Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • To combat the detrimental effects of neuropathological condi

    2021-09-22

    To combat the detrimental effects of neuropathological conditions, additional therapeutic interventions that either dampen chronic neuroinflammation or attenuate reductions in hippocampal neurogenesis are critically needed. The cannabinoid system has already been shown to rescue impaired neurogenesis and reduce BI 2536 due to the HIV-1 protein Gp120 through activation of CB2 receptors (Avraham et al., 2014). Using our chronic, systemic inflammatory paradigm, we investigated if treatment with the GPR55 agonist O-1602 could protect against LPS-induced dysregulation of hippocampal neurogenesis. O-1602 significantly protected against reduction in hippocampal NSC survival (BrdU+), the number of immature neurons (DCX+), and proliferating NSC that ultimately became neuroblasts (DCX+/BrdU+) within the SGZ of the hippocampus. GPR55−/− animals showed reduced rates of NSC proliferation, survival, and neuroblast formation under non-inflammatory conditions similar to our previous studies (Hill et al., 2018). LPS treatment in GPR55−/− animals further reduced the number of immature neurons (DCX+ and DCX+/BrdU+) as compared to saline treated animals. The number of Ki67+ and BrdU+ cells were also diminished yet these results were not significant. It may be that GPR55−/− animals had such low rates of NSC proliferation and immature neuron formation that, although LPS did have a trend in reduction, significance could not be achieved. Administration of O-1602 had no effect in GPR55−/− animals, either under control or inflammatory conditions, further demonstrating that the neuroprotective results seen in C57BL/6 mice were due to GPR55. These results demonstrate for the first time that activation of GPR55 elicits neuroprotective effects within the SGZ of the hippocampus during chronic neuroinflammatory conditions. It should be noted that O-1602 was administered at the same time as LPS suggesting that pre-treatment is therapeutic under inflammatory conditions which may be beneficial as a therapy for people predisposed to inflammatory diseases or at high risk for systemic inflammation. It is therefore necessary to determine if GPR55 is an effective therapeutic target after inflammatory conditions are already present. Since GPR55 is expressed by primary microglia, it is possible that the neuroprotective properties of O-1602 in vivo during inflammatory insult may not have a direct NSC effect (Pietr et al., 2009). Indeed, activation of GPR55 by its endogenous ligand LPI shows neuroprotective effects in hippocampal slice cultures after glutamate induced excitotoxic lesion and on CA1 and CA3 hippocampal neurons after ischemic stroke (Kallendrusch et al., 2013, Blondeau et al., 2002). Protective effects in hippocampal slice cultures were found to be microglia-dependent, suggesting that targeting GPR55 reduces microglial activation under inflammatory conditions. Here we found that chronic LPS administration at a low dose induces microglial activation in both C57BL/6 and GPR55−/− mice as determined by increases in microglial number as well as increases in the volume percentage of the microglial marker IBA-1 and CD68, a protein found in microglial/macrophage lysosomes and endosomes commonly used as a marker for phagocytic microglia (Hoeijmakers et al., 2017, Hoeijmakers et al., 2018). It is known that during inflammatory insult microglia numbers increase as does the expression of CD68 by microglia, especially when these cells are engaging in phagocytosis (Nimmerjahn et al., 2005, Neumann et al., 2009, Schafer et al., 2012). O-1602 had no effect on the number of microglia present within the dentate gyrus, nor on increases in IBA-1 vol, CD68 volume, or the percentage of IBA-1 positive signal colocalized with CD68 suggesting that the neuroprotective outcomes seen on NSCs were not mediated by reductions in microglial activation. Moreover, we did not detect any differences in microglial number or marker expression between C57BL/6 and GPR55−/− animals. The lack of effect on microglia may not necessarily be due to lack of GPR55 signaling but may be due to the agonist used. LPI was seen to reduce microglial activation in the study by Kallendrusch et al., but LPI and O-1602 have different chemical structures and therefore may not act similarly on microglia (Kallendrusch et al., 2013). Another recent study by McHugh et al. describes an increase of microglial migration due to O-1602 on BV-2 microglia in vitro, but this action was mediated through another candidate cannabinoid receptor, GPR18 (McHugh et al., 2012). This other receptor may be present on microglia in the C57BL/6 and GPR55−/− CNS, but we do not believe that O-1602 is having any significant effect through activation of GPR18 because, again, we did not see any differences in microglial activation between LPS-treated animals that received either vehicle or O-1602.