Delayed Pituitary Adenylate Cyclase–Activating Polypeptide Delivery After Brain Stroke Improves Functional Recovery by Inducing M2 Microglia/Macrophage Polarization

Abstract

520S troke is a leading cause of death and long-term disabilities worldwide. Despite years of intense research and preclinical identification of numerous potential neuroprotective compounds, the only available treatment for brain ischemia relies on thrombolysis through injection of a recombinant tissuetype plasminogen activator. However, the treatment benefits to <10% of stroke victims because of a narrow therapeutical time window (<4.5 hours after stroke onset) and side effects. Consequently, there is a crucial need for the development of other strategies that could target later phases of the pathophysiological cascade of events after stroke.Since its initial discovery, several studies have highlighted the neuroprotective effect of pituitary adenylate cyclase-activating polypeptide (PACAP) 2 in in vitro and in vivo models of neurodegenerative diseases.3,4 Administered either before or few hours after middle cerebral artery occlusion, PACAP reduces the infarct volume area and improves functional outcomes. [5][6][7] Beside its well-known antiapoptotic activity, the neuropeptide PACAP exerts potent anti-inflammatory properties on innate immune compartment as illustrated by the decrease of the production of proinflammatory mediators interleukin (IL)-12, tumor necrosis factor (TNF)-α, and nitric oxide and the induction of the anti-inflammatory cytokine IL-10 in PACAP-treated macrophages stimulated by lipopolysaccharides.8-10 Whether PACAP acts directly by reducing apoptotic neuronal death 11 or indirectly via modulation of 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 intracerebroventricularly 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

Neuropeptides and Microglial Activation in Inflammation, Pain, and Neurodegenerative Diseases

“…Treatment with VIP prevented several features of mechanically induced brain trauma, such as microglial activation, proinflammatory cytokine secretion, leukocyte infiltration, and neurodegeneration [133]. In a model of brain focal ischemia, delayed intracerebroventricular delivery of PACAP-producing stem cells promoted fast and stable functional recovery which correlated with reduced inflammatory response and increased number of AG1 + microglia, further supporting a role for PACAP in polarizing microglia towards an M2 neuroprotective phenotype [134]. In an in vitro model of ischemic damage by oxygen and glucose deprivation (OGD) and reoxygenation, pretreatment of BV-2 cells with PACAP alleviated hypoxic injury by preventing TLR4/MyD88/NF- κ B signaling and decreasing proinflammatory cytokine levels and BV-2 apoptosis [135].…”

Partial MHC class II constructs as novel immunomodulatory therapy for stroke

“…It was shown that the switch from M1 to M2 is delayed with ageing (Gordon, 2003; Lee et al, 2013; Miron and Franklin, 2014). Various studies demonstrated the beneficial role of M2 cells in protection against stoke and in the recovery stage (Brifault et al, 2015; Li et al, 2016; Liu et al, 2016). It was reported that M2 microglia/macrophages infiltrated the ischemic core at 24 hrs, peaking at 5 days, and declining in the striatum by 14 days.…”

Exosomes from MiR-30d-5p-ADSCs Reverse Acute Ischemic Stroke-Induced, Autophagy-Mediated Brain Injury by Promoting M2 Microglial/Macrophage Polarization

“…M2 microglia protect neighboring cells by removing cell debris and releasing trophic factors for brain repair, based on their ability to produce interleukin 4 (IL-4) and IL-10 [6]. Meanwhile chronically-activated M1 microglia exacerbate brain injury by producing neurotoxic substances, although they participate in clearing cell debris in the early stages after stroke [7]. Microglia/macrophage phenotype polarization is likely dependent on activation status, and balancing this polarization is a promising therapeutic strategy for stroke treatment.…”