URB597 / Merck (MSD) - LARVOL DELTA

URB597 downregulates DJ-1 expression in the mouse striatum and induces neurodegeneration. (PubMed, Exp Cell Res) - "Gene expression and pathway enrichment analyses revealed that URB597 targets DJ-1 in the mouse striatum and regulates the expression of genes involved in protein acetylation. Collectively, these findings underscore the critical role of DJ-1 in protecting dopaminergic neurons from oxidative damage and uncover its potential implications in regulating protein acetylation."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease

Aging-Associated Amyloid-β Plaques and Neuroinflammation in Bottlenose Dolphins (Tursiops truncatus) and Novel Cognitive Health-Supporting Roles of Pentadecanoic Acid (C15:0). (PubMed, Int J Mol Sci) - "C15:0 was a dose-dependent inhibitor of two targets, fatty acid amide hydrolase (FAAH) (IC50 2.5 µM, 89% maximum inhibition at 50 µM relative to URB597) and monoamine oxidase B (MAO-B) (IC50 19.4 µM, 70% maximum inhibition at 50 µM relative to R(-)-Deprenyl). These activities have demonstrated efficacy against Aβ formation and neuroinflammation, including protection of cognitive function in the hippocampus. These findings suggest that, in addition to protecting against AD co-morbidities, C15:0 may play a distinct role in supporting cognitive health, especially at higher concentrations."

Journal • Alzheimer's Disease • CNS Disorders • Diabetes • Hematological Disorders • Inflammation • Metabolic Disorders • Type 2 Diabetes Mellitus • CD68

The endocannabinoid system offers a target for Alzheimer's disease treatment through inhibition of fatty acid amide hydrolase (FAAH). (PubMed, FEBS J) - "FAAH inhibition induced a decrease in the accumulation, synthesis, and release of β-Amyloid, along with diminished expression of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), and this change may be associated with epigenetic changes induced by the drug. In summary, prolonged treatment with URB597 impinges on different aspects of AD pathophysiology, suggesting its therapeutic relevance in treating AD."

Journal • Alzheimer's Disease • Amyloidosis • CNS Disorders • Inflammation

URB597 Modulates Neuroplasticity, Neuroinflammatory, and Nrf2/HO-1 Signaling Pathways in the Hippocampus and Prefrontal Cortex of Male and Female Rats in a Stress-Induced Model of Depression. (PubMed, Physiol Behav) - "URB597 also exerts neuroprotective effects through region-specific antioxidant properties. These results have implications for sex-specific treatment strategies in stress-related neuropsychiatric disorders."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Depression • Inflammation • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry

EICAS: Evaluation Study of New Compounds with Potential Use in Schizophrenia (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: Central Institute of Mental Health, Mannheim | N=86 ➔ 0 | Trial completion date: Dec 2022 ➔ Jan 2025 | Not yet recruiting ➔ Withdrawn | Trial primary completion date: Jun 2022 ➔ Jan 2025

Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal • CNS Disorders • Psychiatry • Schizophrenia

Role of endocannabinoid neurotransmission in the insular cortex on cardiovascular, autonomic and behavioral responses evoked by acute restraint stress in rats. (PubMed, Neuropharmacology) - "For this, bilateral guide cannulas directed to the IC were implanted in male Wistar rats for intrabrain microinjection of the selective CB1 receptor antagonist AM251, the selective TRPV1 receptor antagonist capsazepine, the fatty acid amide hydrolase (FAAH) inhibitor URB597 or the monoacylglycerol lipase (MAGL) inhibitor JZL184...The other pharmacological treatments did not modify the cardiovascular, autonomic and behavioral responses evoked by restraint. Taken together, these findings suggest that endocannabinoid neurotransmission in the IC, potentially acting through the endocannabinoid 2-arachidonoylglycerol, plays an inhibitory role in both tachycardia and anxiogenic-like effect evoked by stressful events."

Journal • Preclinical • Cardiovascular

The Effects of Indirect and Direct Modulation of Endocannabinoid System Function on Anxiety-Related Behavior in Mice Assessed in the Elevated Plus Maze Test. (PubMed, Molecules) - "In our experiments, we confirmed the clearly significant involvement of the ECS in anxiety-related responses. In particular, the pharmacological indirect manipulation of ECS functions is able to elicit promising anxiolytic effects. Therefore, the ECS could be a potential target for novel anxiolytic drugs; however, further studies are needed."

