Article

GPR55: A therapeutic target for Parkinson's disease?

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Abstract

The GPR55 receptor is expressed abundantly in the brain, especially in the striatum, suggesting it might fulfill a role in motor function. Indeed, motor behavior is impaired in mice lacking GPR55, which also display dampened inflammatory responses. Abnormal-cannabidiol (Abn-CBD), a synthetic cannabidiol (CBD) isomer, is a GPR55 agonist that may serve as a therapeutic agent in the treatment of inflammatory diseases. In this study, we explored whether modulating GPR55 could also represent a therapeutic approach for the treatment of Parkinson's disease (PD). The distribution of GPR55 mRNA was first analyzed by in situ hybridization, localizing GPR55 transcripts to neurons in brain nuclei related to movement control, striatum, globus pallidus, subthalamic nucleus, substantia nigra and cortex. Striatal expression of GPR55 was downregulated in parkinsonian conditions. When Abn-CBD and CBD (5 mg/kg) were chronically administered to mice treated over 5 weeks with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp), Abn-CBD but not CBD prevented MPTPp induced motor impairment. Although Abn-CBD protected dopaminergic cell bodies, it failed to prevent degeneration of the terminals or preserve dopamine levels in the striatum. Both compounds induced morphological changes in microglia that were compatible with an anti-inflammatory phenotype that did not correlate with a neuroprotective activity. The symptomatic relief of Abn-CBD was further studied in the haloperidol-induced catalepsy mouse model. Abn-CBD had an anti-cataleptic effect that was reversed by CBD and PSB1216, a newly synthesized GPR55 antagonist, and indeed, two other GPR55 agonists also displayed anti-cataleptic effects (CID1792197 and CID2440433). These results demonstrate for the first time that activation of GPR55 might be beneficial in combating PD.

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... These processes are attributed to the hypokinetic states observed in the PD, in both in animal models and human patients (Berardelli et al., 2001;Galvan and Wichmann, 2008;Dong et al., 2021). Interestingly, the GPR55 mRNA transcript has been identified, via in situ hybridization, in the GPe and striatum of mice, as well as other nuclei of the BG circuit that are associated with movement control (Celorrio et al., 2017). ...
... Recent studies have reported that GPR55 may serve as a therapeutic agent in the treatment of PD. Celorrio et al. (2017) studied the effect of the peripheral administration of abnormal cannabidiol (a synthetic isomer of CBD), to explore its agonist effects on the GPR55 receptor. They observed a beneficial neuroprotective effect on dopaminergic neurons injured by 2,3, and an anti-inflammatory and anti-cataleptic effect as a result of GPR55 activation in parkinsonian mice models. ...
... The latter finding is of particular interest due to reported alterations in the BG circuit in parkinsonian states, especially those that presented increased GABAergic activity in the GPe (Galvan and Wichmann, 2008). Said reports show the expression of GPR55 mRNA in the BG (mainly in the GPe), the subthalamic nucleus (STN), and the striatum (Henstridge et al., 2011;Celorrio et al., 2017), proposing that the receptor plays an important role in GABA release. Therefore, the agonism of GPR55 to LPI would increase the release of GABA, as has been observed with other agonists such as palmitoylethanolamine (Musella et al., 2017). ...
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Cannabidiol (CBD) presents antiparkinsonian properties and neuromodulatory effects, possibly due to the pleiotropic activity caused at multiple molecular targets. Recently, the GPR55 receptor has emerged as a molecular target of CBD. Interestingly, GPR55 mRNA is expressed in the external globus pallidus (GPe) and striatum, hence, it has been suggested that its activity is linked to motor dysfunction in Parkinson’s disease (PD). The present study aimed to evaluate the effect of the intrapallidal injection of both CBD and a selective GPR55 antagonist (CID16020046) on motor asymmetry, fine motor skills, and GAD-67 expression in hemiparkinsonian rats. The hemiparkinsonian animal model applied involved the induction of a lesion in male Wistar rats via the infusion of the neurotoxin 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle via stereotaxic surgery. After a period of twenty days, a second surgical procedure was performed to implant a guide cannula into the GPe. Seven days later, lysophosphatidylinositol (LPI), CBD, or CID16020046 were injected once a day for three consecutive days (from the 28th to the 30th day post-lesion). Amphetamine-induced turning behavior was evaluated on the 14th and 30th days post-injury. The staircase test and fine motor skills were evaluated as follows: the rats were subject to a ten-day training period prior to the 6-OHDA injury; from the 15th to the 19th days post-lesion, the motor skills alterations were evaluated under basal conditions; and, from the 28th to the 30th day post-lesion, the pharmacological effects of the drugs administered were evaluated. The results obtained show that the administration of LPI or CBD generated lower levels of motor asymmetry in the turning behavior of hemiparkinsonian rats. It was also found that the injection of CBD or CID16020046, but not LPI, in the hemiparkinsonian rats generated significantly superior performance in the staircase test, in terms of the use of the forelimb contralateral to the 6-OHDA-induced lesion, when evaluated from the 28th to the 30th day post-lesion. Similar results were also observed for superior fine motor skills performance for pronation, grasp, and supination. Finally, the immunoreactivity levels were found to decrease for the GAD-67 enzyme in the striatum and the ipsilateral GPe of the rats injected with CBD and CID16020046, in contrast with those lesioned with 6-OHDA. The results obtained suggest that the inhibitory effects of CBD and CID16020046 on GPR55 in the GPe could be related to GABAergic overactivation in hemiparkinsonism, thus opening new perspectives to explain, at a cellular level, the reversal of the motor impairment observed in PD models.
... In this respect, the orphan G protein-coupled receptor GPR55 has been proposed as the putative "type 3" cannabinoid receptor (Ryberg et al., 2007;Yang et al., 2016). GPR55 mRNA is expressed throughout the central nervous system, including the cerebellum, hippocampus, cortex, globus pallidus, striatum (Str), and substantia nigra pars compacta (SNc) (Celorrio et al., 2017;Marichal-Cancino et al., 2017;Ryberg et al., 2007). ...
... Basal ganglia nuclei express mRNA and protein of GPR55 receptors, particularly in striatal medium-sized spiny neurons (MSNs) (Celorrio et al., 2017;Martinez-Pinilla et al., 2014;Ryberg et al., 2007;Wu et al., 2013). However, their presence in striatal projections such as substantia nigra pars reticulate (SNr), their function on GABA release, signaling, and the possible effect on motor behavior have not been studied. ...
... GPR55 transcripts have been reported in basal ganglia structures of rodents, including GPe, SN, STN, and the Str (Celorrio et al., 2017;Ryberg et al., 2007;Wu et al., 2013). This study identified GPR55 protein expression on substance P-positive cells of the direct basal ganglia pathway (Figure 1 The decrease of GPR55 protein levels in synaptosomes from SNr after lesion of the Str with KA and the absence of effect by the GPR55 agonist LPI on [ 3 H]-GABA release indicates that GPR55 is located at the striato-nigral terminals (Figure 3). ...
