The G Protein‐Coupled Receptor 55 Ligand l‐α‐Lysophosphatidylinositol Exerts Microglia‐Dependent Neuroprotection After Excitotoxic Lesion

Abstract

Searching for chemical agents and molecular targets protecting against secondary neuronal damage reflects one major issue in neuroscience. Cannabinoids limit neurodegeneration by activation of neuronal G protein-coupled cannabinoid receptor 1 (CB1 ) and microglial G protein-coupled cannabinoid receptor 2 (CB2 ). However, pharmacological experiments with CB1 /CB2 -deficient mice unraveled the existence of further, so-called non-CB1 /non-CB2 G protein-coupled receptor (GPR) subtypes. GPR55, whose function in the brain is still poorly understood, represents a novel target for various cannabinoids. Here, we investigated whether GPR55 reflects a potential beneficial target in neurodegeneration by using the excitotoxicity in vitro model of rat organotypic hippocampal slice cultures (OHSC). l-α-Lysophosphatidylinositol (LPI), so far representing the most selective agonist for GPR55, protected dentate gyrus granule cells and reduced the number of activated microglia after NMDA (50 µM) induced lesions. The relevance of GPR55 activation for LPI-mediated neuroprotection was determined by using Gpr55 siRNA. Microglia seems to mediate the observed neuroprotection since their depletion in OHSC attenuated the beneficial effects of LPI. Moreover, LPI alone induced microglia chemotaxis but conversely significantly attenuated ATP triggered microglia migration. These effects seemed to be independent from intracellular Ca(2+) and p38 or p44/p42 MAPK phosphorylation. In conclusion, this study unmasked a yet unknown role for GPR55 in neuroprotection driven by LPI-mediated modulation of microglia function.

A putative lysophosphatidylinositol receptor GPR55 modulates hippocampal synaptic plasticity

“…The role of GPR55 in the PNS/CNS, however, has only been demonstrated recently. In the CNS, GPR55 is involved in neuroprotection (Kallendrusch et al, ), hyperalgesia (Staton et al, ), motor coordination (Wu et al, ), pain perception (Deliu et al, ), and axon innervation/guidance (Cherif et al, ; Guy et al, ). GPR55 is widely distributed in the human brain (Sawzdargo et al, ) and in several regions of rodent brain (Coria et al, ; Serrano et al, ), including the hippocampus (Wu et al, ).…”

The multiplicity of spinal AA-5-HT anti-nociceptive action in a rat model of neuropathic pain

“…Because GPR18 and GPR55 have been proposed as novel cannabinoid receptors [8,40], we determined their level of mRNA expression in the DRG and spinal cord (Fig. 6A,B,C,D).…”

Modulating the delicate glial–neuronal interactions in neuropathic pain: Promises and potential caveats

“…But recent evidence suggests that glial activation can also be beneficial, depending upon the type and stage of activation (Glezer et al, 2007; Milligan and Watkins, 2009; Kallendrusch et al, 2013). For example, immune responses in the CNS may benefit patients with Alzheimer’s disease (AD) by reducing the amount of amyloid deposition (Malm et al, 2005).…”

“…Microglia with an inflammatory phenotype release proinflammatory cytokines, neurotoxic factors, and reactive oxygen/nitrogen species that exacerbate neuronal injury (Watkins et al, 2007, Ji et al, 2013). Other studies have shown that microglia and astrocytes can mediate neuronal regeneration, repair, and neurogenesis through anti-inflammatory actions (Milligan and Watkins, 2009; Kallendrusch et al, 2013). However, these studies are difficult to compare directly, as they used different experimental setups that vary in terms of the stimulus used, timing of glial activation, and animal species and age (Luo and Chen, 2012).…”