Journal • Preclinical • Mood Disorders • Psychiatry

FAAH Inhibition Reverses Depressive-like Behavior and Sex-Specific Neuroinflammatory Alterations Induced by Early Life Stress. (PubMed, Cells) - "Some of these effects began in late adolescence, including mPFC-nfκb1 expression in both sexes, mPFC-il6 and mPFC-il1β in females, CA1-il1β and CA1-tnfα in males, and CA1-il1β in females. These findings highlight URB597 as a therapeutic approach for reversing ELS-induced depressive-like behavior by associating with changes in the gene expression of neuroinflammatory cytokines, with notable sex differences."

Journal • CNS Disorders • Depression • Inflammation • Major Depressive Disorder • Mood Disorders • Oncology • Psychiatry • IL1B • IL6 • TNFA

FAAH Inhibition Counteracts Neuroinflammation via Autophagy Recovery in AD Models. (PubMed, Int J Mol Sci) - "URB597 administration restored autophagy in Tg2576 mice via an increase in BECN1 (Beclin1), ATG7 (Autophagy Related 7), LC3 (light chain 3) and SQSTM1/p62 (sequestrome 1) as well as via the activation of the ULK1 (Unc-51 Like Autophagy Activating Kinase 1) signaling pathway, suggesting that it targets mTOR/ULK1-dependent autophagy pathway. The potential of endocannabinoids to rebalance autophagy machinery may be considered as a new perspective for therapeutic intervention in AD."

Journal • Alzheimer's Disease • CNS Disorders • Inflammation • ATG7 • BECN1 • SQSTM1

Effects of increased endocannabinoid levels during adolescence on anxiety-related and cocaine-seeking behaviors in adulthood (Neuroscience 2024) - "Adolescent male Sprague Dawley rats were given daily intraperitoneal injections of either JZL184 (JZL;10 mg/kg), URB597 (URB; 0.4 mg/kg), or vehicle from PND 31-40...During reinstatement testing, JZL-treated animals had reduced drug-seeking behavior following a priming injection of cocaine (10.0 mg/kg, i.p.). In conclusion, the data we gathered indicate that while effects on anxiety-related behaviors do not persist into adulthood, there is an increase in drug seeking in adults when eCB levels are increased during adolescence."

Clinical • CNS Disorders • Mood Disorders • Psychiatry

Insights into Paclitaxel-Induced Neuropathic Pain: The Endocannabinoid System as a Therapeutic Target (Neuroscience 2024) - "Additionally, anxiety-related tests (Elevated Plus Maze and Open Field) were performed on day 16.On day 21, animals received acute i.p. injections of either vehicle, URB597 (FAAH inhibitor, 1mg/kg), SB366791 (TRPV1 antagonist, 1mg/kg) or AA-5-HT (FAAH inhibitor and TRPV1 antagonist, 5mg/kg)...However, only AA-5-HT attenuated the cold hypersensitivity induced by PTX treatment in both sexes. In PTX-treated rats, the FAAH inhibitor increased levels of PEA in the Spinal Cord, Periaqueductal Grey (PAG), Rostral Ventromedial Medulla, and Prefrontal Cortex (PFC), and increased levels of OEA in the PAG and PFC.These results suggest that the endocannabinoid system may be a viable therapeutic target for PTX-induced neuropathic pain."

CNS Disorders • Mood Disorders • Neuralgia • Pain • Psychiatry • TRPV1

Endocannabinoid System Activation Effects in Neuroinflammatory Induced Depressive and Anxiety behaviors and its role on the rat insular cortex. (Neuroscience 2024) - "However, the rats that received URB597+VEH exhibited higher anxiety-like behavior and lower swimming behavior, suggesting a positive effect of this FAAH inhibitor only when the animal is in need of decreasing inflammation. These findings indicate that FAAH inhibitors may have therapeutic potential for the treatment of depression and anxiety when the rodent expresses specific inflammatory markers and may contribute to our understanding of the neural circuits involved in these behaviors."

Preclinical • CNS Disorders • Depression • Mood Disorders • Psychiatry

Examining the role of the endocannabinoid system in reward and aversion in social contexts (Neuroscience 2024) - "To this end male and female mice were trained on this procedure and then underwent 9 test sessions on which they received various doses of the endocannabinoid antagonist AM251, the agonist JZL187, the agonist URB597, each agonist in conjunction with AM251, or vehicle...Further, endocannabinoid manipulations significantly altered several behavioral outcomes in males and females, such as approach towards the conspecific during shock delivery or cues that predict shock. These data suggest a role for endocannabinoid signaling in socially-determined behaviors during reward and aversion."

