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Background and purpose Δ9 -Tetrahydrocannabinolic acid (Δ9 -THCA-A), the precursor of Δ9 -THC, is a non-psychotropic phytocannabinoid that shows PPARγ agonist activity. Here, we investigated the ability of Δ9 -THCA-A to modulate the classic cannabinoid CB1 and CB2 receptors and evaluated its anti-arthritis activity in vitro and in vivo. Experimental approach Cannabinoid receptors binding and intrinsic activity, as well as their downstream signalling, were analysed in vitro and in silico. The anti-arthritis properties of Δ9 -THCA-A were studied in human chondrocytes and in the murine model of collagen-induced arthritis (CIA). Plasma disease biomarkers were identified by LC-MS/MS based on proteomic and elisa assays. Key results Functional and docking analyses showed that Δ9 -THCA-A can act as an orthosteric CB1 receptor agonist and also as a positive allosteric modulator in the presence of CP-55,940. Also, Δ9 -THCA-A seemed to be an inverse agonist for CB2 receptors. In vivo, Δ9 -THCA-A reduced arthritis in CIA mice, preventing the infiltration of inflammatory cells, synovium hyperplasia, and cartilage damage. Furthermore, Δ9 -THCA-A inhibited expression of inflammatory and catabolic genes on knee joints. The anti-arthritic effect of Δ9 -THCA-A was blocked by either SR141716 or T0070907. Analysis of plasma biomarkers, and determination of cytokines and anti-collagen antibodies confirmed that Δ9 -THCA-A mediated its activity mainly through PPARγ and CB1 receptor pathways. Conclusion and implications Δ9 -THCA-A modulates CB1 receptors through the orthosteric and allosteric binding sites. In addition, Δ9 -THCA-A exerts anti-arthritis activity through CB1 receptors and PPARγ pathways, highlighting its potential for the treatment of chronic inflammatory diseases such as rheumatoid arthritis.

Intestinal fibrosis is a common complication of inflammatory bowel disease (IBD) and is defined as an excessive accumulation of scar tissue in the intestinal wall. Intestinal fibrosis occurs in both forms of IBD: ulcerative colitis and Crohn’s disease. Small-molecule inhibitors targeting hypoxia-inducing factor (HIF) prolyl-hydroxylases are promising for the development of novel antifibrotic therapies in IBD. Herein, we evaluated the therapeutic efficacy of hydroxamate of betulinic acid (BHA), a hypoxia mimetic derivative of betulinic acid, against IBD in vitro and in vivo. We showed that BAH (5–20 μM) dose-dependently enhanced collagen gel contraction and activated the HIF pathway in NIH-3T3 fibroblasts; BAH treatment also prevented the loss of trans-epithelial electrical resistance induced by proinflammatory cytokines in Caco-2 cells. In two different murine models (TNBS- and DSS-induced IBD) that cause colon fibrosis, oral administration of BAH (20, 50 mg/kg·d, for 17 days) prevented colon inflammation and fibrosis, as detected using immunohistochemistry and qPCR assays. BAH-treated animals showed a significant reduction of fibrotic markers (Tnc, Col1a2, Col3a1, Timp-1, α-SMA) and inflammatory markers (F4/80(+), CD3(+), Il-1β, Ccl3) in colon tissue, as well as an improvement in epithelial barrier integrity and wound healing. BHA displayed promising oral bioavailability, no significant activity against a panel of 68 potential pharmacological targets and was devoid of genotoxicity and cardiotoxicity. Taken together, our results provide evidence that oral administration of BAH can alleviate colon inflammation and colitis-associated fibrosis, identifying the enhancement of colon barrier integrity as a possible mechanism of action, and providing a solid rationale for additional clinical studies.

