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. 2018 Jun 22;176(10):1361–1369. doi: 10.1111/bph.14369

Effect of endocannabinoid signalling on cell fate: life, death, differentiation and proliferation of brain cells

Moises Garcia‐Arencibia 1, Eduardo Molina-Holgado 2, Francisco Molina‐Holgado 3,✉
PMCID: PMC6487559  PMID: 29797438

Abstract

Cell fate events are regulated by different endogenous developmental factors such as the cell micro‐environment, external or remote signals and epigenetic factors. Among the many regulatory factors, endocannabinoid‐associated signalling pathways are known to conduct several of these events in the developing nervous system and in the adult brain. Interestingly, endocannabinoids exert modulatory actions in both physiological and pathological conditions. Endocannabinoid signalling can promote cell survival by acting on non‐transformed brain cells (neurons, astrocytes or oligodendrocytes) and can have either a protumoural or antitumoural effect on transformed cells. Moreover, endocannabinoids are able to attenuate the detrimental effects on neurogenesis and neuroinflammation associated with ageing. Thus, the endocannabinoid system emerges as an important regulator of cell fate, controlling cell survival/cell death decisions depending on the cell type and its environment.

Linked Articles

This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc

Abbreviations

2‐AG

2‐arachidonoylglycerol

ACEA

arachidonyl‐2′‐chloroethylamide

AEA

anandamide

CB

cannabinoids

DAGL

DAG lipase

eCB

endocannabinoid

GBM

glioblastoma

IL‐1ra

IL‐1 receptor antagonist

LTD

long‐term depression

MBP

myelin basic protein

met‐AEA

R(+)‐methanandamide

mTOR

mammalian target of rapamycin

NSC

neural stem/progenitor cells

OPC

oligodendrocyte progenitor

THC

Δ9‐tetrahydrocannabinol

TRPV1

transient receptor potential vanilloid 1

Introduction

During embryogenesis, development and tissue turnover, some cells undergo different processes, which include proliferation, migration and differentiation to achieve their final cell identity and perform their specific functions, while other die by apoptosis (Sears and Nevins, 2002). In order to maintain tissue homeostasis and normal cell function, these processes must be tightly regulated; otherwise, uncontrolled proliferation or cell death can appear giving rise to different disorders like cancer or neurodegeneration (Flusberg and Sorberg, 2015). Cell fate events are regulated by different endogenous developmental factors such as cell micro‐environment, external or remote signals and epigenetic factors. Among the many regulatory factors, endocannabinoid (eCB)‐associated signalling pathways are known to mediate several of these events in the developing nervous system and in the adult brain (Guzman, 2005; Maccarrone et al., 2014).

The endogenous cannabinoid (CB) system, or eCB system, is a lipid‐based signalling system involved in the control of neuronal function, inflammation and other physiological processes in mammals (Zou and Kumar, 2018). It is composed of GPCRs (CB1 and CB2 receptors), their endogenous ligands (eCBs), and the proteins involved in the synthesis and degradation of those ligands. The two main eCBs are N‐arachidonoyl‐ethanolamine (AEA; anandamide) and 2‐arachidonoylglycerol (2‐AG), which are both derivatives of arachidonic acid (Pertwee et al., 2010). Both endocannabinods are synthetized on demand. AEA is produced from N‐acyl‐phosphatidylethanolamine (NAPE) by NAPE‐specific PLD and is degraded by fatty acid amide hydrolase (Pacher et al., 2006), whereas 2‐AG is synthetized from DAG by DAG lipase α (DAGLα) or DAGLβ and is degraded by monoacylglycerol lipase (Murataeva et al., 2014).