Article
Striatal medium‐sized spiny neurons express mRNA and protein of GPR55 receptors that stimulate neurotransmitter release; thus, GPR55 could be sent to nigral striatal projections, where it might modulate GABA release and motor behavior. Here we study the presence of GPR55 receptors at striato‐nigral terminals, their modulation of GABA release, their signaling pathway, and their effect on motor activity. By double immunohistochemistry, we found the colocation of GPR55 protein and substance P in the dorsal striatum. In slices of the rat substantia nigra, the GPR55 agonists LPI and O‐1602 stimulated [3H]‐GABA release induced by high K+ depolarization in a dose‐dependent manner. The antagonists CID16020046 and cannabidiol prevented agonist stimulation in a dose‐dependent way. The effect of GPR55 on nigral [3H]‐GABA release was prevented by lesion of the striatum with kainic acid, which was accompanied by a decrement of GPR55 protein in nigral synaptosomes, indicating the presynaptic location of receptors. The depletion of internal Ca2+ stores with thapsigargin did not prevent the effect of LPI on [3H]‐GABA release, but the remotion or chelation of external calcium did. Blockade of Gi, Gs, PLC, PKC, or dopamine D1 receptor signaling proteins did not prevent the effect of GPR55 on release. However, the activation of GPR55 stimulated [3H]‐cAMP accumulation and PKA activity. Intranigral unilateral injection of LPI induces contralateral turning. This turning was prevented by CID16020046, cannabidiol, and bicuculline but not by SCH 23390. Our data indicate that presynaptic GPR55 receptors stimulate [3H]‐GABA release at striato‐nigral terminals through [3H]‐cAMP production and stimulate motor behavior. This article is protected by copyright. All rights reserved
... This has limited the studies with this cannabinoid receptor type and redirected the research to non-psychotropic cannabinoid receptors, for example the CB 2 receptor, whose activation with HU-308, Δ 9tetrahydrocannabivarin (Δ 9 -THCV), VCE-004.8 and other agonists entails anti-inflammatory and neuroprotective effects in different experimental models of PD [13,35,39,44,74]. A similar reduction of inflammatory events, resulting in preservation of nigrostriatal dopaminergic neurons in the basal ganglia, has been found with cannabinoids that are able to target the orphan receptor GPR55, which has been recently associated with the endocannabinoid system [14,19]. In addition, the activation of PPAR-γ with glitazones [78], but also with some cannabinoids (e.g., VCE-003.2, ...
... Such elevated motor activity elicited by VCE-003.2 in AAV9-SynA53T-injected mice in comparison with the other two groups was also visible in the data obtained in a computer-aided actimeter (actitrack), with statistically significant increases in locomotor parameters such as general activity (F (2,19) ...
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Background The cannabigerol derivative VCE-003.2, which has activity at the peroxisome proliferator-activated receptor-γ has afforded neuroprotection in experimental models of Parkinson’s disease (PD) based on mitochondrial dysfunction (6-hydroxydopamine-lesioned mice) and neuroinflammation (LPS-lesioned mice). Now, we aim to explore VCE-003.2 neuroprotective properties in a PD model that also involves protein dysregulation, other key event in PD pathogenesis. Methods To this end, an adeno-associated viral vector serotype 9 coding for a mutated form of the α-synuclein gene (AAV9-SynA53T) was unilaterally delivered in the substantia nigra pars compacta (SNpc) of mice. This model leads to motor impairment and progressive loss of tyrosine hydroxylase-labelled neurons in the SNpc. Results Oral administration of VCE-003.2 at 20 mg/kg for 14 days improved the performance of mice injected with AAV9-SynA53T in various motor tests, correlating with the preservation of tyrosine hydroxylase-labelled neurons in the SNpc. VCE-003.2 also reduced reactive microgliosis and astrogliosis in the SNpc. Furthermore, we conducted a transcriptomic analysis in the striatum of mice injected with AAV9-SynA53T and treated with either VCE-003.2 or vehicle, as well as control animals. This analysis aimed to identify gene families specifically altered by the pathology and/or VCE-003.2 treatment. Our data revealed pathology-induced changes in genes related to mitochondrial function, lysosomal cell pathways, immune responses, and lipid metabolism. In contrast, VCE-003.2 treatment predominantly affected the immune response through interferon signaling. Conclusion Our study broadens the neuroprotective potential of VCE-003.2, previously described against mitochondrial dysfunction, oxidative stress, glial reactivity and neuroinflammation in PD. We now demonstrate its efficacy against another key pathogenic event in PD as α-synuclein dysregulation. Furthermore, our investigation sheds light on the molecular mechanisms underlying VCE-003.2 revealing its role in regulating interferon signaling. These findings, together with a favorable ADMET profile, enhance the preclinical interest of VCE-003.2 towards its future clinical development in PD. Supplementary Information The online version contains supplementary material available at 10.1186/s12993-024-00256-9.
... Quantitative RT-PCR assays revealed GPR55 gene expression in the mouse brain, including the frontal cortex, striatum, hippocampus, and cerebellum [9,14]. In situ hybridization (ISH) and immunohistochemistry (IHC) assays also show GPR55 mRNA and immunostaining signals in neurons in the striatum and hippocampus [15][16][17][18]. However, the detected GPR55 signals are very weak, and the phenotypes of neurons that express GPR55 in the striatum and hippocampus are largely unknown. ...
... The first important finding in this study is the identification of GPR55 mRNA in cortical and subcortical glutamate neurons, but not in midbrain DA neurons. This is consistent with a previous report indicating that GPR55 mRNA is colocalized with the neuronal marker NeuN, but not with an astrocytic marker GFAP or microglial marker Iba1 in the striatum [15]. Notably, a high density of GPR55 mRNA was detected in the cortex and hippocampus, while much lower GPR55 mRNA was detected in the thalamus, VTA, red nucleus, and striatum in the present study. ...
Article
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G protein-coupled receptor 55 (GPR55) has been thought to be a putative cannabinoid receptor. However, little is known about its functional role in cannabinoid action and substance use disorders. Here we report that GPR55 is predominantly found in glutamate neurons in the brain, and its activation reduces self-administration of cocaine and nicotine in rats and mice. Using RNAscope in situ hybridization, GPR55 mRNA was identified in cortical vesicular glutamate transporter 1 (VgluT1)-positive and subcortical VgluT2-positive glutamate neurons, with no detection in midbrain dopamine (DA) neurons. Immunohistochemistry detected a GPR55-like signal in both wildtype and GPR55-knockout mice, suggesting non-specific staining. However, analysis using a fluorescent CB1/GPR55 ligand (T1117) in CB1-knockout mice confirmed GPR55 binding in glutamate neurons, not in midbrain DA neurons. Systemic administration of the GPR55 agonist O-1602 didnt impact ∆⁹-THC-induced analgesia, hypothermia and catalepsy, but significantly mitigated cocaine-enhanced brain-stimulation reward caused by optogenetic activation of midbrain DA neurons. O-1602 alone failed to alter extracellar DA, but elevated extracellular glutamate, in the nucleus accumbens. In addition, O-1602 also demonstrated inhibitory effects on cocaine or nicotine self-administration under low fixed-ratio and/or progressive-ratio reinforcement schedules in rats and wildtype mice, with no such effects observed in GPR55-knockout mice. Together, these findings suggest that GPR55 activation may functionally modulate drug-taking and drug-seeking behavior possibly via a glutamate-dependent mechanism, and therefore, GPR55 deserves further study as a new therapeutic target for treating substance use disorders.
