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Delayed Pituitary Adenylate Cyclase–Activating Polypeptide Delivery After Brain Stroke Improves Functional Recovery by Inducing M2 Microglia/Macrophage Polarization
- Source :
- Stroke, Stroke, American Heart Association, 2015, 46 (2), pp.520-528. ⟨10.1161/STROKEAHA.114.006864⟩
- Publication Year :
- 2015
- Publisher :
- HAL CCSD, 2015.
-
Abstract
- Background and Purpose— Until now, except thrombolysis, the therapeutical strategies targeting the acute phase of cerebral ischemia have been proven ineffective, and no approach is available to attenuate the delayed cell death mechanisms and the resulting functional deficits in the late phase. Then, we investigated whether a targeted and delayed delivery of pituitary adenylate cyclase–activating polypeptide (PACAP), a peptide known to exert neuroprotective activities, may dampen delayed pathophysiological processes improving functional recovery. Methods— Three days after permanent focal ischemia, PACAP-producing stem cells were transplanted intracerebro ventricularly in nonimmunosuppressed mice. At 7 and 14 days post ischemia, the effects of this stem cell–based targeted delivery of PACAP on functional recovery, volume lesions, and inflammatory processes were analyzed. Results— The delivery of PACAP in the vicinity of the infarct zone 3 days post stroke promotes fast, stable, and efficient functional recovery. This was correlated with a modulation of the postischemic inflammatory response. Transcriptomic and Ingenuity Pathway Analysis–based bioinformatic analyses identified several gene networks, functions, and key transcriptional factors, such as nuclear factor-κB, C/EBP-β, and Notch/RBP-J as PACAP’s potential targets. Such PACAP-dependent immunomodulation was further confirmed by morphometric and phenotypic analyses of microglial cells showing increased number of Arginase-1 + cells in mice treated with PACAP-expressing cells specifically, demonstrating the redirection of the microglial response toward a neuroprotective M2 phenotype. Conclusions— Our results demonstrated that immunomodulatory strategies capable of redirecting the microglial response toward a neuroprotective M2 phenotype in the late phase of brain ischemia could represent attractive options for stroke treatment in a new and unexploited therapeutical window.
- Subjects :
- Male
Time Factors
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
microglia
Pharmacology
[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity
Mice
Drug Delivery Systems
MESH: Animals
Stroke
Microglia
Brain
Cell Polarity
MESH: Recovery of Function
stroke
pituitary adenylate cyclase-activating polypeptide
MESH: Microglia
medicine.anatomical_structure
[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology
medicine.symptom
Stem cell
MESH: Stem Cell Transplantation
MESH: Cell Polarity
MESH: Injections, Intraventricular
Cardiology and Cardiovascular Medicine
Programmed cell death
Mice, 129 Strain
MESH: Mice, Transgenic
MESH: Drug Delivery Systems
Ischemia
Adenylate kinase
Inflammation
Mice, Transgenic
Neuroprotection
MESH: Stroke
MESH: Brain
MESH: Mice, 129 Strain
medicine
Animals
MESH: Mice
Injections, Intraventricular
Advanced and Specialized Nursing
business.industry
Macrophages
MESH: Pituitary Adenylate Cyclase-Activating Polypeptide
MESH: Time Factors
MESH: Macrophages
Recovery of Function
medicine.disease
MESH: Male
inflammation
Immunology
Neurology (clinical)
business
Stem Cell Transplantation
Subjects
Details
- Language :
- English
- ISSN :
- 00392499 and 15244628
- Database :
- OpenAIRE
- Journal :
- Stroke, Stroke, American Heart Association, 2015, 46 (2), pp.520-528. ⟨10.1161/STROKEAHA.114.006864⟩
- Accession number :
- edsair.doi.dedup.....c202c421be7ff8811015488c03981c98