Inhibiting degradation of 2-arachidonoylglycerol as a therapeutic strategy for neurodegenerative diseases

Chen, Chu

doi:10.1016/j.pharmthera.2023.108394

Cited by 20 publications

(8 citation statements)

References 276 publications

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“…Broadly, we show that the rescue of alterations induced by a concussion during early stages of brain development could be reached a year after injury, which represents a dramatically expanded therapeutic window that is much more amenable for clinical intervention than within minutes after injury, as previously suggested [10][11][12]44 . Our study also further extends the interest of the endocannabinoid system as a potent and future therapeutic target in the treatment of traumatic brain injuries [10][11][12]27,34,[44][45][46][47][48] and possibly other brain injuries such as stroke 49 , or neurodegenerative diseases 27,50 .…”

Section: Discussionsupporting

confidence: 59%

“…as a function of cellular activity). As endocannabinoids are also tightly regulated by their degradation, pharmacological inhibition of endocannabinoid degradative enzymes has been proposed as a potential therapeutic approach for the treatment of TBIs [10][11][12]26,27 . Nonetheless, therapeutic preclinical studies mainly during the early phase of primary injury (i.e.…”

Section: Introductionmentioning

confidence: 99%

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Endocannabinoid-mediated rescue of somatosensory cortex activity, plasticity and related behaviors following an early in life concussion

Badaut,

Hippauf,

Malinconi

et al. 2024

Preprint

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Due to the assumed plasticity of immature brain, early in life brain alterations are thought to lead to better recoveries in comparison to the mature brain. Despite clinical needs, how neuronal networks and associated behaviors are affected by early in life brain stresses, such as pediatric concussions, have been overlooked. Here we provide first evidence in mice that a single early in life concussion durably increases neuronal activity in the somatosensory cortex into adulthood, disrupting neuronal integration while the animal is performing sensory-related tasks. This represents a previously unappreciated clinically relevant mechanism for the impairment of sensory-related behavior performance. Furthermore, we demonstrate that pharmacological modulation of the endocannabinoid system a year post-concussion is well-suited to rescue neuronal activity and plasticity, and to normalize sensory-related behavioral performance, addressing the fundamental question of whether a treatment is still possible once post-concussive symptoms have developed, a time-window compatible with clinical treatment.

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Section: Discussionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Endocannabinoid-mediated rescue of somatosensory cortex activity, plasticity and related behaviors following an early in life concussion

Badaut,

Hippauf,

Malinconi

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…MAGL is primarily localized to presynaptic terminals, while ABDH6 is localized to excitatory dendrites, dendritic spines, and glial cells. Nevertheless, inhibition of either enzyme increases 2-AG and CB1R-mediated signalling [41]. The role of ABDH12 has not been clarified to date.…”

Section: The Enzymesmentioning

confidence: 99%

“…Spatiotemporal distribution of eCBs remains elusive due to a lack of tools capable of directly visualizing them. This is due to the lipid nature of eCBs, the plethora of structural analogues in tissues, and the short half-life of functional eCBs [29,41]. To date, even the simplest immunofluorescence approaches are impeded due to a lack of commercial lipid-targeting antibodies.…”

Section: Imaging the Endocannabinoidsmentioning

confidence: 99%

“…2-AG is a stronger CB 1 R agonist than AEA and also more abundant; therefore, most studies targeting the ECS have focused on modulating 2-AG tone [41,254]. Nevertheless, their actions are thought to be summative towards CBR agonism, with significant overlap in metabolic profiles produced by inhibiting 2-AG or AEA breakdown [85,255].…”

Section: Genetic Mouse Models Of Ecb Metabolic Enzymesmentioning

confidence: 99%

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Imaging and Genetic Tools for the Investigation of the Endocannabinoid System in the CNS

Kouchaeknejad,

Van Der Walt,

De Donato

et al. 2023

IJMS

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As central nervous system (CNS)-related disorders present an increasing cause of global morbidity, mortality, and high pressure on our healthcare system, there is an urgent need for new insights and treatment options. The endocannabinoid system (ECS) is a critical network of endogenous compounds, receptors, and enzymes that contribute to CNS development and regulation. Given its multifaceted involvement in neurobiology and its significance in various CNS disorders, the ECS as a whole is considered a promising therapeutic target. Despite significant advances in our understanding of the ECS’s role in the CNS, its complex architecture and extensive crosstalk with other biological systems present challenges for research and clinical advancements. To bridge these knowledge gaps and unlock the full therapeutic potential of ECS interventions in CNS-related disorders, a plethora of molecular–genetic tools have been developed in recent years. Here, we review some of the most impactful tools for investigating the neurological aspects of the ECS. We first provide a brief introduction to the ECS components, including cannabinoid receptors, endocannabinoids, and metabolic enzymes, emphasizing their complexity. This is followed by an exploration of cutting-edge imaging tools and genetic models aimed at elucidating the roles of these principal ECS components. Special emphasis is placed on their relevance in the context of CNS and its associated disorders.

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ABHD6 suppresses colorectal cancer progression via AKT signaling pathway

Xiong,

Yang,

Jin

et al. 2024

Molecular Carcinogenesis

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Colorectal cancer (CRC) continues to be a prevalent malignancy, posing a significant risk to human health. The involvement of alpha/beta hydrolase domain 6 (ABHD6), a serine hydrolase family member, in CRC development was suggested by our analysis of clinical data. However, the role of ABHD6 in CRC remains unclear. This study seeks to elucidate the clinical relevance, biological function, and potential molecular mechanisms of ABHD6 in CRC. We investigated the role of ABHD6 in clinical settings, conducting proliferation, migration, and cell cycle assays. To determine the influence of ABHD6 expression levels on Oxaliplatin sensitivity, we also performed apoptosis assays. RNA sequencing and KEGG analysis were utilized to uncover the potential molecular mechanisms of ABHD6. Furthermore, we validated its expression levels using Western blot and reactive oxygen species (ROS) detection assays. Our results demonstrated that ABHD6 expression in CRC tissues was notably lower compared to adjacent normal tissues. This low expression correlated with a poorer prognosis for CRC patients. Moreover, ABHD6 overexpression impeded CRC cell proliferation and migration while inducing G0/G1 cell cycle arrest. In vivo experiments revealed that downregulation of ABHD6 resulted in an increase in tumor weight and volume. Mechanistically, ABHD6 overexpression inhibited the activation of the AKT signaling pathway and decreased ROS levels in CRC cells, suggesting the role of ABHD6 in CRC progression via the AKT signaling pathway. Our findings demonstrate that ABHD6 functions as a tumor suppressor, primarily by inhibiting the AKT signaling pathway. This role establishes ABHD6 as a promising prognostic biomarker and a potential therapeutic target for CRC patients.

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Inhibiting degradation of 2-arachidonoylglycerol as a therapeutic strategy for neurodegenerative diseases

Cited by 20 publications

References 276 publications

Endocannabinoid-mediated rescue of somatosensory cortex activity, plasticity and related behaviors following an early in life concussion

Endocannabinoid-mediated rescue of somatosensory cortex activity, plasticity and related behaviors following an early in life concussion

Imaging and Genetic Tools for the Investigation of the Endocannabinoid System in the CNS

ABHD6 suppresses colorectal cancer progression via AKT signaling pathway

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