Background. Rheumatoid arthritis (RA) is a chronic inflammatory joint disease, which can cause cartilage and bone damages as well as pain and disability. In order to prevent disease progression, reduce pain, and major symptoms of RA, one good strategy consists in targeting proinflammatory cytokines that have the key role in the vicious circle of synovial inflammation and pain. The micro-immunotherapy medicine (MIM) 2LARTH® targets cytokines involved in inflammation. Aim. The aim of the study is to evaluate the effect of the MIM compared to vehicle in an in vivo model of RA, induced in mice after immunization with articular bovine type II collagen. Methods. Vehicle and MIM were dissolved in pure water (1 capsule in 100 ml) and 100 µl was given by gavage daily for 14 days. To evaluate the severity of arthritis, wrist and ankle thickness was determined, paw edema was measured, and a clinical score from 0 to 4 was established. Furthermore, histological analysis was performed. To evaluate systemic inflammation, circulating levels of IL-1β and TNF-α were measured by ELISA. Results. Ankle thickness was found to be significantly reduced in MIM-treated mice compared to vehicle-treated mice (P<0.05) and compared to untreated me (P<0.01). Paw edema was reduced, as well as clinical score attributed to MIM-treated mice in comparison with vehicle-treated mice and untreated CIA mice (P<0.01). In line with these results, histological analysis confirmed that MIM reduced inflammation and joint destruction in comparison to controls. No significant changes were found in plasmatic IL-1β levels between CIA and controls, while the levels of TNF-α significantly increased in the CIA group, and were lowered in MIM-treated mice (P<0.05 vs. vehicle and vs. CIA). Conclusion. The results indicate that the tested medicine reduces inflammation, histological, and clinical signs of RA in a CIA model.

BACKGROUND AND PURPOSE: Δ(9)‐Tetrahydrocannabinolic acid (Δ(9)‐THCA‐A), the precursor of Δ(9)‐THC, is a non‐psychotropic phytocannabinoid that shows PPARγ agonist activity. Here, we investigated the ability of Δ(9)‐THCA‐A to modulate the classic cannabinoid CB(1) and CB(2) receptors and evaluated its anti‐arthritis activity in vitro and in vivo. EXPERIMENTAL APPROACH: Cannabinoid receptors binding and intrinsic activity, as well as their downstream signalling, were analysed in vitro and in silico. The anti‐arthritis properties of Δ(9)‐THCA‐A were studied in human chondrocytes and in the murine model of collagen‐induced arthritis (CIA). Plasma disease biomarkers were identified by LC‐MS/MS based on proteomic and elisa assays. KEY RESULTS: Functional and docking analyses showed that Δ(9)‐THCA‐A can act as an orthosteric CB(1) receptor agonist and also as a positive allosteric modulator in the presence of CP‐55,940. Also, Δ(9)‐THCA‐A seemed to be an inverse agonist for CB(2) receptors. In vivo, Δ(9)‐THCA‐A reduced arthritis in CIA mice, preventing the infiltration of inflammatory cells, synovium hyperplasia, and cartilage damage. Furthermore, Δ(9)‐THCA‐A inhibited expression of inflammatory and catabolic genes on knee joints. The anti‐arthritic effect of Δ(9)‐THCA‐A was blocked by either SR141716 or T0070907. Analysis of plasma biomarkers, and determination of cytokines and anti‐collagen antibodies confirmed that Δ(9)‐THCA‐A mediated its activity mainly through PPARγ and CB(1) receptor pathways. CONCLUSION AND IMPLICATIONS: Δ(9)‐THCA‐A modulates CB(1) receptors through the orthosteric and allosteric binding sites. In addition, Δ(9)‐THCA‐A exerts anti‐arthritis activity through CB(1) receptors and PPARγ pathways, highlighting its potential for the treatment of chronic inflammatory diseases such as rheumatoid arthritis.

Background and purpose The endocannabinoid system and PPARγ are important targets for the development of novel compounds against fibrotic diseases such as systemic sclerosis (SSc), also called scleroderma. The aim of this study was to characterize VCE-004.3, a novel cannabidiol derivative, and study its anti-inflammatory and anti-fibrotic activities. Experimental approach The binding of VCE-004.3 to CB1 and CB2 receptors and PPARγ and its effect on their functional activities were studied in vitro and in silico. Anti-fibrotic effects of VCE-004.3 were investigated in NIH-3T3 fibroblasts and human dermal fibroblasts. To assess its anti-inflammatory and anti-fibrotic efficacy in vivo, we used two complementary models of bleomycin-induced fibrosis. Its effect on ERK1/2 phosphorylation induced by IgG from SSc patients and PDGF was also investigated. Key results VCE-004.3 bound to and activated PPARγ and CB2 receptors and antagonized CB1 receptors. VCE-004.3 bound to an alternative site at the PPARγ ligand binding pocket. VCE-004.3 inhibited collagen gene transcription and synthesis and prevented TGFβ-induced fibroblast migration and differentiation to myofibroblasts. It prevented skin fibrosis, myofibroblast differentiation and ERK1/2 phosphorylation in bleomycin-induced skin fibrosis. Furthermore, it reduced mast cell degranulation, macrophage activation, T-lymphocyte infiltration, and the expression of inflammatory and profibrotic factors. Topical application of VCE-004.3 also alleviated skin fibrosis. Finally, VCE-004.3 inhibited PDGF-BB- and SSc IgG-induced ERK1/2 activation in fibroblasts. Conclusions and implications VCE-004.3 is a novel semisynthetic cannabidiol derivative that behaves as a dual PPARγ/CB2 agonist and CB1 receptor modulator that could be considered for the development of novel therapies against different forms of scleroderma.

