Activation of GPR55 induces neuroprotection of hippocampal neurogenesis and immune responses of neural stem cells following chronic, systemic inflammation

Abstract

New neurons are continuously produced by neural stem cells (NSCs) within the adult hippocampus. Numerous diseases, including major depressive disorder and HIV-1 associated neurocognitive disorder, are associated with decreased rates of adult neurogenesis. A hallmark of these conditions is a chronic release of neuroinflammatory mediators by activated resident glia. Recent studies have shown a neuroprotective role on NSCs of cannabinoid receptor activation. Yet, little is known about the effects of GPR55, a candidate cannabinoid receptor, activation on reductions of neurogenesis in response to inflammatory insult. In the present study, we examined NSCs exposed to IL-1β in vitro to assess inflammation-caused effects on NSC differentiation and the ability of GPR55 agonists to attenuate NSC injury. NSC differentiation and neurogenesis was determined via immunofluorescence and flow cytometric analysis of NSC markers (Nestin, Sox2, DCX, S100β, βIII Tubulin, GFAP). GPR55 agonist treatment protected against IL-1β induced reductions in neurogenesis rates. Moreover, inflammatory cytokine receptor mRNA expression was down regulated by GPR55 activation in a neuroprotective manner. To determine inflammatory responses in vivo, we treated C57BL/6 and GPR55 −/− mice with LPS (0.2 mg/kg/day) continuously for 14 days via osmotic mini-pump. Reductions in NSC survival (as determined by BrdU incorporation), immature neurons, and neuroblast formation due to LPS were attenuated by concurrent direct intrahippocampal administration of the GPR55 agonist, O-1602 (4µg/kg/day). Molecular analysis of the hippocampal region showed a suppressed ability to regulate immune responses by GPR55 −/− animals manifesting in a prolonged inflammatory response (IL-1β, IL-6, TNFα) after chronic, systemic inflammation as compared to C57BL/6 animals. Taken together, these results suggest a neuroprotective role of GPR55 activation on NSCs in vitro and in vivo and

O-1602, an Agonist of Atypical Cannabinoid Receptors GPR55, Reverses the Symptoms of Depression and Detrusor Overactivity in Rats Subjected to Corticosterone Treatment

“…According to available data, effects of the GPR55 receptor stimulation in the inflammatory processes may be bi-directional, i.e. pro-inflammatory ( Chiurchiu et al, 2015 ) or anti-inflammatory ( Hill et al, 2019 ), depending on the study design and experimental conditions. In the in vitro studies by Chiurchiu et al (2015) , O-1602 enhanced production of IL-12 and TNF-α in lipopolysaccharide-activated monocytes and negatively affected its ability to phagocytose, whereas in the in vitro studies by Hill et al (2019) , exposure to O-1602 suppressed pro-inflammatory responses within neural stem cells during their insult with IL-1β.…”

“…pro-inflammatory ( Chiurchiu et al, 2015 ) or anti-inflammatory ( Hill et al, 2019 ), depending on the study design and experimental conditions. In the in vitro studies by Chiurchiu et al (2015) , O-1602 enhanced production of IL-12 and TNF-α in lipopolysaccharide-activated monocytes and negatively affected its ability to phagocytose, whereas in the in vitro studies by Hill et al (2019) , exposure to O-1602 suppressed pro-inflammatory responses within neural stem cells during their insult with IL-1β. Furthermore, animals genetically deprived of GPR55 receptors presented prolonged inflammatory response (with elevated IL-1β, IL-6, TNF-α values) after chronic low-level administration of lipopolysaccharide ( Hill et al, 2019 ).…”

“…Existence of GPR55 receptors has also been detected in different parts of the brain, including the striatum, hippocampus, forebrain, cortex, and cerebellum ( Wu et al, 2013 ). As a consequence, involvement of these receptors in hyperlagesia ( Staton et al, 2008 ), pain perception ( Deliu et al, 2015 ), motor coordination ( Wu et al, 2013 ), anxiety ( Rahimi et al, 2015 ; Shi et al, 2017 ), substance abuse, and neuroprotection has been demonstrated ( Alavi et al, 2016 ; Hill et al, 2019 ). Most probably, GPR55 receptors also participate in the hippocampal plasticity, and may play an important role in the modulation of memory and learning ( Hurst et al, 2017 ) as well as in the control of decision-making ( Garcia-Gutierrez et al, 2018 ).…”

The Pro-neurogenic Effects of Cannabidiol and Its Potential Therapeutic Implications in Psychiatric Disorders

“…For instance, no data is available as to the eCB-specific downstream signaling pathways recruited by cannabinoid receptors that would be facilitating neuronal survival and differentiation, despite some approximations in this regard (Luján et al, 2018 ). Furthermore, there also remain some unexplored CBD mechanisms with potential pro-neurogenic properties, such as GPR55 activation for coping reduction of neurogenesis in response to inflammatory insults (Hill et al, 2019 ). Noteworthy, a protective interaction involving neuroinflammation processes has been already observed, showing that CBD-mediated activation of PPARγ is associated with increased neurogenic activity, as well as reduced reactive gliosis, in the granule cell layer of the hippocampal DG (Esposito et al, 2011 ).…”

Connections between Early-Life Neuroinflammation, Neural Stem Cells and Progenitors and Origins of Neuropsychiatric Disorders

“…A recent study showed that the cannabinoid system can modulate NSP proliferation and have a neuroprotective role, rescuing hippocampal neurogenesis during HIV-1 neurotoxic insults [125,126]. Activating a candidate cannabinoid receptor, GPR55, suppressed the pro-inflammatory responses of IL-1β treatment on adult rat hippocampal NSCs in vitro, rescuing the negative effects of IL-1β on neurogenesis [127].…”