The eCB system is phylogenetically widespread, with CB1 and CB2 receptors present in all chordates and the enzymes responsible for the synthesis and degradation of eCBs appearing throughout the animal kingdom (Elphick, 2012). The eCB system is highly conserved among species with strong genomic and non‐genomic effects, acting on cell fate decisions, in a time‐ and dose‐dependent modulatory manner. Low doses enhance cell cycle activity (self‐renewal/division) while high doses induce cell cycle arrest/apoptosis (Guzmán et al., 2002). Furthermore, their effects on cell fate are different in non‐transformed cells (without genetic alterations) or in transformed cells (i.e. tumoural cells) (Guzmán et al., 2002). The binding of eCBs to CB1 or CB2 receptors mediate synaptic plasticity or progenitor cell fate in the CNS (Elphick, 2012) to promote brain self‐repair (Molina‐Holgado and Molina‐Holgado, 2010). Moreover, the orphan GPCRs GPR18, GPR55 and GPR119 have been described as CB receptor‐like receptors (Irving et al., 2017). There is also evidence that the protective actions of eCBs are mediated by CB receptor‐independent mechanisms (García‐Arencibia et al., 2007; Wen et al., 2018). For example, several CB compounds interact with the nuclear hormone receptors PPARs (Pistis and O'Sullivan, 2017) and can also exert their actions through the transient receptor potential vanilloid 1 (TRPV1) (Fatahi et al., 2018; Fonseca et al., 2018).

Effects of the endocannabinoid system on transformed and non‐transformed cells

Effects of the endocannabinoid system on non‐transformed neural cells

Neuroimmune signalling and the bioavailability of brain eCBs contribute to the regulation and maintenance of neurogenesis, as well as the differentiation of neural progenitors and their integration in the brain circuitry (Jiang et al., 2007;Goncalves et al., 2008; Molina‐Holgado and Molina‐Holgado, 2010; Maccarrone et al., 2014). CBs are immunomodulatory and neuroprotective in vivo and in vitro and can modify the production and action of inflammatory mediators such as cytokines and chemokines (García‐Ovejero et al., 2013). These are important neuroinflammatory mediators that are involved in the pathological processes resulting from brain trauma, ischaemia and chronic neurodegenerative diseases (Denes et al., 2010). The eCB system has also been shown to be a key participant in the determination of cell fate in remote cell death and its associated mechanisms (Viscomi et al., 2010). However, eCBs are also involved in brain repair and recovery. Compelling evidence obtained, in vivo and in vitro, establishes a dynamic interplay between the eCB system, the immune system and neural stem/progenitor cells (NSC) in order to promote brain self‐repair (Molina‐Holgado and Molina‐Holgado, 2010). Crosstalk between inflammatory mediators and NSC might have important consequences for neural development and brain repair.

eCBs are well‐stablished neuroprotective agents in the CNS as demonstrated in vivo and in vitro. Recently, it has been demonstrated that long‐term depression (LTD) induced by endogenous CBs produces neuroprotection via astroglial CB1 receptors after stroke in rodents (Wang et al., 2018a). eCBs block the astroglial glutamate transporter GLT1 (also known as EAAT2) and activate GluN2B receptors (also known as NR2B), inducing postsynaptic AMPA receptor endocytosis to trigger astroglial eCB‐LTD. Thus, the LTD preconditioning induced by endogenous CBs protects neurons against subsequent lethal ischaemia (Wang et al., 2018a). However, the role of the eCB system in ischaemia is more complicated, as CB1 receptor antagonists have been demonstrated to be neuroprotective too (Reichenbach et al., 2016).

The presence of CB1 receptors in intracellular compartments, such as mitochondria, offers new strategies to pharmacologically act on this receptor in different pathologies (Hebert‐Chatelain et al., 2016). Importantly, eCB protection against mitochondrial dysfunction and oxidative stress is one of the proposed mechanisms to induce neuroprotection (Rangel‐López et al., 2015; Cai et al., 2017). Specifically, the mitochondrial CB1 receptor is involved in arachidonyl‐2′‐chloroethylamide (ACEA)‐induced protective effects on neurons and mitochondrial functions (Ma et al., 2015). Recently, it has been described as a new pathway for the pool of CB1 receptors located on corticostriatal terminals that efficiently safeguards dopamine D1receptors from different insults, and this is particularly relevant in neurodegenerative diseases (Ruiz‐Calvo et al., 2018).