Background and Purpose Phytocannabinoids are produced in Cannabis sativa L. in acidic form and are decarboxylated upon heating, processing and storage. While the biological effects of decarboxylated cannabinoids such as Δ9-tetrahydrocannabinol have been extensively investigated, the bioactivity of Δ9-tetahydrocannabinol acid (Δ9-THCA) is largely unknown, despite its occurrence in different Cannabis preparations. Here we have assessed possible neuroprotective actions of Δ9-THCA through modulation of PPARγ pathways. Experimental Approach The effects of six phytocannabinoids on PPARγ binding and transcriptional activity were investigated. The effect of Δ9-THCA on mitochondrial biogenesis and PPARγ coactivator 1-α expression was investigated in Neuro-2a (N2a) cells. The neuroprotective effect was analysed in STHdhQ111/Q111 cells expressing a mutated form of the huntingtin protein and in N2a cells infected with an adenovirus carrying human huntingtin containing 94 polyQ repeats (mHtt-q94). The in vivo neuroprotective activity of Δ9-THCA was investigated in mice intoxicated with the mitochondrial toxin 3-nitropropionic acid (3-NPA). Key Results Cannabinoid acids bind and activate PPARγ with higher potency than their decarboxylated products. Δ9-THCA increased mitochondrial mass in neuroblastoma N2a cells and prevented cytotoxicity induced by serum deprivation in STHdhQ111/Q111 cells and by mutHtt-q94 in N2a cells. Δ9-THCA, through a PPARγ-dependent pathway, was neuroprotective in mice treated with 3-NPA, improving motor deficits and preventing striatal degeneration. In addition, Δ9-THCA attenuated microgliosis, astrogliosis and up-regulation of proinflammatory markers induced by 3-NPA. Conclusions and Implications Δ9-THCA shows potent neuroprotective activity, which is worth considering for the treatment of Huntington's disease and possibly other neurodegenerative and neuroinflammatory diseases.

Cannabis has remarkable therapeutic potential, but its clinical use is limited by the psychotropic activity of Δ9-tetrahydrocannabinol (Δ9-THC). Surprisingly, the biological profile of the non-narcotic native precursor of Δ9-THC (Δ9-THC acid A, Δ9-THCA-A) is still largely unexplored. We present evidence that Δ9-THCA-A is a partial and selective PPARγ modulator, endowed with lower adipogenic activity than the full PPARγ agonist rosiglitazone (RGZ) and with an enhanced osteoblastogenic activity in human mesenchymal stem cells. Docking andin vitrofunctional assays indicated that Δ9-THCA-A binds to and activates PPARγ by acting at both the canonical and the alternative sites of the ligand-binding domain. Transcriptomic signatures at inguinal white adipose tissue (iWAT) from mice treated with Δ9-THCA-A confirmed its mode of action on PPARγ. Administration of Δ9-THCA-A in a mouse model of high fat diet (HFD)-induced obesity significantly reduced fat mass and body weight gain, markedly ameliorating glucose intolerance and insulin resistance, and largely preventing liver steatosis, adipogenesis and macrophage infiltration in fat tissues. Additionally, immunohistochemistry, transcriptomic, and plasma biomarker analyses showed that treatment with Δ9-THCA-A caused browning of iWAT and displayed potent anti-inflammatory actions in HFD mice. Altogether, our data validate the potential of Δ9-THCA-A as a low adipogenic PPARγ agonist, capable of substantially improving the symptoms of obesity-associated metabolic syndrome and inflammation. These findings suggest that Δ9-THCA-A, and perhaps non-decarboxylatedCannabis sativaextracts, are worth considering for addition to our inventory of cannabis medicines.SIGNIFICANCE STATEMENTThe medicinal use of Cannabis is gaining momentum, despite the adverse psychotropic effects of Δ9-THC, the decarboxylation product of its naturally occurring and non-psychotropic precursor Δ9-THCA-A. We present evidence that Δ9-THCA-A is a partial ligand agonist of PPARγ with lower adipogenic activity compared to the full PPARγ agonist rosiglitazone (RGZ). Moreover, chronic administration of Δ9-THCA-A in a mouse model of high fat diet (HFD)-induced obesity significantly reduced body weight gain and fat mass, improved glucose intolerance and insulin resistance, and prevented liver steatosis and macrophage infiltration in fat tissues, additionally inducing white adipose tissue browning. Collectively, these observations qualify Δ9-THCA-A, a compound devoid of psychotropic effects, as an efficacious pharmacological agent to manage metabolic syndrome and obesity-associated inflammation.Highlights- Δ9-THCA-A is a partial PPARγ ligand agonist with low adipogenic activity- Δ9-THCA-A enhances osteoblastogenesis in bone marrow derived mesenchymal stem cells.- Δ9-THCA-A reduces body weight gain, fat mass, and liver steatosis in HFD-fed mice- Δ9-THCA-A improves glucose tolerance, insulin sensitivity, and insulin profilesin vivo- Δ9-THCA-A induces browning of iWAT and has a potent anti-inflammatory activity

