Possible involvement of the endocannabinoid system in the actions of three clinically used drugs

doi:10.1016/j.tips.2003.12.001

Trends in Pharmacological Sciences

Volume 25, Issue 2, February 2004, Pages 59-61

https://doi.org/10.1016/j.tips.2003.12.001 Get rights and content

Abstract

There is considerable interest in developing new therapies that are based on compounds that modulate the endocannabinoid system to treat several disease states (e.g. pain, neurodegeneration and cancer). However, recent evidence from studies in experimental animals has suggested that three clinically used drugs, the anaesthetic agent propofol and the non-steroidal anti-inflammatory drugs indomethacin and flurbiprofen (when given spinally), activate cannabinoid receptors as an important part of their actions. In this article, the findings of these studies are summarized and possible spectra of actions of these drugs are discussed.

Section snippets

Modulation of endocannabinoid function in experimental animals in vivo by propofol, indomethacin and flurbiprofen

Recent reports have suggested that CB₁ receptor activation might be involved in the actions of three drugs used clinically. Patel et al. [5] investigated the pharmacology of the anaesthetic agent propofol in the mouse. They found that treatment with the CB₁ receptor antagonist rimonabant [SR141716A (see Chemical names)] reduced (but did not remove) the incidence of the loss of the righting reflex induced by a sedative dose of propofol [100 mg kg⁻¹ by intraperitoneal injection (i.p.)], whereas

Involvement of fatty acid amide hydrolase (FAAH)

Elucidation of the mechanism of these endocannabinoid effects is of considerable importance because it could suggest a therapeutically viable target. One obvious such target would be fatty acid amide hydrolase (FAAH), the enzyme responsible for the metabolism of anandamide, given that mice lacking this enzyme show a reduced pain sensitivity in both thermal and inflammatory models of pain [10]. Propofol was shown to inhibit FAAH in vitro with an IC₅₀ value of 52 μM, and increase the brain

Conclusions and future perspectives

Recent studies provide evidence that three drugs, propofol, indomethacin and flurbiprofen, affect endocannabinoid function in vivo, and that this modulation can contribute to their pharmacological effects. The key word here is ‘contribute’; it would be too simplistic to attribute their pharmacological actions solely to effects on endocannabinoid function. Furthermore, it is a large step to take to extrapolate data in experimental animals to the situation in humans. Nevertheless, the data do