Effects of the endocannabinoid system on oligodendrocytes

The function of CB receptors in oligodendrocytes has received less attention even though classical autoradiographic studies demonstrated that CB receptors were expressed in several white matter regions of the CNS (Herkenham et al., 1991). Later reports presented evidence that functional CB receptors are expressed in oligodendrocyte cultures, in the postnatal and adult corpus callosum and in the spinal cord white matter (Molina‐Holgado et al., 2002; Arevalo‐Martín et al., 2007; Garcia‐Ovejero et al., 2009). Thus, post‐natal rats treated with the CB1/CB2 agonist WIN 55,212‐2 up‐regulated myelin basic protein (MBP)‐immunoreactivity in the subcortical white matter, an effect overridden with CB1 or CB2 antagonists (Arevalo‐Martín et al., 2007). In oligodendrocyte cultures, the synthetic CB agonists, ACEA, JWH133 and HU210, were potent at increasing MBP levels, a marker of oligodendrocyte differentiation, mediated by the PI3K/Akt and mammalian target of rapamycin (mTOR) signalling pathways (Gomez et al., 2011). Moreover, we demonstrated that constitutive release of 2‐AG by late oligodendrocyte progenitors (OPCs) permits oligodendrocyte maturation through the ERK signalling cascade activated by CB receptors (Gomez et al., 2010). However, a basal level of 2‐AG synthesized by OPCs acting via CB1 and CB2 receptors is required to maintain proliferation of early progenitors in culture (Gomez et al., 2015). Indeed, OPC proliferation appears to be mediated by the activation of the PI3K/Akt/mTOR signalling pathways. In addition, inhibition of 2‐AG synthesis or antagonist binding to CB receptors seems to induce cell cycle arrest as evidenced by the down‐regulation of Ki67 or by the increase in the cell cycle inhibitor p27Kip1 (Gomez et al., 2015).

Effects of the endocannabinoid system on tumoural brain cell fate

The in vivo or in vitro effects of eCBs in tumoural cell fate are an open debate in the scientific community that needs deeper investigation. Conflicting reports, suggesting a role for CB signalling in tumour generation and progression or anticancer activity, have been published recently (Velasco et al., 2012; Malfitano et al., 2012; Proto et al., 2012; Pérez‐Gómez et al., 2015; Velasco et al., 2016a) (Figure 1).

Figure 1.

Figure 1

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Schematic depiction of the effect of the endocannabinoid system on brain cell survival/cell death decision.

Increased levels of eCBs and their receptors are associated with tumour aggressiveness (Malfitano et al., 2012). In support of the above, a dysregulation of eCB levels, which produced a modified responsiveness to specific ligands, has been shown in different cancer cell lines (Proto et al., 2012). In contrast, intracranially administered Δ9‐tetrahydrocannabinol (THC) has been demonstrated to have an antiproliferative action in a pilot clinical study in patients with recurrent study glioblastoma (GBM) (Guzmán et al., 2006). Interestingly, in the above study, CB receptors were present in GBM biopsies, with no correlation between receptor‐type expression and survival (Guzmán et al., 2006). THC induced both a down‐regulation of CB1 receptors (but not CB2 receptors) and decreased the number of viable cells. These antiproliferative effects of THC were due to apoptosis. However, other studies have suggested that THC induces proliferation of cells in vitro by a CB‐mediated inhibition of host antitumour activation (McKallip et al., 2005). Interestingly, the peripheral CB receptor CB2 has been characterized as a novel murine proto‐oncogen and confirmed to have a role in leukaemia development (Alberich‐Jorda et al., 2003) and in the promotion of renal cell carcinoma prognosis and progression (Wang et al., 2018b). Other studies have implicated CB2 receptors as regulators of HER2 pro‐oncogenic signalling, demonstrating that genetic inactivation of the CB2 receptor impairs tumour generation and progression in MMTV‐neu mice (Pérez‐Gómez et al., 2015).

Furthermore, pharmacological blockade of the CB2 receptor signalling pathway with a selective antagonist/inverse agonist (AM630) impairs the proliferation of human glioblastoma (U87) cells, suggesting that the CB2 receptor is somehow involved in the promoting the proliferation of these glioblastoma cells (Nikoloudakou and Molina‐Holgado, 2017).