The endocannabinoid system (ECS) may play a role in the pathophysiology of systemic sclerosis (SSc). Cannabinoids acting as dual PPARγ/CB2 agonists, such as VCE-004.8 and Ajulemic acid (AjA), have been shown to alleviate skin fibrosis and inflammation in SSc models. Since both compounds are being tested in humans, we compared their activities in the bleomycin (BLM) SSc model. Specifically, the pharmacotranscriptomic signature of the compounds was determined by RNA-Seq changes in the skin of BLM mice treated orally with AjA or EHP-101, a lipidic formulation of VCE-004.8. While both compounds down-regulated the expression of genes involved in the inflammatory and fibrotic components of the disease and the pharmacotranscriptomic signatures were similar for both compounds in some pathways, we found key differences between the compounds in vasculogenesis. Additionally, we found 28 specific genes with translation potential by comparing with a list of human scleroderma genes. Immunohistochemical analysis revealed that both compounds prevented fibrosis, collagen accumulation and Tenascin C (TNC) expression. The endothelial CD31+/CD34+ cells and telocytes were reduced in BLM mice and restored only by EHP-101 treatment. Finally, differences were found in plasmatic biomarker analysis; EHP-101, but not AjA, enhanced the expression of some factors related to angiogenesis and vasculogenesis. Altogether the results indicate that dual PPARγ/CB2 agonists qualify as a novel therapeutic approach for the treatment of SSc and other fibrotic diseases. EHP-101 demonstrated unique mechanisms of action related to the pathophysiology of SSc that could be beneficial in the treatment of this complex disease without current therapeutic options.

Background The administration of certain cannabinoids provides neuroprotection in models of neurodegenerative diseases by acting through various cellular and molecular mechanisms. Many cannabinoid actions in the nervous system are mediated by CB1 receptors, which can elicit psychotropic effects, but other targets devoid of psychotropic activity, including CB2 and nuclear PPARγ receptors, can also be the target of specific cannabinoids. Methods We investigated the pro-neurogenic potential of the synthetic cannabigerol derivative, VCE-003.2, in striatal neurodegeneration by using adeno-associated viral expression of mutant huntingtin in vivo and mouse embryonic stem cell differentiation in vitro. Results Oral administration of VCE-003.2 protected striatal medium spiny neurons from mutant huntingtin-induced damage, attenuated neuroinflammation and improved motor performance. VCE-003.2 bioavailability was characterized and the potential undesired side effects were evaluated by analyzing hepatotoxicity after chronic treatment. VCE-003.2 promoted subventricular zone progenitor mobilization, increased doublecortin-positive migrating neuroblasts towards the injured area, and enhanced effective neurogenesis. Moreover, we demonstrated the proneurogenic activity of VCE-003.2 in embryonic stem cells. VCE-003.2 was able to increase neuroblast formation and striatal-like CTIP2-mediated neurogenesis. Conclusions The cannabigerol derivative VCE-003.2 improves subventricular zone-derived neurogenesis in response to mutant huntingtin-induced neurodegeneration, and is neuroprotective by oral administration. Electronic supplementary material The online version of this article (10.1186/s40035-019-0148-x) contains supplementary material, which is available to authorized users.