CNS Disorders

The effect of URB597 on repetitive/restricted behaviors in the BTBR mouse model of Autism Spectrum Disorder (Neuroscience 2024) - "URB597 did not affect reversal learning in the BTBR mice in the water T-maze, suggesting that URB597 does not work on higher-order RRBs at the doses tested. These results suggest that the effects of URB597 may be specific to the sex of the mouse and the type of RRBs (i.e., lower-order or higher-order repetitive behaviors) tested."

Preclinical • CNS Disorders • Psychiatry

Unraveling neuroprotective pathways: targeting enzymes that inactivate endocannabinoids for ALS therapeutic management (Neuroscience 2024) - "We have employed three experimental strategies using these TDP43A315T mice: (i) to induce genetic ablation of FAAH enzyme in these mice by their crossing with FAAH-deficient mice; (ii) to inhibit FAAH enzyme with the selective FAAH inhibitor URB597 (0.2 mg/kg) given i.p. from presymptomatic (PND65) to symptomatic stages (PND95); and (iii) to inhibit MAGL enzyme using the irreversible inhibitor RO727 (3 mg/kg) or the reversible inhibitor RO723 (10 mg/kg)...In summary, our results strongly suggest the neuroprotective potential of modulating endocannabinoid inactivation in ALS using genetic or pharmacological tools. This inactivation increased neuronal survival and attenuated glial reactivity, providing a promising avenue for further development toward the clinical scenario with pharmacological agents inhibiting FAAH and/or MAGL enzymes."

Amyotrophic Lateral Sclerosis • CNS Disorders • CLSPN,

FAAH inhibitor URB597 shows anti-hyperalgesic action and increases brain and intestinal tissues fatty acid amides in a model of CRF1 agonist mediated visceral hypersensitivity in male rats. (PubMed, Neurogastroenterol Motil) - "URB597 shows efficacy to elevate brain and intestinal FAAs and to counteract the colonic hypersensitivity induced by peripheral activation of CRF1 signaling supporting a potential strategy of FAAH inhibitors to alleviate stress-related visceral hypersensitivity."

Journal • Preclinical • Gastrointestinal Disorder • Immunology • Pain

The region-specific effects of the fatty acid amide hydrolase inhibitor URB597 on JAK2/STAT3 signaling in chronic unpredictable stress-induced depressive rats (ECNP 2024) - "These findings suggest that URB597 had region-specific effects on JAK2/STAT3 signaling and an anti-inflammatory impact through regulation of IL-6 and BDNF."

Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Depression • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry • IL6

Endocannabinoids suppress inflammation-induced tumor necrosis factor alpha up-regulation in human and Guinea-pig lungs (ERS 2024) - "2020: 101920.), however, their mechanism remain partially understood.Aims: To examine the effect of the endogenous and exogenous cannabinoids on inflammation-induced TNF-α production in the airways. Guinea pig (n=4) and human (n=3) lung tissues were incubated by LPS (1uM/ml) or monoacylglycerol lipase (MAGL) inhibitor JZL184 (1uM/ml), fatty acid amide hydrolase (FAAH) inhibitor URB597 (1uM/ml), MAGL/FAAH dual inhibitor JZL195 (1uM/ml), 2-arachidonoylglycerol (30uM/ml), anandamide (30uM/ml), oleoylethanolamide (10uM/ml), cannabinoid receptor CB1 antagonist AM281 (10uM/ml), CB2 agonist JWH133 (10uM/ml), and dexamethasone (0.1uM/ml) in the presence of LPS in a culture medium. ECs demonstrate a suppressive effect on TNF-α production induced by LPS exposure, acting through CB2 receptors in both human and Guinea pig models. Concurrent administration of ECs and an inhibitor of EC metabolism tends to elicit an enhanced effect when compared to single treatments."

