Unique pathway for anandamide synthesis and liver regeneration

Izzo, Angelo A.; Deutsch, Dale G.

doi:10.1073/pnas.1103566108

Cited by 20 publications

(14 citation statements)

References 16 publications

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“…Mechanistic studies showed that 40 hours after hepatectomy, cyclin decreased in the liver of CB1 -/mice, but not in wild type mice, suggesting that CB1 activation during liver resection promotes the regeneration of liver cells by increasing cell proliferation (16). Other studies have demonstrated that CB2 receptor gene transcription increased in wild type mice in 24 to 72 hours after liver resection, and such changes were obviously delayed in CB2 -/mice, indicating that CB2 receptors may also promote liver regeneration during liver resection (28). In animals with acute liver injury induced by carbon tetrachloride, the CB2 receptor expression in liver tissue of mice increased significantly with enhanced liver cell proliferation.…”

Section: Hepatocyte Regeneration In Response To Injurymentioning

confidence: 95%

Endocannabinoids signaling Molecular mechanisms of liver regulation and diseases

et al. 2016

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The endocannabinoid system (ECS) includes endocannabinoids (eCBs), cannabinoid (CB) receptors and the enzymes that are responsible for endocannabinoid production and metabolism. The ECS has been reported to be present in both brain and peripheral tissues. Recent studies have indicated that eCBs and their receptors are involved in the development of various liver diseases. They were found to be altered in response to many danger factors. It is generally accepted that eCB may exert a protective action via CB2 receptors in different liver diseases. However, eCBs have also been demonstrated to have pathogenic role via their CB1 receptors. Although the therapeutic potential of CB1 receptor blockade in liver diseases is limited by its neuropsychiatric side effects, many studies have been conducted to search for novel, peripherally restricted CB1 antagonists or CB2 agonists, which may minimize their neuropsychiatric side effects in clinical use. This review summarizes the current understanding of the ECS in liver diseases and provides evidence for the potential to develop new therapeutic strategies for the treatment of these liver diseases.

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Section: Hepatocyte Regeneration In Response To Injurymentioning

confidence: 95%

Endocannabinoids signaling Molecular mechanisms of liver regulation and diseases

et al. 2016

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“…The CB1 receptor is also found to be expressed in the frontal-limbic regions of the brain, which significantly regulate the emotional manifestations of the human brain [ 47 ]. CB1 receptor regulates a descending inhibitory pathway from the supraspinal level to the spinal cord nociceptive system via inhibiting GABA release [ 48 , 49 ]. At the spinal cord level, the CB1 receptor significantly mediates the noxious stimulation to the brain [ 50 ].…”

Section: The Endocannabinoid Systemmentioning

confidence: 99%

Distinctive Evidence Involved in the Role of Endocannabinoid Signalling in Parkinson’s Disease: A Perspective on Associated Therapeutic Interventions

Behl

Kaur

Bungău

et al. 2020

IJMS

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Current pharmacotherapy of Parkinson’s disease (PD) is symptomatic and palliative, with levodopa/carbidopa therapy remaining the prime treatment, and nevertheless, being unable to modulate the progression of the neurodegeneration. No available treatment for PD can enhance the patient’s life-quality by regressing this diseased state. Various studies have encouraged the enrichment of treatment possibilities by discovering the association of the effects of the endocannabinoid system (ECS) in PD. These reviews delineate the reported evidence from the literature on the neuromodulatory role of the endocannabinoid system and expression of cannabinoid receptors in symptomatology, cause, and treatment of PD progression, wherein cannabinoid (CB) signalling experiences alterations of biphasic pattern during PD progression. Published papers to date were searched via MEDLINE, PubMed, etc., using specific key words in the topic of our manuscript. Endocannabinoids regulate the basal ganglia neuronal circuit pathways, synaptic plasticity, and motor functions via communication with dopaminergic, glutamatergic, and GABAergic signalling systems bidirectionally in PD. Further, gripping preclinical and clinical studies demonstrate the context regarding the cannabinoid compounds, which is supported by various evidence (neuroprotection, suppression of excitotoxicity, oxidative stress, glial activation, and additional benefits) provided by cannabinoid-like compounds (much research addresses the direct regulation of cannabinoids with dopamine transmission and other signalling pathways in PD). More data related to endocannabinoids efficacy, safety, and pharmacokinetic profiles need to be explored, providing better insights into their potential to ameliorate or even regress PD.