... Quantitative RT-PCR assays revealed GPR55 gene expression in the mouse brain, including the frontal cortex, striatum, hippocampus, and cerebellum 9,14 . In situ hybridization (ISH) and immunohistochemistry (IHC) assays also show GPR55 mRNA and immunostaining signals in neurons in the striatum and hippocampus [15][16][17][18] . However, the detected GPR55 signals are very weak and the phenotypes of neurons that express GPR55 in the striatum and hippocampus are largely unknown. ...
... The rst important nding in this study is the identi cation of GPR55 mRNA in cortical and subcortical glutamate neurons, but not in midbrain DA neurons. This nding is consistent with a previous report indicating that GPR55 mRNA is colocalized with the neuronal marker NeuN, but not with an astrocytic marker GFAP or microglial marker Iba1 in the striatum 15 . Notably, a high density of GPR55 mRNA was detected in the cortex, while much lower GPR55 mRNA was detected in subcortical regions such as the hippocampus, thalamus, VTA, red nucleus, and striatum. ...
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Cannabis legalization continues to progress in the USA for medical and recreational purposes. G protein-coupled receptor 55 (GPR55) is a putative “CB3” receptor. However, its functional role in cannabinoid action and drug abuse is not explored. Here we report that GPR55 is mainly expressed in cortical and subcortical glutamate neurons and its activation attenuates nicotine taking and seeking in rats and mice. RNAscope in situ hybridization detected GPR55 mRNA in cortical vesicular glutamate transporter 1 (VgluT1)-positive and subcortical VgluT2-positive glutamate neurons in wildtype, but not GPR55-knockout, mice. GPR55 mRNA was not detected in midbrain dopamine (DA) neurons in either genotype. Immunohistochemistry assays detected GPR55-like staining, but the signal is not GPR55-specific as the immunostaining was still detectable in GPR55-knockout mice. We then used a fluorescent CB1-GPR55 ligand (T1117) and detected GPR55 binding in cortical and subcortical glutamate neurons, but not in midbrain DA neurons, in CB1-knockout mice. Systemic administration of O-1602, a GPR55 agonist, dose-dependently increased extracellular glutamate, not DA, in the nucleus accumbens. Pretreatment with O-1602 failed to alter Δ ⁹ -tetrahydrocannabinol (D ⁹ -THC)-induced triad effects or intravenous cocaine self-administration, but it dose-dependently inhibited nicotine self-administration under fixed-ratio and progressive-ratio reinforcement schedules in rats and wildtype mice, not in GPR55-knockout mice. O-1602 itself is not rewarding or aversive as assessed by optical intracranial self-stimulation (oICSS) in DAT-Cre mice. These findings suggest that GPR55 is functionally involved in nicotine reward process possibly by a glutamate-dependent mechanism, and therefore, GPR55 deserves further research as a new therapeutic target for treating nicotine use disorder.
... In contrast, a 2016 study showed that 5 mg/kg CBD for 5 weeks did not affect dopaminergic neuron loss or motor impairments caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [74]. Another investigation in the same year tested different doses of CBD (15,30, and 60 mg/kg, for 3 days) in a mouse model of LID by giving L-DOPA for 21 days after receiving 6-OHDA treatment. ...
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Background Parkinson’s disease (PD) is primarily known as a motor disorder; however, its debilitating non-motor symptoms have a significant impact on patients’ quality of life. The current standard treatment, l-DOPA, is used to relieve motor symptoms, but prolonged use is often associated with severe side effects. This creates an urgent need for effective alternatives targeting both motor and non-motor symptoms. Objectives Over the past decade, Cannabis sativa and its cannabinoids have been widely studied across various health conditions. Among these compounds, cannabidiol (CBD), a non-psychoactive component, is garnering growing interest due to its multi-targeted pleiotropic properties. This work aims to provide a comprehensive overview of CBD’s efficacy in PD. Methods This review compiles data on both motor and non-motor symptoms of PD, integrating results from preclinical animal studies and available clinical trials. Results Preclinical research has demonstrated promising results regarding CBD’s potential benefits in PD; however, the total number of clinical trials is limited (with only seven studies to date), making it difficult to draw definitive conclusions on its efficacy. Conclusions While preclinical findings suggest that CBD may have therapeutic potential in PD, the limited number of clinical trials highlights the need for further research. This review emphasizes the gaps that need to be addressed in future studies to fully understand CBD’s role in treating both motor and non-motor symptoms of PD.
... Also using this rat model, Giuliano et al. [42] administered CBD chronically for 28 days. Animals treated with CBD showed reduced nigrostriatal degeneration and neuroinflammatory response together with improved motor performance. ...
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The potential of botanical cannabinoids as potential anti-inflammatory and neuroprotective agents.
... AbnCBD has been shown to possess a range of protective disease-treating effects in-vivo. Previous studies have also shown comp 3 to be anti-inflammatory, cardioprotective [53], neuroprotective [54], anti-diabetic [55], anti-colitis [43] and even anti-cancer [56]. ...
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Abnormal cannabinoids (including comp 3) are a class of synthetic lipid compounds with non-psychoactive properties and regioisomer configurations, but distinct from traditional cannabinoids since they do not interact with the established CB1 and CB2 receptors. Previous research showed the cardioprotective and anti-inflammatory potentials of comp 3 and more recently its antimicrobial effect on methicillin-resistant Staphylococcus aureus (MRSA). Given the escalating challenges posed by Candida infections and the rise of antifungal drug resistance, the exploration of novel therapeutic avenues is crucial. This study aimed to assess the anti-Candida properties of newly synthesized AbnCBD derivatives. AbnCBD derivatives were synthesized by acid catalysis-induced coupling and further derivatized. We evaluated the potential of the AbnCBD derivatives to inhibit the growth stages of various Candida species. By in vitro colorimetric assays and in vivo mice experiments, we have shown that AbnCBD derivatives induce differential inhibition of Candida growth. The AbnCBD derivatives, especially comp 3, comp 10, and comp 9 significantly reduced the growth of C. albicans, including FLC-resistant strains, and of C. tropicalis and C. parapsilosis but not of C auris compared to their controls (FLC and 0.5 % DMSO). Comp 3 also disrupted C. albicans biofilm formation and eradicated mature biofilms. Notably, other derivatives of AbnCBD disrupted the biofilm formation and maturation of C. albicans but did not affect yeast growth. In a murine model of VVC, comp 3 demonstrated significant fungal clearance and reduced C. albicans burden compared to vehicle and FLC controls. These findings highlight the potential of AbnCBDs as promising antifungal agents against Candida infections
... Previous reports indicate that LPI hinders microglial phagocytosis via G protein coupled receptor 55 (GPR55)-dependent pathway and suppresses NO production via GPR55-independent pathway, exhibiting an anti-inflammatory effect in cultured activated microglia [77]. GPR55 is widely expressed in the nervous system, and LPI is its endogenous ligand, which is involved in various brain functions such as social interaction, memory, and anxiety [78][79][80][81]. Additionally, GPR55 has been shown to influence barrier susceptibility by modulating T lymphocyte migration [82]. ...
