URB597 Prevents the Short-Term Excitotoxic Cell Damage in Rat Cortical Slices: Role of Cannabinoid 1 Receptors

Chavira-Ramos, Karla; Orozco‐Morales, Mario; Karasu, Çi̇men; Tinkov, Alexey A.; Aschner, Michael; Santamarı́a, Abel; Colín-González, Ana Laura

doi:10.1007/s12640-020-00301-1

Cited by 5 publications

(4 citation statements)

References 46 publications

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“…Our last objective was to explore whether inducing local elevations of anandamide (and its congeners PEA and OEA) by inhibiting FAAH with the selective inhibitor URB597 [ 59 ], may have beneficial effects in delaying the progression of the pathological phenotype in FTD mice. Such strategy has been already used for other neurological disorders with promising results [ 1 , 11 , 51 , 73 , 81 , 82 ] and the fact that, in our study, FAAH enzyme experiences in FTD mice a reduction associated with trends of anandamide, PEA and OEA to be elevated, supports its pharmacological interest. Our results confirmed the benefits of FAAH inhibition, since we found significant improvements in the behaviours altered in FTD mice after treatment with URB597, as well as in the loss of pyramidal neurons and associated astroglial and microglial reactivities visible in the mPFC (URB597 reduced both astrogliosis and microgliosis), and the hippocampus (the reduction was restricted to microgliosis).…”

Section: Discussionsupporting

confidence: 76%

“…Lastly, given that changes found in this system affected the balance between the synthesis and degradation of endocannabinoids, in particular anandamide, changes that could be interpreted as an endogenous protective response, we also explored the therapeutic potential of the inhibition of the key anandamide hydrolysing enzyme FAAH in these mice. To this end, we used the selective inhibitor URB597 [ 59 ], which has been also investigated as a potential neuroprotective therapy in different neuronal injury conditions [ 1 , 11 , 51 , 73 , 81 , 82 ].…”

Section: Introductionmentioning

confidence: 99%

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Preclinical investigation in FAAH inhibition as a neuroprotective therapy for frontotemporal dementia using TDP-43 transgenic male mice

Santos‐García

Rodríguez‐Cueto

Villegas

et al. 2023

J Neuroinflammation

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Background Frontotemporal dementia (FTD) is a heterogeneous group of early onset and progressive neurodegenerative disorders, characterized by degeneration in the frontal and temporal lobes, which causes deterioration in cognition, personality, social behavior and language. Around 45% of the cases are characterized by the presence of aggregates of the RNA-binding protein TDP-43. Methods In this study, we have used a murine model of FTD that overexpresses this protein exclusively in the forebrain (under the control of the CaMKIIα promoter) for several biochemical, histological and pharmacological studies focused on the endocannabinoid system. Results These mice exhibited at postnatal day 90 (PND90) important cognitive deficits, signs of emotional impairment and disinhibited social behaviour, which were, in most of cases, maintained during the first year of life of these animals. Motor activity was apparently normal, but FTD mice exhibited higher mortality. Their MRI imaging analysis and their ex-vivo histopathological evaluation proved changes compatible with atrophy (loss of specific groups of pyramidal neurons: Ctip2- and NeuN-positive cells) and inflammatory events (astroglial and microglial reactivities) in both cortical (medial prefrontal cortex) and subcortical (hippocampus) structures at PND90 and also at PND365. The analysis of the endocannabinoid system in these mice proved a decrease in the hydrolysing enzyme FAAH in the prefrontal cortex and the hippocampus, with an increase in the synthesizing enzyme NAPE-PLD only in the hippocampus, responses that were accompanied by modest elevations in anandamide and related N-acylethanolamines. The potentiation of these elevated levels of anandamide after the pharmacological inactivation of FAAH with URB597 resulted in a general improvement in behaviour, in particular in cognitive deterioration, associated with the preservation of pyramidal neurons of the medial prefrontal cortex and the CA1 layer of the hippocampus, and with the reduction of gliosis in both structures. Conclusions Our data confirmed the potential of elevating the endocannabinoid tone as a therapy against TDP-43-induced neuropathology in FTD, limiting glial reactivity, preserving neuronal integrity and improving cognitive, emotional and social deficits.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Preclinical investigation in FAAH inhibition as a neuroprotective therapy for frontotemporal dementia using TDP-43 transgenic male mice

Santos‐García

Rodríguez‐Cueto

Villegas

et al. 2023

J Neuroinflammation

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“… 53 CB1R activation is one prime underlying mechanism, it can be mediated by URB597, as has been substantiated. 54 URB597 increases CB1R-mediated neuronal survival and neurotransmission, meanwhile up-regulating the levels of BDNF expression in the brain. 55 , 56 Recently, we found that brain ischemia reduced BDNF expression in the cerebral cortex and hippocampus in rats with vascular dementia, which was reversed by chronic URB597 treatment.…”