Inflammation • Oncology • Respiratory Diseases • TNFA

Targeting dysfunctional endocannabinoid signaling in a mouse model of Gulf War Illness. (PubMed, Neuropharmacology) - "Behavioral deficits exhibited by these animals, including heightened anxiety-like and depression-like behaviors, and defective extinction of fearful memories, were corrected by administration of the FAAH inhibitor, URB597, which normalized brain anandamide levels...Together, these results suggest that exposure to GW chemicals produce a deficit in brain ECB signaling which is associated with persistent alterations in microglial function. Pharmacological normalization of anandamide-mediated ECB signaling may offer an effective therapeutic strategy for ameliorating GWI symptomology."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Depression • Fatigue • Mood Disorders • Pain • Psychiatry

Schisandra chinensis lignans regulate and cooperate with endogenous cannabinoid systems to ameliorate intestinal barrier injury associated with depression. (PubMed, Phytomedicine) - "Overall, SCL, in collaboration with the endogenous cannabinoid system regulated by SCL, alleviates depression associated IBI. The specific mechanism involes SCL decreasing AEA levels to inhibit colon tissue cell apoptosis by up-regulating FAAH. Simultaneously, it directly triggers CB2R to reduce inflammation responses, further alleviating IBI."

Journal • CNS Disorders • Depression • Inflammation • Psychiatry

Characterization of a Fatty Acid Amide Hydrolase (FAAH) in Hirudo Verbana. (PubMed, Neurochem Res) - "Activity was also blocked by the known FAAH inhibitor, URB597...The Hirudo CNS has been a useful system in which to study properties of endocannabinoid modulation of nociception relevant to vertebrates. Therefore, this characterization of HirFAAH is an important contribution to comparative studies of the endocannabinoid system."

Journal

Protective effects of fatty acid amide hydrolase inhibition in UVB-activated microglia. (PubMed, Biochim Biophys Acta Mol Cell Biol Lipids) - "Pharmacological FAAH inhibition via URB597 counteracted the effects of UVB exposure, decreasing tumor necrosis factor α (TNF-α) and nitric oxide (NO) release and reverting reactive oxidative species (ROS), interleukin-1β (IL-1β), and interleukin-10 (IL-10) levels to the control levels. Our findings support the potential of enhanced fatty acid amide signaling in mitigating UVB-induced cellular damage, paving the way to further exploration of these lipids in light-induced immune responses."

Journal • CNS Disorders • Inflammation • Oncology • IL10 • IL1B • PTGS2 • TNFA

Cannabidiol and positive effects on object recognition memory in an in vivo model of Fragile X Syndrome: obligatory role of hippocampal GPR55 receptors. (PubMed, Pharmacol Res) - "Blockade of CA1 hippocampal GPR55 receptors prevented the beneficial effect of both CBD and the fatty acid amide hydrolase (FAAH) inhibitor URB597 in the short-term recognition memory deficits displayed by Fmr1-Δexon 8 rats...Docking analysis further confirmed that the mechanism of action of CBD might involve competition for brain fatty acid binding proteins (FABPs) that deliver anandamide and related bioactive lipids to their catabolic enzyme FAAH. These findings demonstrate that CBD reduced cognitive deficits in a rat model of FXS and provide initial mechanistic insights into its therapeutic potential in neurodevelopmental disorders."

Journal • Preclinical • Autism Spectrum Disorder • CNS Disorders • Cognitive Disorders • Developmental Disorders • Epilepsy • Fragile X Syndrome • Genetic Disorders • Psychiatry • GPR55

Quantification of arachidonic acid using LC-MS/MS | Poster Board #1318 (ACS-Sp 2024) - "On day six, a subset of rodents was treated with a FAAH inhibitor, URB597, and rimonabant to induce withdrawal. For the quantification of AA in the liver, tissue homogenized by a sonication probe will be measured through tandem liquid chromatography, mass spectrometry (LC-MS/MS) to measure for FAAH inhibition. FAAH expression in the liver is high so rats treated with URB597 should experience decreased levels of AA."

Inhibition of fatty acid amide hydrolase reverses aberrant prefrontal gamma oscillations in the sub-chronic PCP model for schizophrenia. (PubMed, Exp Brain Res) - "Intriguingly, the pharmacological blockade of CB1 receptors by AM251 unmasked a reduced gamma oscillatory activity in PCP-treated animals. The findings are consistent with the observed effects of URB597 and AM251 on behavioral deficits reminiscent of the symptoms of schizophrenia and further validate the potential for cannabinoid-based drugs as a treatment for schizophrenia."

Journal • Anesthesia • CNS Disorders • Psychiatry • Schizophrenia