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Background Atmospheric particulate matter (PM) exposure-induced neuroinflammation is critical in mediating nervous system impairment. However, effective intervention is yet to be developed. Results In this study, we examine the effect of β-nicotinamide mononucleotide (NMN) supplementation on nervous system damage upon PM exposure and the mechanism of spatial regulation of lipid metabolism. 120 C57BL/6 male mice were exposed to real ambient PM for 11 days (subacute) or 16 weeks (sub-chronic). NMN supplementation boosted the level of nicotinamide adenine dinucleotide (NAD⁺) in the mouse brain by 2.04 times. This augmentation effectively reduced neuroinflammation, as evidenced by a marked decrease in activated microglia levels across various brain regions, ranging from 29.29 to 85.96%. Whole brain lipidomics analysis revealed that NMN intervention resulted in an less increased levels of ceramide (Cer) and lysophospholipid in the brain following subacute PM exposure, and reversed triglyceride (TG) and glycerophospholipids (GP) following sub-chronic PM exposure, which conferred mice with anti-neuroinflammation response, improved immune function, and enhanced membrane stability. In addition, we demonstrated that the hippocampus and hypothalamus might be the most sensitive brain regions in response to PM exposure and NMN supplementation. Particularly, the alteration of TG (60:10, 56:2, 60:7), diacylglycerol (DG, 42:6), and lysophosphatidylcholine (LPC, 18:3) are the most profound, which correlated with the changes in functional annotation and perturbation of pathways including oxidative stress, inflammation, and membrane instability unveiled by spatial transcriptomic analysis. Conclusions This study demonstrates that NMN intervention effectively reduces neuroinflammation in the hippocampus and hypothalamus after PM exposure by modulating spatial lipid metabolism. Strategies targeting the improvement of lipid homeostasis may provide significant protection against brain injury associated with air pollutant exposure.
... Modulation of speci c elements of the ECS exerts different effects in experimental models of PD, symptomatic (29), neuroprotective (30) or accelerating (31) the time course of the disease. In this study we have focused on the neuroprotective effect of monoacylglycerol lipase (MAGL) inhibition with JZL184 in vivo (30). ...
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Background Neuroinflammation is a key feature of Parkinson´s disease (PD), a neurodegenerative disease for which there is no cure. The cannabinoid receptor type 2 (CB2R) is expressed by cells of the innate and adaptive immune systems. Inhibition of monoacylglycerol lipase increases the levels of the endocannabinoid 2-arachidonoylglycerol (2-AG), which is neuroprotective in an experimental model of PD. We hypothesize that the beneficial effect of MAGL inhibition with JZL184 is mediated by the activation of CB2R on specific immune cell populations. Methods Experimental parkinsonism was induced by chronic administration of MPTP and probenecid for 5 weeks in wild-type (WT), CB2R transgenic and knockout (KO) mice. Motor behavior and histological techniques were used to determine the status of the nigrostriatal pathway. Myeloid and lymphoid subpopulations and their TNFα⁺ production were analyzed by low cytometry in the striatum and ventral midbrain. To distinguish whether a central or peripheral CB2R activation is required for neuroprotection, mice were treated with the CB2R agonists JWH133 and RO304. In addition, WT mice were irradiated and transplanted with CB2R KO hematopoietic stem cells to generate chimeric animals lacking CB2R in the peripheral immune system. Finally, we analyzed the transcriptomic profile of the endocannabinoid system in midbrain microglia and astrocytes from PD patients. Results Parkinsonian mice experimented a specific increase in CD4⁺ T cell infiltration in the midbrain. The neuroprotective effect of JZL184 was accompanied by a reduction in CD4⁺ T cell infiltration, these effects were abolished in CB2R KO mice. CB2R expression was restricted to myeloid cells and lymphocytes, and increased in microglia under parkinsonian conditions. Administration of JWH133, but not RO304, exerted a neuroprotective and immunomodulatory effect similar to that of JZL184. Using chimeric mice, we demonstrated that central CB2R activation is required for neuroprotection. Transcripts related to 2-AG biosynthesis are downregulated in the midbrain microglia from PD patients. Conclusions Activation of CB2R in the brain prevents nigrostriatal degeneration, CD4⁺ T cell infiltration and TNFα production in the midbrain of parkinsonian mice. The reduced 2-AG signaling in microglia from PD patients suggests that activation of microglial CB2R may be an interesting strategy for the treatment of PD.
... Due to its abundant expression in the striatum, the GPR55 receptor appears to play a role in the modulation of motor function [79]. Studies conducted by Celorrio et al. demonstrated that GPR55 receptor activation, through agonism with abnormal cannabidiol (a synthetic isomer of cannabidiol with high afnity towards GPR55), prevents dopaminergic cell death, motor defcits, and damage-associated morphological changes in microglia in a chronic MPTPp model in C57BL/6 mice [80]. Additionally, agonism of the GPR55 receptor with VCE-006.1 has been shown to reverse motor defcit induced by 6-OHDA in pole test and cylinder rearing tests, as well as prevent the loss of dopaminergic neurons and inhibit the reactivity of glial cells in SNpc [81]. ...
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Parkinson’s disease (PD) is a neurodegenerative disorder characterized by alterations in motor capacity resulting from a decrease in the neurotransmitter dopamine due to the selective death of dopaminergic neurons of the nigrostriatal pathway. Unfortunately, conventional pharmacological treatments fail to halt disease progression; therefore, new therapeutic strategies are needed, and currently, some are being investigated. The endocannabinoid system (ECS), highly expressed in the basal ganglia (BG) circuit, undergoes alterations in response to dopaminergic depletion, potentially contributing to motor symptoms and the etiopathogenesis of PD. Substantial evidence supports the neuroprotective role of the ECS through various mechanisms, including anti-inflammatory, antioxidative, and antiapoptotic effects. Therefore, the ECS emerges as a promising target for PD treatment. This review provides a comprehensive summary of current clinical and preclinical evidence concerning ECS alterations in PD, along with potential pharmacological targets that may exert the protection of dopaminergic neurons.
... GPR55 has gained attention in the last decades, and various signal pathways associated with inflammation and oxidative stress are controlled by this receptor. The pathways modulated by GPR55 might contribute to psychiatric and neuropsychiatric pathologies, therefore, targeting this receptor might enfold beneficous effects in some disorders [39][40][41][42][43]. ...
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Pharmacological treatment of psychiatric disorders remains challenging in clinical, pharmacological, and scientific practice. Even if many different substances are established for treating different psychiatric conditions, subgroups of patients show only small or no response to the treatment. The neuroinflammatory hypothesis of the genesis of psychiatric disorders might explain underlying mechanisms in these non-responders. For that reason, recent research focus on neuroinflammatory processes and oxidative stress as possible causes of psychiatric disorders. G-protein coupled receptors (GPCRs) form the biggest superfamily of membrane-bound receptors and are already well known as pharmacological targets in various diseases. The G-protein coupled receptor 55 (GPR55), a receptor considered part of the endocannabinoid system, reveals promising modulation of neuroinflammatory and oxidative processes. Different agonists and antagonists reduce pro-inflammatory cytokine release, enhance the synthesis of anti-inflammatory mediators, and protect cells from oxidative damage. For this reason, GPR55 ligands might be promising compounds in treating subgroups of patients suffering from psychiatric disorders related to neuroinflammation or oxidative stress. New approaches in drug design might lead to new compounds targeting different pathomechanisms of those disorders in just one molecule.