Effect of the endocannabinoid signalling pathways on cell death (apoptosis and necrosis)

The eCB system has emerged as an important neuroprotective system through the control of glutamatergic excitotoxicity, calcium influx, oxidative stress, inflammation and autophagy (Fernández‐Ruiz et al., 2015). In contrast, other evidence indicates that the eCB system can also induce cell death in neural and non‐neural cells (Table 1). Thus, the eCB system can control cell fate by determining whether a cell survives or dies.

Table 1.

Signalling mechanisms by which the activation of the endocannabonoid system can cause different types of cell death

Cell death mechanism Signalling References
Apoptosis Cell cycle arrest via CB1/CB2 activation Melck et al., 1999; Caffarel et al., 2006
Cell cycle arrest independent of CB receptor activation Almada et al., 2017
Inhibition of cell survival signalling cascades via CB1/CB2 receptor activation Greenhough et al., 2007; Jia et al., 2006; Orellana‐Serradell et al., 2015
De novo synthesis of ceramide via CB1/CB2 activation Galve‐Roperh et al., 2000; Herrera et al., 2006
NF‐κB‐dependent apoptosis via CB1/CB2 activation Do et al., 2004
Superoxide anion formation and activation of caspase‐3 via CB1/CB2 activation Sarker et al., 2000
AEA induction of oxidative stress, calcium influx and caspase activation via TRPV1 receptor Maccarone and Finazzi‐Agró, 2003
met‐AEA induction of prostaglandins synthesis via PPARγ Eichele et al., 2009
AEA‐mediated recruitment and activation of the Fas/FasL death complex via GPR55 receptor Huang et al., 2011
AEA and met‐AEA receptor‐independent production of prostaglandins Hinz et al., 2004b; Soliman and Van Dross, 2016
Necrosis Endocannabinoid action on lipid rafts Fonseca et al., 2009; Fonseca et al., 2010
AEA induction of ROS production and intracellular calcium Siegmund et al., 2005
Autophagy ER stress via CB1/CB2 receptor activation Velasco et al., 2016b
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eCBs have been shown to induce apoptosis through different signalling mechanisms in several cell types. One of the most common mechanisms is by inhibiting the cell cycle progression, as has been demonstrated, among others, in human breast carcinoma cells where activation of CB1 receptors by AEA causes an inhibition of cAMP production leading to cell cycle arrest at the G1/S phase (Melck et al., 1999), while activation of CB2 receptors by THC in these same cells leads to their arrest in G2‐M (Caffarel et al., 2006). Interestingly, AEA has recently been demonstrated to have the ability to arrest cell cycle through a receptor‐independent pathway, inducing G2/M arrest in a human‐derived endometrial cell line (St‐T1b) directly and by inhibiting the Akt survival pathway (Almada et al., 2017).

This effect on the cell survival signalling cascades emerges as another common mechanism by which the eCB system induces apoptosis. Thus, CB1 receptor activation by THC inhibits both PI3K/Akt and RAS‐MAPK/ERK survival pathways in colorectal cancer cells (Greenhough et al., 2007). Similarly, activation of either CB1 or CB2 receptors with THC was demonstrated to induce an inhibitory effect on ERK and Akt in human Jurkat leukaemia T cells (Jia et al., 2006). However, in prostate cancer cells, the apoptosis induced by eCBs (either AEA or 2‐AG) acting on CB1 receptors was found to be the result of an inhibitory effect on the Akt pathway whereas the ERK signalling cascade was activated (Orellana‐Serradell et al., 2015).

Another major mechanism by which the eCB system can cause apoptosis is by stimulating the de novo synthesis of ceramide, a pro‐apoptotic sphingolipid. This can be due to activation of CB1 receptors in, for example, C6 glioma cells (Galve‐Roperh et al., 2000) and primary astrocytes (Blazquez et al., 2000) where it then causes a sustained accumulation of ceramide that activates the JNK/p38 MAPK pathway leading to cell death. Activation of CB2 receptors, which can also cause ceramide accumulation, has been shown to occur in human Jurkat leukaemia T cells (Herrera et al., 2006), and to lead to mitochondrial‐related apoptosis and in human pancreatic tumour cells by a mechanism that involves endoplasmic reticulum stress related genes (Carracedo et al., 2006). However, in colon cancer cells TNF‐α has been shown to mediate the de novo synthesis of ceramide, induced by activation of either CB1 or CB2 receptors, which then induces apoptosis (Cianchi et al., 2008).

