study, the lower exendin‑4 dose was neuroprotective only when started at 1.5 hour.
In plain wordsIn mice, the lower exendin‑4 dose protected the brain only when started at 1.5 hour after stroke.
Peptide
Exenatide (exendin-4)
Outcome
MixedNeuroprotection with lower dose
Study
mousen: not reported in source
Young healthy and aged diabetic/obese mice after middle cerebral artery occlusion
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
5 µg/kg initially, then 0.2 µg/kg/day · intraperitoneal · 1 weekAs given in this study (mouse).
Source sentences
Summary
The 5 µg/kg dose was neuroprotective at 1.5 hour only.
3 context sentences(design, population, supporting numbers)
Summary · context
Two-month-old healthy and 14-month-old type 2 diabetic/obese mice were subjected to middle cerebral artery occlusion.
Summary · context
5 or 50 µg/kg Exendin-4 was administered intraperitoneally at 1.5, 3 or 4.5 hours thereafter.
Summary · context
The treatment was continued (0.2 µg/kg/day) for 1 week.
Show in the study text Report a problemFND-2510167902
03AnimalAnimal study (in vivo)Mechanism
In the mouse stroke study, exendin‑4 did not affect proinflammatory markers.
In plain wordsIn mice after stroke, exendin‑4 did not change proinflammatory markers.
Peptide
Exenatide (exendin-4)
Outcome
No significant changeProinflammatory markers
Study
mousen: not reported in source
Young healthy and aged diabetic/obese mice after middle cerebral artery occlusion
Outcome group
Inflammation markers · Nervous system and cognition
Studied dose
Dose not stated · intraperitoneal · 1 weekAs given in this study (mouse).
Source sentences
Summary
Proinflammatory markers and M1 phenotype were not impacted by Exendin-4 treatment while M2 markers were significantly up regulated.
3 context sentences(design, population, supporting numbers)
Summary · context
Two-month-old healthy and 14-month-old type 2 diabetic/obese mice were subjected to middle cerebral artery occlusion.
Summary · context
5 or 50 µg/kg Exendin-4 was administered intraperitoneally at 1.5, 3 or 4.5 hours thereafter.
Summary · context
The treatment was continued (0.2 µg/kg/day) for 1 week.
Show in the study text Report a problemFND-2510167903
04AnimalAnimal study (in vivo)Mechanism
In the mouse stroke study, exendin‑4 did not affect the M1 phenotype.
In plain wordsIn mice after stroke, exendin‑4 did not change the M1 immune-cell phenotype.
Peptide
Exenatide (exendin-4)
Outcome
No significant changeM1 phenotype
Study
mousen: not reported in source
Young healthy and aged diabetic/obese mice after middle cerebral artery occlusion
Outcome group
Immune response · Nervous system and cognition
Studied dose
Dose not stated · intraperitoneal · 1 weekAs given in this study (mouse).
Source sentences
Summary
Proinflammatory markers and M1 phenotype were not impacted by Exendin-4 treatment while M2 markers were significantly up regulated.
3 context sentences(design, population, supporting numbers)
Summary · context
Two-month-old healthy and 14-month-old type 2 diabetic/obese mice were subjected to middle cerebral artery occlusion.
Summary · context
5 or 50 µg/kg Exendin-4 was administered intraperitoneally at 1.5, 3 or 4.5 hours thereafter.
Summary · context
The treatment was continued (0.2 µg/kg/day) for 1 week.
Show in the study text Report a problemFND-2510167904
05AnimalAnimal study (in vivo)Mechanism
In the mouse stroke study, exendin‑4 increased M2 markers.
In plain wordsIn mice after stroke, exendin‑4 increased M2 immune-cell markers.
Peptide
Exenatide (exendin-4)
Outcome
IncreaseM2 markers
Study
mousen: not reported in source
Young healthy and aged diabetic/obese mice after middle cerebral artery occlusion
Outcome group
Immune response · Nervous system and cognition
Studied dose
Dose not stated · intraperitoneal · 1 weekAs given in this study (mouse).
Source sentences
Summary
Proinflammatory markers and M1 phenotype were not impacted by Exendin-4 treatment while M2 markers were significantly up regulated.
3 context sentences(design, population, supporting numbers)
Summary · context
Two-month-old healthy and 14-month-old type 2 diabetic/obese mice were subjected to middle cerebral artery occlusion.
Summary · context
5 or 50 µg/kg Exendin-4 was administered intraperitoneally at 1.5, 3 or 4.5 hours thereafter.
Summary · context
The treatment was continued (0.2 µg/kg/day) for 1 week.
Show in the study text Report a problemFND-2510167905

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

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Version 2Current
22 Oct 2026, 02:26 UTC
Study results updated
Version 1
21 Oct 2026, 18:59 UTC
First added · source update from Europe PMC

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