Section: Discussionmentioning

confidence: 95%

Neuroprotective Effects of VEGF-A Nanofiber Membrane and FAAH Inhibitor URB597 Against Oxygen–Glucose Deprivation-Induced Ischemic Neuronal Injury

Wang¹,

Jin²,

Zhao

et al. 2021

IJN

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Introduction Brain ischemia is a common neurological disorder worldwide that activates a cascade of pathophysiological events involving decreases in oxygen and glucose levels. Despite substantial efforts to explore its pathogenesis, the management of ischemic neuronal injury remains an enormous challenge. Accumulating evidence suggests that VEGF modified nanofiber (NF) materials and the fatty-acid amide hydrolase (FAAH) inhibitor URB597 exert an influence on alleviating ischemic brain damage. We aimed to further investigate their effects on primary hippocampal neurons, as well as the underlying mechanisms following oxygen–glucose deprivation (OGD). Methods Different layers of VEGF-A loaded polycaprolactone (PCL) nanofibrous membranes were first synthesized by using layer-by-layer (LBL) self-assembly of electrospinning methods. The physicochemical and biological properties of VEGF-A NF membranes, and their morphology, hydrophilicity, and controlled-release of VEGF-A were then estimated. Furthermore, the effects of VEGF-A NF and URB597 on OGD-induced mitochondrial oxidative stress, inflammatory responses, neuronal apoptosis, and endocannabinoid signaling components were assessed. Results The VEGF-A NF membrane and URB597 can not only promote hippocampal neuron adhesion and viability following OGD but also exhibited antioxidant/anti-inflammatory and mitochondrial membrane potential protection. The VEGF-A NF membrane and URB597 also inhibited OGD-induced cellular apoptosis through activating CB1R signaling. These results indicate that VEGF-A could be controlled-released by LBL self-assembled NF membranes. Discussion The VEGF-A NF membrane and URB597 displayed positive synergistic neuroprotective effects through the inhibition of mitochondrial oxidative stress and activation of CB1R/PI3K/AKT/BDNF signaling, suggesting that a VEGF-A loaded NF membrane and the FAAH inhibitor URB597 could be of therapeutic value in ischemic cerebrovascular diseases.

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“…Preclinical studies with FAAH inhibitors and transgenic models with genetic inactivation of the enzyme have highlighted a potential therapeutic role for FAAH inhibition in the treatment of brain injury and neurodegeneration. Recent studies have shown that inhibition of FAAH reduces hippocampal ischemia–reperfusion injury (Abdel Mageed et al, 2021) and prevents quinolinic acid‐induced excitotoxic damage (Chavira‐Ramos et al, 2021). Elevation of AEA has demonstrated neuroprotective properties in epilepsy, where synaptic function and behavioral alterations are rescued by FAAH inhibition (Colangeli et al, 2020).…”

Section: Selected Recent Discoveries Regarding Components Of the Ecs ...mentioning

confidence: 99%

Endocannabinoid signaling in the central nervous system

Ramirez

Ruiz‐Pérez

Stollenwerk

et al. 2022

Glia

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It is hard to overestimate the influence of the endocannabinoid signaling (ECS) system on central nervous system (CNS) function. In the 40 years since cannabinoids were found to trigger specific cell signaling cascades, studies of the ECS system continue to cause amazement, surprise, and confusion! CB1 cannabinoid receptors are expressed widely in the CNS and regulate cell-cell communication via effects on the release of both neurotransmitters and gliotransmitters. CB2 cannabinoid receptors are difficult to detect in the CNS but seem to "punch above their weight" as compounds targeting these receptors have significant effects on inflammatory state and behavior. Positive and negative allosteric modulators for both receptors have been identified and examined in preclinical studies. Concentrations of the endocannabinoid ligands, N-arachidonoylethanolamine and 2-arachidonoylglycerol (2-AG), are regulated by a combination of enzymatic synthesis and degradation and inhibitors of these processes are available and making their way into clinical trials. Importantly, ECS regulates many essential brain functions, including regulation of reward, anxiety, inflammation, motor control, and cellular development. While the field is on the cusp of preclinical discoveries providing impactful clinical and therapeutic insights into many CNS disorders, there is still much to be learned about this remarkable and versatile modulatory system.

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URB597 Prevents the Short-Term Excitotoxic Cell Damage in Rat Cortical Slices: Role of Cannabinoid 1 Receptors

Cited by 5 publications

References 46 publications

Preclinical investigation in FAAH inhibition as a neuroprotective therapy for frontotemporal dementia using TDP-43 transgenic male mice

Preclinical investigation in FAAH inhibition as a neuroprotective therapy for frontotemporal dementia using TDP-43 transgenic male mice

Neuroprotective Effects of VEGF-A Nanofiber Membrane and FAAH Inhibitor URB597 Against Oxygen–Glucose Deprivation-Induced Ischemic Neuronal Injury

Endocannabinoid signaling in the central nervous system

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