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Propofol is an established anesthetic widely used for induction and maintenance of anesthesia. We investigated propofol for its anti-inflammatory effects on microglia and found that propofol treatment is associated with substantial lower levels of extracellular vesicles (EVs) in immune activated microglia. Importantly, EVs collected from immune activated microglia reversed propofol-mediated anti-inflammatory and neuroprotective effects, suggesting that propofol reduces proinflammatory microglia activation and microglia-mediated neurotoxicity through inhibition of EV release. These data shed new insight into a novel molecular mechanism of propofol-mediated neuroprotective and immunomodulatory effects through inhibition of EV release.
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While many studies have linked prediction errors and event related potentials at a single processing level, few consider how these responses interact across levels. In response, we present a factorial analysis of a multi-level oddball task – the local-global task – and we explore it when participants are sedated versus recovered. We found that the local and global levels in fact interact. This is of considerable current interest, since it has recently been argued that the MEEG response evoked by the global effect corresponds to a distinct processing mode that moves beyond predictive coding. This interaction suggests that the two processing modes are not distinct. Additionally, we observed that sedation modulates this interaction, suggesting that conscious awareness may not be completely restricted to a single (global) processing level.
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2017, Essentials of Neuroanesthesia
Drugs used in neuroanesthesia should be able to provide optimal brain conditions for surgery and also help maintain adequate brain tissue perfusion to meet increased regional metabolic demands. The ability to not only rapidly achieve deeper intraoperative anesthesia levels but also allow quick postoperative recovery of consciousness, good analgesic effects, no epileptogenic effects, minimal interference with neuromonitoring modalities, no adverse effects on other body organs, and capability of preserving systemic and cerebral hemodynamic stability are some of the desirable attributes of a neuroanesthetic drug. The beneficial cerebral effects of these drugs would be maintenance of cerebral autoregulation, vasoreactivity to carbon dioxide (CO₂) and coupling of cerebral blood flow and cerebral metabolic rate, and prevention of increases in intracranial pressures and cerebral blood volume.
Protective effect of acetyl-l-carnitine on propofol-induced toxicity in embryonic neural stem cells
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Propofol is a widely used general anesthetic. A growing body of data suggests that perinatal exposure to general anesthetics can result in long-term deleterious effects on brain function. In the developing brain there is evidence that general anesthetics can cause cell death, synaptic remodeling, and altered brain cell morphology. Acetyl-l-carnitine (l-Ca), an anti-oxidant dietary supplement, has been reported to prevent neuronal damage from a variety of causes. To evaluate the ability of l-Ca to protect against propofol-induced neuronal toxicity, neural stem cells were isolated from gestational day 14 rat fetuses and on the eighth day in culture were exposed for 24 h to propofol at 10, 50, 100, 300 and 600 μM, with or without l-Ca (10 μM). Markers of cellular proliferation, mitochondrial health, cell death/damage and oxidative damage were monitored to determine: (1) the effects of propofol on neural stem cell proliferation; (2) the nature of propofol-induced neurotoxicity; (3) the degree of protection afforded by l-Ca; and (4) to provide information regarding possible mechanisms underlying protection. After propofol exposure at a clinically relevant concentration (50 μM), the number of dividing cells was significantly decreased, oxidative DNA damage was increased and a significant dose-dependent reduction in mitochondrial function/health was observed. No significant effect on lactase dehydrogenase (LDH) release was observed at propofol concentrations up to 100 μM. The oxidative damage at 50 μM propofol was blocked by l-Ca. Thus, clinically relevant concentrations of propofol induce dose-dependent adverse effects on rat embryonic neural stem cells by slowing or stopping cell division/proliferation and causing cellular damage. Elevated levels of 8-oxoguanine suggest enhanced oxidative damage [reactive oxygen species (ROS) generation] and l-Ca effectively blocks at least some of the toxicity of propofol, presumably by scavenging oxidative species and/or reducing their production.
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Citation Excerpt :
While it is possible that this cell line expresses GABRP protein in the absence of high levels of mRNA, it is more likely that propofol induces migration of these cells through GABA(A) receptors lacking the pi subunit. Alternatively, propofol has been reported to inhibit sodium channels as well as impact endocannabinoid metabolism, and these pathways may also contribute to its effects on MDA-MB-468 cells (44, 45). Our studies reveal that HCC1187 cells do not mobilize calcium in response to GABA stimulation suggesting that GABRP may act in a ligand-independent manner, or that these cells intrinsically produce high quantities of GABA.
Breast cancer is a heterogeneous disease comprised of distinct subtypes predictive of patient outcome. Tumors of the basal-like subtype have a poor prognosis due to inherent aggressiveness and the lack of targeted therapeutics. Basal-like tumors typically lack estrogen receptor-α, progesterone receptor and HER2/ERBB2, or in other words they are triple negative (TN). Continued evaluation of basal-like breast cancer (BLBC) biology is essential to identify novel therapeutic targets. Expression of the pi subunit of the GABA(A) receptor (GABRP) is associated with the BLBC/TN subtype, and herein, we reveal its expression also correlates with metastases to the brain and poorer patient outcome. GABRP expression in breast cancer cell lines also demonstrates a significant correlation with the basal-like subtype suggesting that GABRP functions in the initiation and/or progression of basal-like tumors. To address this postulate, we stably silenced GABRP in two BLBC cell lines, HCC1187 and HCC70 cells. Decreased GABRP reduces in vitro tumorigenic potential and migration concurrent with alterations in the cytoskeleton, specifically diminished cellular protrusions and expression of the BLBC-associated cytokeratins, KRT5, KRT6B, KRT14, and KRT17. Silencing GABRP also decreases phosphorylation of extracellular regulated kinase 1/2 (ERK1/2) in both cell lines and selective inhibition of ERK1/2 similarly decreases the basal-like cytokeratins as well as migration. Combined, these data reveal a GABRP-ERK1/2-cytokeratin axis that maintains the migratory phenotype of basal-like breast cancer. GABRP is a component of a cell surface receptor, thus, these findings suggest that targeting this new signaling axis may have therapeutic potential in BLBC.
Synergistic activation of lipopolysaccharide-stimulated glial cells by propofol
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Citation Excerpt :
The classical mechanism of propofol action includes the potentiation of GABAA receptor activity and blockade of sodium channel, none of which is directly involved in the activation of MAPK pathways or inflammatory stimulation in astrocytes. Recently, it has been suggested that endocannabinoid system is involved in the anesthetic and other unique features of propofol [23]. It has been suggested that propofol increases brain N-arachidonylethanolamine (anandamide) content and inhibits fatty acid amide hydrolase [24–26], which might be associated with the propofol’s effects on memory formation and anti-nociceptive effects.
Despite the extensive use of propofol in general anesthetic procedures, the effects of propofol on glial cell were not completely understood. In lipopolysaccharide (LPS)-stimulated rat primary astrocytes and BV2 microglial cell lines, co-treatment of propofol synergistically induced inflammatory activation as evidenced by the increased production of NO, ROS and expression of iNOS, MMP-9 and several cytokines. Propofol augmented the activation of JNK and p38 MAPKs induced by LPS and the synergistic activation of glial cells by propofol was prevented by pretreatment of JNK and p38 inhibitors. When we treated BV2 cell culture supernatants treated with LPS plus propofol on cultured rat primary neuron, it induced a significant neuronal cell death. The results suggest that the repeated use of propofol in immunologically challenged situation may induce glial activation in brain.

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Trends in Pharmacological Sciences

Research FocusPossible involvement of the endocannabinoid system in the actions of three clinically used drugs

Abstract

Section snippets

Modulation of endocannabinoid function in experimental animals in vivo by propofol, indomethacin and flurbiprofen

Involvement of fatty acid amide hydrolase (FAAH)

Conclusions and future perspectives

Prog. Neurobiol.

Lancet Neurol.

Trends Pharmacol. Sci.

Eur. J. Pharmacol.

Neurosci. Lett.

Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716

Arch. Gen. Psychiatry

The general anesthetic propofol increases brain N-arachidonoylethanolamine (anandamide) content and inhibits fatty acid amide hydrolase

Br. J. Pharmacol.

Research Focus
Possible involvement of the endocannabinoid system in the actions of three clinically used drugs