... Results of in vivo studies of effects of CBD on dopaminergic cells in animal models of PD are conflicting. The administration of CBD (5 mg/kg) for 5 weeks did not impact dopaminergic neuronal loss in mice that were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; Celorrio et al., 2017). In other study, the daily administration of CBD (3 mg/kg) for 13 days decreased dopamine levels and TH expression in the striatum in rats that received unilateral injections of 6-OHDA in the MFB . ...
Article
Objective To investigate the effects of cannabidiol (CBD) on emotional and cognitive symptoms in rats with intra-nigral 6-hydroxydopamine (6-OHDA) lesions. Methods Adult male Wistar rats received bilateral intranigral 6-OHDA infusions and were tested in a battery of behavioral paradigms to evaluate nonmotor symptoms. The brains were obtained to evaluate the effects of CBD on hippocampal neurogenesis. Results 6-hydroxydopamine-lesioned rats exhibited memory impairments and despair-like behavior in the novelty-suppressed feeding test and forced swim test, respectively. The animals also exhibited dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), striatum, and ventral tegmental area and a reduction of hippocampal neurogenesis. Cannabidiol decreased dopaminergic neuronal loss in the SNpc, reduced the mortality rate and decreased neuroinflammation in 6-OHDA-lesioned rats. In parallel, CBD prevented memory impairments and attenuated despair-like behavior that were induced by bilateral intranigral 6-OHDA lesions. Repeated treatment with CBD favored the neuronal maturation of newborn neurons in the hippocampus in Parkinsonian rats. Conclusion The present findings suggest a potential beneficial effect of CBD on nonmotor symptoms induced by intra-nigral 6-OHDA infusion in rats.
... Although LPIs are much less explored compared to lysophosphatidic acid (LPA), over the years they have come to be considered as bioactive lipids, and their role as endogenous agonists for GPR55 is now widely accepted [53,54]. GPR55 is implicated in many physiological processes and its activation has been found beneficial in combating PD [55]. Moreover, a neuroprotective effect of LPI against glutamate-induced neuronal cell death and altered neurotransmission in PD has been reported [56]. ...
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Parkinson's disease (PD) is a prevalent neurodegenerative disorder with a poorly understood etiology. An accurate diagnosis of idiopathic PD remains challenging as misdiagnosis is common in routine clinical practice. Moreover, current therapeutics focus on symptomatic management rather than curing or slowing down disease progression. Therefore, identification of potential PD biomarkers and providing a better understanding of the underlying disease pathophysiology are urgent. Herein, hydrophilic interaction liquid chromatography–mass spectrometry (LC-MS/MS) and gas chromatography-mass spectrometry (GC-TOF MS) based metabolomics approaches were used to profile the serum metabolome of 50 patients with different stages of idiopathic PD (early, mid and advanced) and 45 age-matched controls. Levels of 57 metabolites including cysteine-S-sulfate and N-acetyl tryptophan were significantly higher in patients with PD compared to controls, with lower amounts of additional 51 metabolites including vanillic acid, and N-acetylaspartic acid. Xanthines, including caffeine and its downstream metabolites, were lowered in patients with PD relative to controls indicating a potential role caffeine and its metabolites against neuronal damage. Seven metabolites, namely cysteine-S-sulfate, 1-methylxanthine, vanillic acid, N-acetylaspartic acid, 3-N-acetyl tryptophan, 5-methoxytryptophol, and 13-HODE yielded a ROC curve with a high classification accuracy (AUC 0.977). Comparison between different PD stages showed that cysteine-S-sulfate levels were significantly increasing with the advancement of PD stages while LPI 20:4 was significantly decreasing with disease progression. Our findings provide new biomarker candidates to assist in the diagnosis of PD and monitor its progression. Unusual metabolites like cysteine-S-sulfate might point to therapeutic targets that could enhance the development of novel PD treatments, such as NMDA antagonists.
... Regarding GPR55, it has been shown to act in the nervous system, being a therapeutic target for Parkinson's disease [91][92][93], Alzheimer's disease (Medina-Vera et al, 2020), epilepsy (Gaston et al, 2016; Kaplan et al., 2017), in memory and spatial learning [94]. Furthermore, that it exerts antiproliferative effects through inhibition of protein kinase B (PKB) and extracellular signal-regulated kinase (ERK) in which CBD acts as a GPR55 antagonist [90], as well as, that PEA has high affinity for GPR55 as a full agonist [95]. ...
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Neurodegenerative diseases have complex etiologies, however, neuroinflammation and oxidative stress are important markers in this pathogenesis and, in this sense, cannabinoids, especially CBD, have been identified as potential therapeutics for playing a neuroprotective role. Studies have demonstrated the neuroprotective effect of cannabinoids and derivatives of Cannabis sativa L in diseases of the central nervous system due to their interaction with the endocannabinoid system through receptors and other molecular targets. The aim of this review was to provide an overview of the endocannabinoid system and a summary of the clinical and preclinical findings of the therapeutic use of cannabinoids in epilepsy, multiple sclerosis and Parkinson’s disease, pointing out interactions with molecular targets and the potential for neuroprotection of CBD. Electronic searches were carried out in international databases, including studies that presented consistent data on this subject. Significant therapeutic effects of CBD were shown for epilepsy and Parkinson’s disease, while nabiximols contributed to the reduction of spasticity, being a frequent option for the treatment of multiple sclerosis. Although much has been projected on the therapeutic potential of cannabinoids for neurological disorders, there is a long way to go in the search for strong scientific evidence of their pharmacological effectiveness.
... 206 Given the high expression of GPR55 in the striatum, GPR55 signaling is suspected to be involved in motor impairment in Parkinson's disease. 207 Dopamine receptor. Dopamine is a catecholamine neurotransmitter in the brain. ...
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Neuropsychiatric disorders are multifactorial disorders with diverse aetiological factors. Identifying treatment targets is challenging because the diseases are resulting from heterogeneous biological, genetic, and environmental factors. Nevertheless, the increasing understanding of G protein-coupled receptor (GPCR) opens a new possibility in drug discovery. Harnessing our knowledge of molecular mechanisms and structural information of GPCRs will be advantageous for developing effective drugs. This review provides an overview of the role of GPCRs in various neurodegenerative and psychiatric diseases. Besides, we highlight the emerging opportunities of novel GPCR targets and address recent progress in GPCR drug development.
... The CB 1 , CB 2 and TRPV1 receptors are activated by anandamide. The summary of CBD's mechanisms of action in the treatment of PD is shown in Fig. 4. Celorrio and colleagues [77] investigated the possibility of regulating GPR55 using a synthetic CBD isomer which may be used as a therapeutic method in treating PD. They reported improved motor behavior in animals treated with CBD and anti-cataleptic properties. ...