Medicinal cannabis has remarkable therapeutic potential, but its clinical use is limited by the psychotropic activity of Δ9-tetrahydrocannabinol (Δ9-THC). However, the biological profile of the carboxylated, non-narcotic native precursor of Δ9-THC, the Δ9-THC acid A (Δ9-THCA-A), remains largely unexplored. Here we present evidence that Δ9-THCA-A is a partial and selective PPARγ modulator, endowed with lower adipogenic activity than the full PPARγ agonist rosiglitazone (RGZ) and enhanced osteoblastogenic effects in hMSC. Docking and in vitro functional assays indicated that Δ9-THCA-A binds to and activates PPARγ by acting at both the canonical and the alternative sites of the ligand-binding domain. Transcriptomic signatures in iWAT from mice treated with Δ9-THCA-A confirmed its mode of action through PPARγ. Administration of Δ9-THCA-A in a mouse model of HFD-induced obesity significantly reduced fat mass and body weight gain, markedly ameliorating glucose intolerance and insulin resistance, and largely preventing liver steatosis, adipogenesis and macrophage infiltration in fat tissues. Additionally, immunohistochemistry, transcriptomic, and plasma biomarker analyses showed that treatment with Δ9-THCA-A caused browning of iWAT and displayed potent anti-inflammatory actions in HFD mice. Our data validate the potential of Δ9-THCA-A as a low adipogenic PPARγ agonist, capable of substantially improving the symptoms of obesity-associated metabolic syndrome and inflammation.

Over the past few years, the endocannabinoid system (ECs) has emerged as a crucial player for the regulation of food intake and energy metabolism, and its pharmacological manipulation represents a novel strategy for the management of metabolic diseases. The discovery that VCE-004.8, a dual PPARγ and CB2 receptor agonist, also inhibits prolyl-hydroxylases (PHDs) and activates the HIF pathway provided a rationale to investigate its effect in in vitro models of adipogenesis and in a murine model of metabolic syndrome, all processes critically regulated by these targets of VCE-004.8. In accordance with its different binding mode to PPARγ compared to rosiglitazone (RGZ), VCE-004.8 neither induced adipogenic differentiation, nor affected osteoblastogenesis. Daily administration of VCE-004.8 (20 mg/kg) to HFD mice for 3-wks induced a significant reduction in body weight gain, total fat mass, adipocyte volume and plasma triglycerides levels. VCE-004.8 could also significantly ameliorate glucose tolerance, reduce leptin levels (a marker of adiposity) and increase adiponectin and incretins (GLP-1 and GIP) levels. Remarkably, VCE-004.8 increased the FGF21 mRNA expression in white and brown adipose, as well as in a BAT cell line, qualifying cannabinoaminoquinones as a class of novel therapeutic candidates for the management of obesity and its common metabolic co-morbidities.

N-acyl-dopamines are endolipids with neuroprotective, antiinflammatory and immunomodulatory properties. Previously, we showed the ability of these compounds to induce HIF-1α stabilization. Hypoxia and HIF-1α play an important role in the most relevant stages of diabetic pathogenesis. This work analyzes the possible role of these molecules on beta cell differentiation, insulin production and diabetic foot ulcer. Hypoxia response pathway has been characterized in beta-cell differentiation in rat pancreatic acinar cell line and human islet-derived precursor cells. Protein and mRNA expression of key proteins in this process have been analyzed, as well as those involved in beta cells reprogramming. The effect of N-acyl-dopamines on hypoxia response pathway, beta cells reprogramming and insulin production have been studied in both cell types, as well as its role in angiogenesis models in vitro and wound closure in type 2 diabetic mice. Our results show how the hypoxia response pathway is altered during beta cells differentiation, accompanied by an induction of the transcription factor HIF-1α. We demonstrate how some N-acyl-dopamines induce beta cell differentiation and insulin production in two different cell models. In parallel, these endolipids promote angiogenesis in vitro and wound closure in type 2 diabetic mice. These results provide a biological mechanism through which some endolipids could induce beta cell differentiation. We demonstrate how N-acyl-dopamines can modulate insulin production and, in parallel, reverse HIF-1α inhibition in a wound healing model in diabetic mice. Therefore, the potential use of the pharmacological modulation of N-acyl-dopamines may have implications for diabetes prevention and treatment strategies.

