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Paclitaxel induces microglial activation and production of proinflammatory mediators in the dorsal horn, which contribute to the development and maintenance of central sensitization and pain behavior. MDA7, 1-([3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl]carbonyl) piperidine, is a novel highly selective cannabinoid type 2 (CB2) agonist. We tested the hypothesis that activation of CB2 receptor by MDA7 modulates microglial dysregulation, suppresses the overexpression of brain-derived neurotrophic factor (BDNF) in microglia in the dorsal horn, and attenuates the central sensitization and pain behavior induced by paclitaxel. For 4 consecutice days, groups of rats randomly received saline or 1.0 mg/kg of paclitaxel daily intraperitoneally for a total cumulative dose of 4 mg/kg. MDA7 15 mg/kg intraperitoneally or vehicle were administered 15 min before administering paclitaxel for 4 days and then continued for another 10 days. Behavioral and molecular studies were performed. Paclitaxel induced the expression of CB2 receptors and production of interleukin (IL)-6 in microglia in the dorsal horn. MDA7 attenuated the expression of IL-6 and promoted the expression of IL-10. Paclitaxel induced epigenetic upregulation of IRF8 and P2X purinoceptor 4 (P2X4) in microglia and subsequently increased the expression of alpha isoform of calcium/calmodulin-dependent protein kinase II (CaMKIIα), transcriptional factors p-CREB and ΔFosB, leading to the overproduction of BDNF in microglia. Paclitaxel also upregulated the expression of glutamate receptor subunits GluR1 and NR2B, decreased the expression of K + -Cl - cotransporter, and induced mechanical allodynia in rats. All of the aforementioned molecular changes were attenuated by MDA7. Our data show that MDA7 attenuated paclitaxel-induced molecular and behavioral changes in rats. Perspective: This study provides evidence that paclitaxel induced microglia dysregulation and epigenetically upregulated the microglial expression of BDNF, which led to sensitization of dorsal horn neurons and mechanical allodynia in rats. The CB2 agonist MDA7 alleviated these pathological processes. MDA7 represents an innovative therapeutic approach for treatment of chemotherapy-induced neuropathy., (Copyright © 2018 the American Pain Society. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: This narrative review summarizes recent insights into the role of the cannabinoid type 2 (CB2) receptor as potential therapeutic target in neuropathic pain and neurodegenerative conditions., Recent Findings: The cannabinoid system continues to receive attention as a therapeutic target. The CB2 receptor is primarily expressed on glial cells only when there is active inflammation and appears to be devoid of undesired psychotropic effects or addiction liability. The CB2 receptor has been shown to have potential as a therapeutic target in models of diseases with limited or no currently approved therapies, such as neuropathic pain and neurodegenerative conditions such as Alzheimer's disease., Summary: The functional involvement of CB2 receptor in neuropathic pain and other neuroinflammatory diseases highlights the potential therapeutic role of drugs acting at the CB2 receptor.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuroinflammation, extensive deposits of amyloid-β aggregates, and loss of memory and cognitive abilities. The brains of patients with AD show increased expression of cannabinoid receptor type 2 (CB 2 ) receptors and glial markers. CB 2 receptors act as a negative feedback regulator; when activated by a CB 2 agonist, they can help limit the extent of the neuroinflammatory response and the subsequent development of neuronal damage in the central nervous system. In a double transgenic APP/PS1 mice model of AD, we evaluated the effect of MDA7, a CB2 agonist, on several neuropathological conditions of AD including amyloid deposition, inflammatory reaction, Sox2 (sex-determining region Y-box 2) expression, and spatial memory. Activation of microglia CB 2 receptors by MDA7 suppressed neuroinflammation, demonstrated by decreased immunosignal of Iba1 in the hippocampal CA1 and dentate gyrus (DG) areas, promoted clearance of amyloid plaques in the DG area, restored Sox2 expression, and promoted recovery of the neuronal synaptic plasticity in hippocampal CA1. In addition, treatment with MDA7 improved the behavioral performance in the Morris water maze in APP/PS1mice. Collectively, these findings suggest that MDA7 has a potential therapeutic effect in the setting of AD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Complex regional pain syndrome type 1 (CRPS-I) remains one of the most clinically challenging neuropathic pain syndromes and its mechanism has not been fully characterized. Cannabinoid receptor 2 (CB2) has emerged as a promising target for treating different neuropathic pain syndromes. In neuropathic pain models, activated microglia expressing CB2 receptors are seen in the spinal cord. Chemokine fractalkine receptor (CX3CR1) plays a substantial role in microglial activation and neuroinflammation. We hypothesized that a CB2 agonist could modulate neuroinflammation and neuropathic pain in an ischemia model of CRPS by regulating CB2 and CX3CR1 signaling. We used chronic post-ischemia pain (CPIP) as a model of CRPS-I. Rats in the CPIP group exhibited significant hyperemia and edema of the ischemic hindpaw and spontaneous pain behaviors (hindpaw shaking and licking). Intraperitoneal administration of MDA7 (a selective CB2 agonist) attenuated mechanical allodynia induced by CPIP. MDA7 treatment was found to interfere with early events in the CRPS-I neuroinflammatory response by suppressing peripheral edema, spinal microglial activation and expression of CX3CR1 and CB2 receptors on the microglia in the spinal cord. MDA7 also mitigated the loss of intraepidermal nerve fibers induced by CPIP. Neuroprotective effects of MDA7 were blocked by a CB2 antagonist, AM630. Our findings suggest that MDA7, a novel CB2 agonist, may offer an innovative therapeutic approach for treating neuropathic symptoms and neuroinflammatory responses induced by CRPS-I in the setting of ischemia and reperfusion injury., (© 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Cannabinoid type 2 (CB(2)) agonists are neuroprotective and appear to play modulatory roles in neurodegenerative processes in Alzheimer's disease. We have studied the effect of 1-((3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl) carbonyl) piperidine (MDA7)-a novel selective CB(2) agonist that lacks psychoactivity-on ameliorating the neuroinflammatory process, synaptic dysfunction, and cognitive impairment induced by bilateral microinjection of amyloid-β (Aβ)(1-40) fibrils into the hippocampal CA1 area of rats. In rats injected with Aβ(1-40) fibrils, compared with the administration of intraperitoneal saline for 14 days, treatment with 15 mg/kg of intraperitoneal MDA7 daily for 14 days (1) ameliorated the expression of CD11b (microglia marker) and glial fibrillary acidic protein (astrocyte marker), (2) decreased the secretion of interleukin-1β, (3) decreased the upsurge of CB(2) receptors, (4) promoted Aβ clearance, and (5) restored synaptic plasticity, cognition, and memory. Our findings suggest that MDA7 is an innovative therapeutic approach for the treatment of Alzheimer's disease., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Enabling formulations based on hydroxypropyl-β-cyclodextrins (HPβCD), micellar preparation, and liposomes have been designed to deliver the racemic mixture of a lipophilic cannabinoid type 2 agonist, MDA7. The antiallodynic effects of MDA7 formulated in these three different systems were compared after intravenous (i.v.) administration in rats. Stoichiometry of the inclusion complex formed by MDA7 in HPβCD was determined by continuous variation plot, electrospray ionization-mass spectrometry (ESI-MS) analysis, phase solubility, and nuclear magnetic resonance studies and indicate formation of exclusively 1:1 adduct. Morphology and particle sizes determined by dynamic light scattering and transmission electron microscopy show the presence of a homogeneous population of closed round-shaped oligolamellar MDA7 containing liposomes, with an average size of 118 nm [polydispersity index (PDI) 0.03]. Monodisperse micelles exhibited an average size of 14 nm (PDI 0.09). HPβCD-based formulation administrated in vivo was composed of two discrete particles populations with a narrow size distribution of 3 nm (PDI 0.04) and 510 nm (PDI 0.02). HPβCD-based formulation dramatically improved antiallodynic effect of MDA7 in comparison with the liposomes preparation. Through inclusion complexation and possibly formation of aggregates, HPβCD can enhance the aqueous solubility of lipophilic drugs, thereby improving their bioavailability for i.v. administration., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Peripheral neuropathy is a major dose-limiting toxicity of chemotherapy, especially after multiple courses of paclitaxel. The development of paclitaxel-induced neuropathy is associated with the activation of microglia followed by the activation and proliferation of astrocytes, and the expression and release of proinflammatory cytokines in the spinal dorsal horn. Cannabinoid type 2 (CB(2)) receptors are expressed in the microglia in neurodegenerative disease models., Methods: To explore the potential of CB(2) agonists for preventing paclitaxel-induced neuropathy, we designed and synthesized a novel CB(2)-selective agonist, namely, MDA7. The effect of MDA7 in preventing paclitaxel-induced allodynia was assessed in rats and in CB(2)(+/+) and CB(2)(-/-) mice. We hypothesized that the CB(2) receptor functions in a negative-feedback loop and that early MDA7 administration can blunt the neuroinflammatory response to paclitaxel and prevent mechanical allodynia through interference with specific signaling pathways., Results: We found that MDA7 prevents paclitaxel-induced mechanical allodynia in rats and mice in a dose- and time-dependent manner without compromising paclitaxel's antineoplastic effect. MDA7's neuroprotective effect was absent in CB(2)(-/-) mice and was blocked by CB(2) antagonists, suggesting that MDA7's action directly involves CB(2) receptor activation. MDA7 treatment was found to interfere with early events in the paclitaxel-induced neuroinflammatory response as evidenced by relatively reduced toll-like receptor and CB(2) expression in the lumbar spinal cord, reduced levels of extracellular signal-regulated kinase 1/2 activity, reduced numbers of activated microglia and astrocytes, and reduced secretion of proinflammatory mediators in vivo and in in vitro models., Conclusions: Our findings suggest an innovative therapeutic approach to prevent chemotherapy-induced neuropathy and may permit more aggressive use of active chemotherapeutic regimens with reduced long-term sequelae.