Article
Cannabidiol (CBD), a nonpsychotropic phytocannabinoid that was once largely disregarded, is currently the subject of significant medicinal study. CBD is found in Cannabis sativa, and has a myriad of neuropharmacological impacts on the central nervous system, including the capacity to reduce neuroinflammation, protein misfolding and oxidative stress. On the other hand, it is well established that CBD generates its biological effects without exerting a large amount of intrinsic activity upon cannabinoid receptors. Because of this, CBD does not produce undesirable psychotropic effects that are typical of marijuana derivatives. Nonetheless, CBD displays the exceptional potential to become a supplementary medicine in various neurological diseases. Currently, many clinical trials are being conducted to investigate this possibility. This review focuses on the therapeutic effects of CBD in managing neurological disorders like Alzheimer’s disease, Parkinson’s disease and epilepsy. Overall, this review aims to build a stronger understanding of CBD and provide guidance for future fundamental scientific and clinical investigations, opening a new therapeutic window for neuroprotection.
... An overall neuroprotective effect and an improvement in motor function were seen in a mouse model treated with CB and a GPR55 agonist. This could be a primary objective of PD therapy (Pertwee 2007;Martínez-Pinilla et al. 2020;Celorrio et al. 2017). ...
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Parkinson's disease is a neurodegenerative disorder which is characterised mostly by loss of dopaminergic nerve cells throughout the nigral area mainly as a consequence of oxidative stress. Muscle stiffness, disorganised bodily responses, disturbed sleep, weariness, amnesia, and voice impairment are all symptoms of dopaminergic neuron degeneration and existing symptomatic treatments are important to arrest additional neuronal death. Some cannabinoids have recently been demonstrated as robust antioxidants that might protect the nerve cells from degeneration even when cannabinoid receptors are not triggered. Cannabinoids are likely to have property to slow or presumably cease the steady deterioration of the brain's dopaminergic systems, a condition for which there is now no treatment. The use of cannabinoids in combination with currently available drugs has the potential to introduce a radically new paradigm for treatment of Parkinson's disease, making it immensely useful in the treatment of such a debilitating illness.
... [8][9][10][11][12][13] Cannabidiol also antagonizes G protein-coupled receptor 55, which may help improve PD symptoms. [14,15] These processes are all related to PD pathogenesis. Cannabidiol, the main modulator of the endocannabinoid system, may have beneficial effects in PD. ...
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Objectives The objective of this study was to assess cannabidiol-enriched cannabis extraction product (CBDEP) efficacy in patients with Parkinson’s disease (PD). Materials and Methods Forty patients with PD were randomly assigned to the sublingual CBDEP ( n = 20) or placebo ( n = 20) group. All patients were prescribed a low initial dose with gradual titration within 2 weeks based on individual response – including side effects – followed by 6 weeks of stable dosing. The primary outcome was the Unified Parkinson’s Disease Rating Scale (UPDRS) score. The secondary outcomes were as follows: Quality of life (QOL) evaluated by the EQ-5D-5L, timed up and go (TUG) test, 5 times sit to stand (FTSTS) test, gait velocity, hospital anxiety and depression scale (HADS), renal and liver function indices, and adverse events. All outcomes were measured at baseline and at 8 weeks. The generalized estimating equation adjusted for baseline scores was used to compare the values at baseline and at 8 weeks, and between the groups. Results Four patients were lost to follow-up (CBDEP group, n = 1; placebo group, n = 3) and 36 were included in the analysis (CBDEP group, n = 19; placebo group, n = 17). The CBDEP group received mean cannabidiol and tetrahydrocannabinol dosages of 15.59 ± 5.04 mg/day and 0.61 ± 0.19 mg/day, respectively. No significant differences were found between the groups in terms of the UPDRS, TUG test, FTSTS test, gait velocity, HADS-anxiety, and HADS-depression. The placebo group had significantly improved EQ-5D-5L scores for QOL ( P = 0.004). The CBDEP group showed significantly improved blood urea nitrogen (BUN), serum albumin, serum globulin levels, and albumin/globulin ratio ( P = 0.037, P < 0.001, P = 0.011, and P = 0.002, respectively) compared with the placebo group. Neither group had serious side effects. Conclusion No evidence was found that CBDEP can reduce disease severity or improve functional performance, anxiety, or depression in PD. However, CBDEP is safe and can improve the levels of BUN, serum albumin, serum globulin, and albumin/globulin ratio in patients with PD. Trial Registration Thai Clinical Trials Registry (registration number: TCTR 20210303005).
... Orphan GPCRs are those whose endogenous ligands have not yet been discovered. Some of the orphan GPCRs take part in significant physiological process, thus serving as potential targets for treating numerous diseases, such as GPR119 for diabetes [13], GPR55 for Parkinson's disease [14], and GPR84 for ulcerative colitis [15]. ...
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Germinal center (GC) reaction greatly contributes to the humoral immune response, which begins in lymph nodes or other secondary lymphoid organs after follicular B cells are activated by T-dependent antigens. The GCs then serve as a platform for follicular B cells to complete clonal expansion and somatic hypermutation and then interact with follicular dendritic cells (FDC) and follicular helper T cells (Tfh). Through the interaction between the immune cells, significant processes of the humoral immune response are accomplished, such as antibody affinity maturation, class switching, and production of memory B cells and plasma cells. Cell positioning during the GC reaction is mainly mediated by the chemokine receptors and lipid receptors, which both belong to G protein-coupled receptors (GPCRs) family. There are some orphan GPCRs whose endogenous ligands are unclear yet contribute to the regulation of GC reaction as well. This review will give an introduction on the ligands and functions of two types of GC-relating GPCRs—chemokine receptors like CXCR4 and CXCR5, as well as emerging de-orphanized GPCRs like GPR183, GPR174, and P2RY8. The roles these GPCRs play in several antibody-mediated autoimmune skin diseases will be also discussed, including systemic lupus erythematosus (SLE), pemphigus, scleroderma, and dermatomyositis. Besides, GPCRs are excellent drug targets due to the unique structure and vital functions. Therefore, this review is aimed at providing readers with a focused knowledge about the role that GPCRs play in GC reaction, as well as in provoking the development of GPCR-targeting agents for immune-mediated diseases besides autoimmune diseases.
... The expression of GPR55 in mouse tissue has been reported in the nervous system including the hippocampus, though its function remains unknown (Sylantyev et al. 2013). GPR55 agonists have been shown to have a neuroprotective effect on Parkinson's disease (Celorrio et al. 2017), anxiety (Rahimi et al. 2015), and pain perception (Deliu et al. 2015). In addition, it has been reported that activation of GPR55 can strongly protect from ER stress-induced apoptosis in pancreatic β-cells (Vong et al. 2019). ...
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Our previous research found that activation of GPR55 can alleviate cognitive impairment induced by amyloid-beta 1–42 (Aβ1-42) and streptozotocin in mice, but the role of GPR55 in the pathogenesis of cognitive impairment remains unknown. Here, we used a lipopolysaccharide (LPS) mouse model to further investigate the role and mechanism of O-1602, a GPR55 agonist, on cognitive dysfunction. ICR mice were treated with an intracerebroventricular (i.c.v.) injection of LPS, followed by cognitive function tests. The expression of GPR55, NF-κB p65, caspase-3, Bax, and Bcl-2 in the hippocampus was examined by Western blotting. Inflammatory cytokines and microglia were detected by ELISA kit and immunohistochemical analyses, respectively. The levels of MDA, GSH, SOD, and CAT were examined by assay kits. Furthermore, TUNEL-staining was used to detect neuronal apoptosis. Our results showed that i.c.v. injection of LPS in mice exhibited impaired performance in the behavior tests, which were ameliorated by O-1602 treatment (2.0 or 4.0 μg/mouse, i.c.v.). Importantly, we found that O-1602 treatment reversed GPR55 downregulation, decreased the expression of NF-κB p65, suppressed the accumulation of proinflammatory cytokines and microglia activation, increased the anti-inflammatory cytokines, and reduced the levels of MDA, increased the levels of GSH, SOD, and CAT in the hippocampus. In addition, O-1602 treatment also significantly reduced Bax and increased Bcl-2 expression as well as decreased caspase-3 activity and TUNEL-positive cells in the hippocampus. These observations indicate that O-1602 may ameliorate LPS-induced cognition deficits via inhibiting neuroinflammation, oxidative stress, and apoptosis mediated by the NF-κB pathway in mice.
