title: Delayed pituitary adenylate cyclase-activating polypeptide delivery after brain stroke improves functional recovery by inducing m2 microglia/macrophage polarization.
abstract: OBJECTIVE
  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.
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (INSERM) U982, Rouen, France (C.B., M.G., D.L., D.V., O.W.); Institute for Research and Innovation in Biomedicine, Normandy University, Rouen, France (C.B., M.G., D.L., D.V., O.W.); Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Rouen University, Mont-Saint-Aignan Cedex, France (C.B., M.G., D.L., D.V., O.W.); and Departments of Neurological Sciences and Pharmacology, University of Vermont College of Medicine, Burlington (V.M.).
authors.forename: Coralie
authors.initials: C
authors.lastname: Brifault
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (INSERM) U982, Rouen, France (C.B., M.G., D.L., D.V., O.W.); Institute for Research and Innovation in Biomedicine, Normandy University, Rouen, France (C.B., M.G., D.L., D.V., O.W.); Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Rouen University, Mont-Saint-Aignan Cedex, France (C.B., M.G., D.L., D.V., O.W.); and Departments of Neurological Sciences and Pharmacology, University of Vermont College of Medicine, Burlington (V.M.).
authors.forename: Marjorie
authors.initials: M
authors.lastname: Gras
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (INSERM) U982, Rouen, France (C.B., M.G., D.L., D.V., O.W.); Institute for Research and Innovation in Biomedicine, Normandy University, Rouen, France (C.B., M.G., D.L., D.V., O.W.); Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Rouen University, Mont-Saint-Aignan Cedex, France (C.B., M.G., D.L., D.V., O.W.); and Departments of Neurological Sciences and Pharmacology, University of Vermont College of Medicine, Burlington (V.M.).
authors.forename: Donovan
authors.initials: D
authors.lastname: Liot
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (INSERM) U982, Rouen, France (C.B., M.G., D.L., D.V., O.W.); Institute for Research and Innovation in Biomedicine, Normandy University, Rouen, France (C.B., M.G., D.L., D.V., O.W.); Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Rouen University, Mont-Saint-Aignan Cedex, France (C.B., M.G., D.L., D.V., O.W.); and Departments of Neurological Sciences and Pharmacology, University of Vermont College of Medicine, Burlington (V.M.).
authors.forename: Victor
authors.initials: V
authors.lastname: May
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (INSERM) U982, Rouen, France (C.B., M.G., D.L., D.V., O.W.); Institute for Research and Innovation in Biomedicine, Normandy University, Rouen, France (C.B., M.G., D.L., D.V., O.W.); Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Rouen University, Mont-Saint-Aignan Cedex, France (C.B., M.G., D.L., D.V., O.W.); and Departments of Neurological Sciences and Pharmacology, University of Vermont College of Medicine, Burlington (V.M.).
authors.forename: David
authors.initials: D
authors.lastname: Vaudry
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (INSERM) U982, Rouen, France (C.B., M.G., D.L., D.V., O.W.); Institute for Research and Innovation in Biomedicine, Normandy University, Rouen, France (C.B., M.G., D.L., D.V., O.W.); Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Rouen University, Mont-Saint-Aignan Cedex, France (C.B., M.G., D.L., D.V., O.W.); and Departments of Neurological Sciences and Pharmacology, University of Vermont College of Medicine, Burlington (V.M.). olivier.wurtz@univ-rouen.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Wurtz
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016764:Cell Polarity / Q000187:drug effects / Q000502:physiology*; D016503:Drug Delivery Systems / Q000379:methods; D007276:Injections, Intraventricular; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000008:administration & dosage*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D033581:Stem Cell Transplantation / Q000379:methods; D020521:Stroke / Q000378:metabolism* / Q000628:therapy; D013997:Time Factors
chemical_list: C495402:Adcyap1 protein, mouse; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide
keywords: inflammation; microglia; pituitary adenylate cyclase-activating polypeptide; stroke