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Abn CBD induced changes reduced microglial cell density cell
Abn-CBD induced changes (reduced microglial cell density, Dioscin sale size and a lower density of ramification) in the microglial morphology that could be compatible with a blockade of the neuroinflammation provoked by MPTPp. The absence of GPR55 transcripts in microglial cells in striatum and the similar effect of both drugs on microglia suggest that this effect might be independent of the GPR55 activation in the brain. Furthermore, these changes do not correlate with the degree of dopaminergic degeneration. Using a similar experimental approach, we identified a neuroprotective microglial phenotype in MPTPp mice treated with a monoacylglycerol lipase inhibitor, the main morphological characteristic of these cells being the abundance of large and thin ramifications (Fernández-Suárez et al., 2014). The specific modulation of microglial morphology seems to reflect the different microglial activation states that exert a distinct effect in terms of neuroprotection.
Acknowledgements
This work was supported by the projects PI14/02070 and SAF2012-39875-C02-01 from the Spanish Government (Plan estatal I+D+I 2013–2016 and ISCIII-FEDER) and by the Fundación Gangoiti. Estefanía Rojo was supported by a predoctoral fellowship from Colfuturo. We thank Diana Horn for the synthesis, and Dr. Viktor Rempel for the in vitro testing of PSB-1216. Diana Horn and Christa Müller were supported by the Deutsche Forschungsgemeinschaft (GRK1873). The authors have no conflict of interest.
Introduction
Within the adult brain, new neurons are generated from neural stem cells in two major sub-regions: the subventricular zone of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus (Zhao et al., 2008, van Praag et al., 2002, Spalding et al., 2013). New neurons formed within the hippocampus, a process known as hippocampal neurogenesis, integrate newly differentiating neural stem/progenitor cells into existing neural networks of the hippocampus and are integral for processes such as learning and memory (Deng et al., 2010, Sahay and Hen, 2007). Decrease of hippocampal neurogenesis can result in detrimental outcomes including cognitive impairment, stress-induced behavior changes, and depression (Coras et al., 2010, Lagace et al., 2010, Sahay and Hen, 2007, Snyder et al., 2011). Thus, there is great interest in understanding of biological processes which alter hippocampal neurogenesis and therapeutic approaches to alleviate such dysregulation.
Pro-inflammatory cytokines, such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), and Type 1 Interferons (interferon α and β), are essential soluble mediators of the innate immune response. Systemic inflammation that can be modeled by lipopolysaccharide (LPS) administration initiates molecular signaling and cellular processes leading to pathological neuroinflammation (Valero et al., 2014, Qin et al., 2007, Godbout et al., 2005). Neuroinflammation, cranial irradiation, and increased expression of pro-inflammatory cytokines within the hippocampal micro-environment suppress neurogenesis and can induce long lasting behavioral alterations including reduced memory formation and depression as well as alterations in the functional integration of adult born neurons (Ekdahl et al., 2003, Valero et al., 2014, Zonis et al., 2015, Monje et al., 2002, Iosif et al., 2006, Jakubs et al., 2008, Wood et al., 2011). In support of this, it has been found that blockade of inflammatory mediators upregulated by either systemic administration of LPS or cranial irradiation rescued disrupted neurogenesis rates within the hippocampus (Monje et al., 2003). Importantly, selective activation of PPARγ was highly effective at protecting both hippocampal neurogenesis and memory formation during LPS-induced transient illness (Ormerod et al., 2013).
Recently, the cannabinoid system has been proposed to regulate the neural stem cell (NSC) niche within the hippocampus both under homeostatic and pathologic conditions. During homeostatic conditions, the cannabinoid 1 (CB1) receptor has been implicated in neuronal differentiation of NSCs while activation of the cannabinoid 2 (CB2) receptor increases NSC proliferation (Xapelli et al., 2013, Molina-Holgado et al., 2007, Palazuelos et al., 2012, Rodrigues et al., 2017). Importantly, evidence suggests that NSCs have bi-directional cross-talk between the cannabinoid system (CB1 and CB2) and inflammatory cytokines (IL-1β, TNFα) that is necessary for NSC proliferation (Rubio-Araiz et al., 2008, Garcia-Ovejero et al., 2013). Activation of CB2 receptors rescued impaired hippocampal neurogenesis caused by chronic insult by HIV-1 neurotoxic protein gp120 further suggesting a neuroprotective role of cannabinoid-like ligands and cannabinoid receptor activation in the NSC niche (Avraham et al., 2014).