... Another possible cannabinoid receptor is GPR55, which is highly expressed in the striatum and has been found to exert a neuroprotective effect in a rat model of excitotoxic injury (Sawzdargo et al., 1999;Ryberg et al., 2007;Celorrio et al., 2017). In addition, GPR55 may also interact with cannabinoids and may be regulated by CB1 receptors (Ulrich et al., 2014;Zheng et al., 2017). ...
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Guidance molecules regulate the navigation of retinal ganglion cell (RGC) projections toward targets in the visual thalamus. In this study, we demonstrate that the G-protein-coupled receptor 55 (GPR55) is expressed in the retina during development, and regulates growth cone (GC) morphology and axon growth. In vitro, neurons obtained from gpr55 knock-out (gpr55-/-) mouse embryos have smaller GCs, less GC filopodia, and have a decreased outgrowth compared with gpr55+/+ neurons. When gpr55+/+ neurons were treated with GPR55 agonists, lysophosphatidylinositol (LPI) and O-1602, we observed a chemo-attractive effect and an increase in GC size and filopodia number. In contrast, cannabidiol (CBD) decreased the GC size and filopodia number inducing chemo-repulsion. In absence of the receptor (gpr55-/-), no pharmacologic effects of the GPR55 ligands were observed. In vivo, compared to their wild-type (WT) littermates, gpr55-/- mice revealed a decreased branching in the dorsal terminal nucleus (DTN) and a lower level of eye-specific segregation of retinal projections in the superior colliculus (SC) and in the dorsal lateral geniculate nucleus (dLGN). Moreover, a single intraocular injection of LPI increased branching in the DTN, whereas treatment with CBD, an antagonist of GPR55, decreased it. These results indicate that GPR55 modulates the growth rate and the targets innervation of retinal projections and highlight, for the first time, an important role of GPR55 in axon refinement during development.
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Simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylases (HDAC) has recently been validated as a potentially novel therapeutic approach for Alzheimer’s Disease (AD). To further extend this concept, we designed and synthesized the first chemical series of dual acting PDE5 and HDAC inhibitors, and we validated this systems therapeutics approach. Following the implementation of structure- and knowledge-based approaches, initial hits were designed and were shown to validate our hypothesis of dual in vitro inhibition. Then, an optimization strategy was pursued to obtain a proper tool compound for in vivo testing in AD models. Initial hits were translated into molecules with adequate cellular functional responses (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation in the nanomolar range), an acceptable therapeutic window (>1 log unit) and the ability to cross the blood-brain barrier, leading to the identification of 7 as a candidate for in vivo proof-of-concept testing (described in ref 23).
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Elements of the endocannabinoid system are strongly expressed in the basal ganglia where they suffer profound rearrangements after dopamine depletion. Modulation of the levels of the endocannabinoid 2-arachidonoyl glycerol by inhibiting monoacylglycerol lipase alters glial phenotypes and provides neuroprotection in a mouse model of Parkinsońs disease. In this study, we assessed whether inhibiting fatty acid amide hydrolase could also provide beneficial effects on the time course of this disease. The fatty acid amide hydrolase inhibitor, URB597, was administered chronically to mice treated with probenecid and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTPp) over 5 weeks. URB597 (1 mg/kg) prevented MPTPp induced motor impairment but it did not preserve the dopamine levels in the nigrostriatal pathway or regulate glial cell activation. The symptomatic relief of URB597 was confirmed in haloperidol-induced catalepsy assays, where its anti-cataleptic effects were both blocked by antagonists of the two cannabinoid receptors (CB1 and CB2), and abolished in animals deficient in these receptors. Other fatty acid amide hydrolase inhibitors, JNJ1661010 and TCF2, also had anti-cataleptic properties. Together, these results demonstrate an effect of fatty acid amide hydrolase inhibition on the motor symptoms of Parkinsońs disease in two distinct experimental models that is mediated by cannabinoid receptors.
Article
To investigate the role of GPR55 receptors, which are expressed in human and rat striatum (a structure that regulates procedural memory), Wistar rats received five training sessions (10 trials/session, 1 session/day) to solve a T-maze paradigm. From these data, we constructed learning curves following pharmacological manipulation of GPR55. Five minutes before each session, animals received bilateral intradorsolateral striatum injections of noladin-ether (3.1 nmol/l; endogenous agonist of GPR55 and CB1 receptors), CID16020036 (5.6 nmol/l; GPR55 antagonist), AM251 (5.6 nmol/l; CB1 antagonist), or a combination of noladin-ether with each antagonist. Noladin-ether by itself induced no significant changes in the learning curve. Nevertheless, while simultaneously blocking CB1 receptors (with AM251), noladin-ether improved acquisition. In contrast, while simultaneously blocking GPR55 (with CID16020036), noladin-ether weakened acquisition. CID16020036 by itself impaired learning, whereas AM251 by itself improved learning. There were no differences between groups in the latency to reach the arms from the starting point; thus, no motor coordination impairments interfered with this task. These results strongly suggest a role of GPR55 in procedural memory and constitute the first evidence indicating that this receptor regulates cognitive processes.