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“…This enzyme was purified and cloned (Ueda et al, 2005 ) and subsequent papers using null mice confirmed that it was mainly responsible for the synthesis of AEA (Tsuboi et al, 2011 ; Leishman et al, 2016 ) although other minor pathways may be involved under certain conditions (Liu et al, 2008 ; Simon and Cravatt, 2010 ) depending upon the mouse construct (Leishman et al, 2016 ). FAAH can also mediate the reverse reaction for the synthesis of AEA and this has been implicated physiologically in liver regeneration (Devane and Axelrod, 1994 ; Arreaza et al, 1997 ; Izzo and Deutsch, 2011 ; Mukhopadhyay et al, 2011 ).…”

Section: Anandamide Synthesismentioning

confidence: 99%

A Personal Retrospective: Elevating Anandamide (AEA) by Targeting Fatty Acid Amide Hydrolase (FAAH) and the Fatty Acid Binding Proteins (FABPs)

Deutsch

2016

Front. Pharmacol.

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This perspective was adapted from a Career Achievement Award talk given at the International Cannabinoid Research Society Symposium in Bukovina, Poland on June 27, 2016. As a biochemist working in the neurosciences, I was always fascinated with neurotransmitter inactivation. In 1993 we identified an enzyme activity that breaks down anandamide. We called the enzyme anandamide amidase, now called FAAH. We and other laboratories developed FAAH inhibitors that were useful reagents that also proved to have beneficial physiological effects and until recently, new generations of inhibitors were in clinical trials. Nearly all neurotransmitters are water soluble and as such, require a transmembrane protein transporter to pass through the lipid membrane for inactivation inside the cell. However, using model systems, we and others have shown that this is unnecessary for anandamide, an uncharged hydrophobic molecule that readily diffuses across the cellular membrane. Interestingly, its uptake is driven by the concentration gradient resulting from its breakdown mainly by FAAH localized in the endoplasmic reticulum. We identified the FABPs as intracellular carriers that “solubilize” anandamide, transporting anandamide to FAAH. Compounds that bind to FABPs block AEA breakdown, raising its level. The cannabinoids (THC and CBD) also were discovered to bind FABPs and this may be one of the mechanisms by which CBD works in childhood epilepsy, raising anandamide levels. Targeting FABPs may be advantageous since they have some tissue specificity and do not require reactive serine hydrolase inhibitors, as does FAAH, with potential for off-target reactions. At the International Cannabis Research Society Symposium in 1992, Raphe Mechoulam revealed that his laboratory isolated an endogenous lipid molecule that binds to the CB1 receptor (cannabinoid receptor type 1) and this became the milestone paper published in December of that year describing anandamide (AEA, Devane et al., 1992). As to be expected, this discovery raised the issues of AEA's synthesis and breakdown.

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Unique pathway for anandamide synthesis and liver regeneration

Cited by 20 publications

References 16 publications

Endocannabinoids signaling Molecular mechanisms of liver regulation and diseases

Endocannabinoids signaling Molecular mechanisms of liver regulation and diseases

Distinctive Evidence Involved in the Role of Endocannabinoid Signalling in Parkinson’s Disease: A Perspective on Associated Therapeutic Interventions

A Personal Retrospective: Elevating Anandamide (AEA) by Targeting Fatty Acid Amide Hydrolase (FAAH) and the Fatty Acid Binding Proteins (FABPs)

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