GPR55 as a novel target in disease control of multiple sclerosis

Abstract

Multiple sclerosis (MS) is a neurodegenerative disease associated with immune attack of the central nervous system (CNS) leading to neuronal and axonal loss. This affects neurotransmission accumulating residual disability and the development of neurological signs such as spasticity. Numerous studies have reported a beneficial role of cannabinoids in alleviating symptoms associated with neurological damage. The endocannabinoid system has been shown to control experimental spasticity in experimental autoimmune encephalomyelitis (EAE) an animal model of multiple sclerosis (MS). The orphan G-protein coupled receptor 55 (GPR55) has been identified as a functionally –related cannabinoid receptor known to be stimulated by lysophosphatidylinositol. In the current study a novel GPR55 gene knockoutmouse and GPR55-transfected cell line was obtained and characterised andthe function and distribution of GPR55 was analyzed. Due to the lack of GPR55 specific antibodies, we attempted to generate GPR55-specific monoclonal antibodies in GPR55 knockout mice, however none of these reacted only specifically to the native protein. As alternatives to antibodies, GPR55 mRNA levels were quantified using quantitative polymerase chain reaction (qPCR) and in situ hybridization. The GPR55 knockout mice on the C57BL/6 mouse background failed to generate an autoimmune response during EAE in an initial experiment suggesting that GPR55 controls immune function. Disease was variable in the C57BL/6 mice and EAE was induced in the GPR55 knockout mice on the ABH background and animals developed spasticity. VSN16R is a drug that has shown to inhibit experimental spasticity and binds specifically to GPR55, without the typical side effects associated with cannabis. This compound was found to be an allosteric modulator of GPR55. Animals were treated with VSN16R however the anti-spastic effect remained in the GPR55 knockout mice. Hence, the effect of VSN16R is not mediated by GPR55 in EAE and a novel target needs to be identified.