[Background] Multiple sclerosis (MS) is characterized by a combination of inflammatory and neurodegenerative processes variously dominant in different stages of the disease. Thus, immunosuppression is the goal standard for the inflammatory stage, and novel remyelination therapies are pursued to restore lost function. Cannabinoids such as 9Δ-THC and CBD are multi-target compounds already introduced in the clinical practice for multiple sclerosis (MS). Semisynthetic cannabinoids are designed to improve bioactivities and druggability of their natural precursors. VCE-004.8, an aminoquinone derivative of cannabidiol (CBD), is a dual PPARγ and CB2 agonist with potent anti-inflammatory activity. Activation of the hypoxia-inducible factor (HIF) can have a beneficial role in MS by modulating the immune response and favoring neuroprotection and axonal regeneration., [Methods] We investigated the effects of VCE-004.8 on the HIF pathway in different cell types. The effect of VCE-004.8 on macrophage polarization and arginase 1 expression was analyzed in RAW264.7 and BV2 cells. COX-2 expression and PGE2 synthesis induced by lipopolysaccharide (LPS) was studied in primary microglia cultures. The efficacy of VCE-004.8 in vivo was evaluated in two murine models of MS such as experimental autoimmune encephalomyelitis (EAE) and Theiler’s virus-induced encephalopathy (TMEV)., [Results] Herein, we provide evidence that VCE-004.8 stabilizes HIF-1α and HIF-2α and activates the HIF pathway in human microvascular endothelial cells, oligodendrocytes, and microglia cells. The stabilization of HIF-1α is produced by the inhibition of the prolyl-4-hydrolase activity of PHD1 and PDH2. VCE-004.8 upregulates the expression of HIF-dependent genes such as erythropoietin and VEGFA, induces angiogenesis, and enhances migration of oligodendrocytes. Moreover, VCE-004.8 blunts IL-17-induced M1 polarization, inhibits LPS-induced COX-2 expression and PGE2 synthesis, and induces expression of arginase 1 in macrophages and microglia. In vivo experiments showed efficacy of VCE-004.8 in EAE and TMEV. Histopathological analysis revealed that VCE-004.8 treatments prevented demyelination, axonal damage, and immune cells infiltration. In addition, VCE-004.8 downregulated the expression of several genes closely associated with MS physiopathology, including those underlying the production of chemokines, cytokines, and adhesion molecules., [Conclusions] This study provides new significant insights about the potential role of VCE-004.8 for MS treatment by ameliorating neuroinflammation and demyelination., This work was supported by grants SAF2014-53763-P (EM), SAF2017-87701-R (EM), and SAF2016-76449-R (GC) from the Ministry of the Economy and Competition (MINECO) co-financed with the European Union FEDER funds. GC was also supported by the Red Española de Esclerosis Múltiple (REEM: RD16/0015/0021) sponsored by the Fondo de Investigación Sanitaria (FIS); MAC was supported by the Instituto de Salud Carlos III (PIE14/00005) co-funded by the European Regional Development Fund/European Social Fund “Investing in your future”.

Phytocannabinoids are produced in Cannabis sativa L. in acidic form and are decarboxylated upon heating, processing and storage. While the biological effects of decarboxylated cannabinoids such as ΔThe effects of six phytocannabinoids on PPARγ binding and transcriptional activity were investigated. The effect of ΔCannabinoid acids bind and activate PPARγ with higher potency than their decarboxylated products. ΔΔ

Cannabinoids have shown to exert neuroprotective actions in animal models by acting at different targets including canonical cannabinoid receptors and PPARγ. We previously showed that VCE-003, a cannabigerol (CBG) quinone derivative, is a novel neuroprotective and anti-inflammatory cannabinoid acting through PPARγ. We have now generated a non-thiophilic VCE-003 derivative named VCE-003.2 that preserves the ability to activate PPARγ and analyzed its neuroprotective activity. This compound exerted a prosurvival action in progenitor cells during neuronal differentiation, which was prevented by a PPARγ antagonist, without affecting neural progenitor cell proliferation. In addition, VCE-003.2 attenuated quinolinic acid (QA)-induced cell death and caspase-3 activation and also reduced mutant huntingtin aggregates in striatal cells. The neuroprotective profile of VCE-003.2 was analyzed using in vivo models of striatal neurodegeneration induced by QA and 3-nitropropionic acid (3NP) administration. VCE-003.2 prevented medium spiny DARPP32+ neuronal loss in these Huntington’s-like disease mice models improving motor deficits, reactive astrogliosis and microglial activation. In the 3NP model VCE-003.2 inhibited the upregulation of proinflammatory markers and improved antioxidant defenses in the brain. These data lead us to consider VCE-003.2 to have high potential for the treatment of Huntington’s disease (HD) and other neurodegenerative diseases with neuroinflammatory traits.