Article
Cannabidiol has been reported to act as an antagonist of cannabinoid agonists at type 1 cannabinoid receptors (CB1 ). We hypothesized that cannabidiol can inhibit cannabinoid agonist activity through negative allosteric modulation of CB1 . CB1 internalization, arrestin2 recruitment, and PLCβ3 and ERK1/2 phosphorylation, were quantified in HEK 293A cells heterologously expressing CB1 and in the STHdh(Q7/Q7) cell model of striatal neurons endogenously expressing CB1 . Cells were treated with 2-arachidonylglycerol or Δ(9) -tetrahydrocannabinol alone and in combination with different concentrations of cannabidiol. Cannabidiol reduced the efficacy and potency of 2-arachidonylglycerol and Δ(9) -tetrahydrocannabinol on PLCβ3- and ERK1/2-dependent signaling in cells heterologously (HEK 293A) or endogenously (STHdh(Q7/Q7) ) expressing CB1 . By reducing arrestin2 recruitment to CB1 , cannabidiol treatment prevented CB1 internalization. The allosteric activity of cannabidiol depended upon polar residues being present at positions 98 and 107 in the extracellular amino-terminus. Cannabidiol behaved as a non-competitive negative allosteric modulator of CB1 . Allosteric modulation, in conjunction with non-CB1 effects, may explain the in vivo effects of cannabidiol. Allosteric modulators of CB1 have the potential to treat central nervous system and peripheral disorders while avoiding the adverse effects associated with orthosteric agonism or antagonism of CB1 . This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Article
Cannabinoids have been reported to mediate changes in vascular resistance through endothelial receptor targets. We examined involvement of the endothelium in cannabinoid-mediated vasoactive responses in resistance arterioles of the retina. Vascular responses to both intraluminal (IL) and extraluminal (EL) administration of the atypical cannabinoid, abnormal cannabidiol (abn-CBD), a prototypical agonist at the non-CB1/CB2 endothelial cannabinoid receptor (CBeR), were studied in endothelial intact and endothelial denuded, isolated perfused porcine retinal arterioles with and without endothelin-1 (ET-1) precontraction. The effects of AM251, a CB1 receptor antagonist, and O-1918, an analog of CBD reported to antagonize CBeR, were also studied. Dose-dependent vasocontractile responses were induced by both IL and EL administration of abn-CBD in the absence of precontraction. Significantly greater vasoconstriction was induced by IL administration of abn-CBD than with EL administration. In contrast, only vasodilation to abn-CBD was observed in ET-1 precontracted retinal arterioles. Endothelium removal significantly reduced abn-CBD-induced vasoactivity when abn-CBD was used IL but not when applied EL. IL abn-CBD-induced vasoactivity was antagonized by O-1918 and AM251. Cannabinoids show complex vasoactive actions in isolated perfused retinal arterioles. The fact that abn-CBD-mediated vasorelaxation was seen only in precontracted retinal vessels indicates that the abn-CBD-induced vasoactive response is highly dependent on vascular tone. Furthermore, IL and EL administration produced differential responses, and removal of endothelium blunted abn-CBD vasoactivity, highlighting the critical role of endothelium in abn-CBD vasoactivity. AM251 and O-1918 inhibition of abn-CBD-induced vasoactivity suggests the possibility of modulating abn-CBD-induced vasoactivity.
Article
Growing evidence suggests that the endocannabinoid system plays a role in neuroprotection in Parkinson's disease. Recently, we have shown the neuroprotective effect of monoacylglycerol lipase (MAGL) inhibition with JZL184 in the chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. However, further investigation is needed to determine the neuroprotective mechanisms of the endocannabinoid system on the nigrostriatal pathway. The aim of this work was to investigate whether the neuroprotective effect of JZL184 in mice could be extended to an in vitro cellular model to further understand the mechanism of action of the drug. The SH-SY5Y cell line was selected based on its dopaminergic-like phenotype and its susceptibility to 1-methyl-4-phenylpyridinium iodide (MPP(+)) toxicity. Furthermore, SH-SY5Y cells express both cannabinoid receptors, CB1 and CB2. The present study describes the neuroprotective effect of MAGL inhibition with JZL184 in SH-SY5Y cells treated with MPP(+). The effect of JZL184 in cell survival was blocked by AM630, a CB2 receptor antagonist, and it was mimicked with JWH133, a CB2 receptor agonist. Rimonabant, a CB1 receptor antagonist, did not affect JZL184-induced cell survival. These results demonstrate that the neuroprotective effect of MAGL inhibition with JZL184 described in animal models of Parkinson's disease could be extended to in vitro models such as SH-SY5Y cells treated with MPP(+). This represents a useful tool to study mechanisms of neuroprotection mediated by MAGL inhibition, and we provide evidence for the possible involvement of CB2 receptors in the improvement of cell survival.
Article
Originally synthesized for research purposes, indole- and pyrrole-derived synthetic cannabinoids are the most common psychoactive compounds contained in abused products marketed as "spice" or "herbal incense." While CB1 and CB2 receptor affinities are available for most of these research chemicals, in vivo pharmacological data are sparse. In mice, cannabinoids produce a characteristic profile of dose-dependent effects: antinociception, hypothermia, catalepsy and suppression of locomotion. In combination with receptor binding data, this tetrad battery has been useful in evaluation of the relationship between the structural features of synthetic cannabinoids and their in vivo cannabimimetic activity. Here, published tetrad studies are reviewed and additional in vivo data on synthetic cannabinoids are presented. Overall, the best predictor of likely cannabimimetic effects in the tetrad tests was good CB1 receptor affinity. Further, retention of good CB1 affinity and in vivo activity was observed across a wide array of structural manipulations of substituents of the prototypic aminoalkylindole molecule WIN55,212-2, including substitution of an alkyl for the morpholino group, replacement of an indole core with a pyrrole or phenylpyrrole, substitution of a phenylacetyl or tetramethylcyclopropyl group for JWH-018's naphthoyl, and halogenation of the naphthoyl group. This flexibility of cannabinoid ligand-receptor interactions has been a particular challenge for forensic scientists who have struggled to identify and regulate each new compound as it has appeared on the drug market. One of the most pressing future research needs is determination of the extent to which the pharmacology of these synthetic cannabinoids may differ from those of classical cannabinoids.
Article
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. GLIA 2013.
Article
G-protein coupled receptor (GPR)55 is a novel lipid sensing receptor activated by both cannabinoid endogenous ligands (endocannabinoids) and other non-cannabinoid lipid transmitters. This study assessed the effects of various GPR55 agonists on glucose homeostasis. Insulin secretion and changes in intracellular Ca(2+) and cAMP in response to glucose and a range of GPR55 agonists (endogenous ligands (OEA, PEA), chemically synthetic CBD analogues (Abn-CBD, 0-1602), an analogue of rimonabant (AM-251) and antagonist (CBD)) were investigated in clonal BRIN-BD11 cells and mouse pancreatic islets. Cytotoxicity was assessed by LDH release, cellular localisation by double-staining immunohistochemistry and in vivo effects assessed in mice. The most potent and selective GPR55 agonist was the synthetic CBD analogue, Abn-CBD (pEC50 10.33), maximum stimulation of 67% at 10(-4) mol/l (p<0.001) in BRIN-BD11 cells. AM-251 (pEC50 7.0), OEA (pEC50 7.0), 0-1602 (pEC50 7.3) and PEA (pEC50 6.0) stimulated insulin secretion. Results were corroborated by islet studies, with no cytotoxic effects. Concentration-dependent insulin secretion by GPR55 agonists was glucose-sensitive and accompanied by elevations of [Ca(2+) ]i (p<0.01-p<0.001) and cAMP (p<0.05-p<0.01). GPR55 agonists exhibited insulinotropic and glucose lowering activity in vivo. GPR55 was expressed on BRIN-BD11 cells and confined to islet beta cells with no distribution on alpha cells. These results demonstrate GPR55 is distributed in pancreatic beta cells and is a strong activator of insulin secretion, with glucose-lowering effects in vivo. Development of agents agonising the GPR55 receptor may have therapeutic potential in the treatment of type 2 diabetes.
Article
The superior efficiency of systematic sampling at all levels in stereological studies is emphasized and various commonly used ways of implementing it are briefly described. Summarizing recent theoretical and experimental studies a set of very simple estimators of efficiency are presented and illustrated with a variety of biological examples. In particular, a nomogram for predicting the necessary number of points when performing point counting is provided. The very efficient and simple unbiased estimator of the volume of an arbitrary object based on Cavalieri's principle is dealt with in some detail. The efficiency of the systematic fractionating of an object is also illustrated.