Background: Cannabinoid receptor 2 (CB2) agonists have recently gained attention as potential therapeutic targets in the management of neuropathic pain. In this study, we characterized the pharmacological profile of the novel compound N'-[(3Z)-1-(1-hexyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]benzohydrazide (MDA19), a CB2 agonist., Methods: We used radioligand binding assays and multiple in vitro functional assays at human and rat CB(1) and CB(2) receptors. The effects of MDA19 in reversing neuropathic pain were assessed in various neuropathic pain models in rats and in CB2(+/+) and CB2(-/-) mice., Results: MDA19 displayed 4-fold-higher affinity at the human CB(2) than at the human CB1 receptor (K(i) = 43.3 +/- 10.3 vs 162.4 +/- 7.6 nM) and nearly 70-fold-higher affinity at the rat CB2 than at the rat CB1 receptor (K(i) = 16.3 +/- 2.1 vs 1130 +/- 574 nM). In guanosine triphosphate (GTP)gamma[(35)S] functional assays, MDA19 behaved as an agonist at the human CB1 and CB2 receptors and at the rat CB1 receptor but as an inverse agonist at the rat CB2 receptor. In 3',5'-cyclic adenosine monophosphate (cAMP) assays, MDA19 behaved as an agonist at the rat CB1 receptor and exhibited no functional activity at the rat CB(2) receptor. In extracellular signal-regulated kinases 1 and 2 activation assays, MDA19 behaved as an agonist at the rat CB2 receptor. MDA19 attenuated tactile allodynia produced by spinal nerve ligation or paclitaxel in a dose-related manner in rats and CB2(+/+) mice but not in CB2(-/-) mice, indicating that CB2 receptors mediated the effects of MDA19. MDA19 did not affect rat locomotor activity., Conclusions: We found that MDA19 exhibited a distinctive in vitro functional profile at rat CB2 receptors and behaved as a CB1/CB2 agonist in vivo, characteristics of a protean agonist. MDA19 has potential for alleviating neuropathic pain without producing adverse effects in the central nervous system.

We recently discovered and reported a series of N-alkyl-isatin acylhydrazone derivatives that are potent cannabinoid receptor 2 (CB(2)) agonists. In an effort to improve the druglike properties of these compounds and to better understand and improve the treatment of neuropathic pain, we designed and synthesized a new series of 2,3-dihydro-1-benzofuran derivatives bearing an asymmetric carbon atom that behave as potent selective CB(2) agonists. We used a multidisciplinary medicinal chemistry approach with binding mode prediction through ligand-steered modeling. Enantiomer separation and configuration assignment were carried out for the racemic mixture for the most selective compound, MDA7 (compound 18). It appeared that the S enantiomer, compound MDA104 (compound 33), was the active enantiomer. Compounds MDA42 (compound 19) and MDA39 (compound 30) were the most potent at CB(2). MDA42 was tested in a model of neuropathic pain and exhibited activity in the same range as that of MDA7. Preliminary ADMET studies for MDA7 were performed and did not reveal any problems.

Recently, we discovered and reported a series of N-alkyl isatin acylhydrazone derivatives that are potent CB2 agonists. Here, we describe a novel series of selective CB2 inverse agonists resulting from introduction of a methoxy moiety in position 6 of the isatin scaffold. These novel 6-methoxy-N-alkyl isatin acylhydrazone derivatives exhibited high CB2 functional activity and selectivity at human CB2. Compound 16 (MDA77) had high activity (EC(50) = 5.82 nM) at CB2 and no activity at CB1. Compound 15 (MDA55) (K(i) = 89.9 nM, EC(50) = 88.2 nM at CB2) inhibited the effect of compound 1 (MDA7), a selective CB2 agonist, in an animal model of neuropathic pain. The molecular modeling study presented here represents a first study of CB2 based on the structure of beta(2)-adrenergic receptor. A ligand-based homology model of the CB2 binding site was developed, and on the basis of our results, we propose a general binding mode for this class of inverse agonists with CB2.

There is growing interest in using cannabinoid receptor 2 (CB2) agonists for the treatment of neuropathic pain. We have synthesized a novel series of N-alkyl isatin acylhydrazone derivatives and have identified and characterized several of them as novel analogues with high functional activity and selectivity at human CB2 receptors using [(35)S]GTP-gamma-S assays. Binding affinities at human CB2 and CB1 were determined for compounds 28, 33, 40, 48, and 58. Structure-activity relationship studies of this novel series led to optimization of our lead compound, compound 33 (MDA19). Compound 33 possessed potent antiallodynic effects in a rat model of neuropathic pain but did not affect rat locomotor activity. More potent and more CB2-receptor-selective compounds, including compounds 37, 40, and 48, were also discovered.