Moreover, activation of CB1 and CB2 receptors on dentritic cells by AEA or THC induces NF‐κB‐dependent apoptosis (Do et al., 2004). When acting through the CB1 receptor, AEA can cause apoptotic cell death of rat phaeochromocytoma PC‐12 cells by increasing superoxide anion formation and activating caspase‐3 (Sarker et al., 2000).

However, eCB‐mediated apoptosis is not exclusively through CB receptors; apoptosis induced by AEA can occur be mediated by stimulation of TRPV1, increasing oxidative stress, calcium influx and caspase activation (Maccarone and Finazzi‐Agró, 2003). R(+)‐methanandamide (met‐AEA), a non‐hydrolysable AEA derivative, induce the synthesis of prostaglandins that lead to the induction of apoptosis in human cervical carcinoma cells by activating PPARγ (Eichele et al., 2009). GPR55, an orphan receptor proposed as a novel CB receptor, may mediate the apoptosis induced by AEA in cholangiocarcinoma cells, which involves the recruitment and activation of the Fas/FasL death complex in lipid rafts (Huang et al., 2011).

eCBs can also induce apoptosis by receptor‐independent effects. In human glioma cells, treatment with met‐AEA causes apoptosis by a mechanism involving the up‐regulation of COX‐2 expression via a pathway linked to lipid raft microdomains (Hinz et al., 2004a) and leading to the production of PGE2 (Hinz et al., 2004b). AEA can be directly metabolized by COX‐2 to form different prostamides (PGE2, PGF2α and PD2). Recently, a novel series of AEA‐derived prostamides, prostamides J, have been demonstrated to induce apoptosis in a receptor‐independent way (Soliman and Van Dross, 2016). Some of the effects previously mentioned to be responsible for the apoptosis induced by AEA, such as ER stress, oxidative stress and action on lipid raft microdomains, have now been reported to be receptor‐independent (Soderstrom et al., 2017).

Besides this ability to induce apoptosis, eCBs can also induce necrosis in some circumstances. Thus, AEA and 2‐AG have a dual effect on rat primary decidual cells. At low concentrations, the eCBs induce apoptosis via CB1 receptors, while at high concentrations they can cause necrosis through a mechanism involving lipid rafts, as methyl‐β‐cyclodextrin (a membrane cholesterol depletor) can block this effect (Fonseca et al., 2009; Fonseca et al., 2010). In primary hepatic stellate cells, high concentrations of AEA cause necrosis, an effect dependent on membrane cholesterol and the induction of ROS and intracellular calcium (Siegmund et al., 2005).

Effect of the endocannabinoid signalling pathways on autophagy

Macroautophagy, hereafter referred to as autophagy, is an evolutionary conserved process in which double‐membrane bound structures called autophagosomes engulf portions of cytoplasm that are delivered to lysosomes for degradation. Basal autophagy plays an important role in maintaining homeostasis, acting during starvation to restore nutrient levels in the cell, and in pathogen infections, removing long‐lived proteins, protein aggregates and damaged organelles. Autophagy dysfunction has been associated with various diseases (Ravikumar et al., 2010).

Autophagy malfunction can cause ‘type II programmed cell death’, which is different from apoptosis or ‘type I programmed cell death’ (Liu and Levine, 2015). Autophagy can be a survival mechanism against apoptosis or can promote apoptotic cell death.

The eCB system can up‐regulate autophagy in transformed and non‐transformed cells. While this up‐regulation generally leads to cell death in cancer cells, it can have therapeutic potential in the case of non‐cancer cells. AEA activation of CB1 receptors induces autophagy in fully differentiated Caco‐2 cells, a model of mature intestinal epithelium, leading to a reduction of the regulatory protein SOCS3 levels (Koay et al., 2014). In contrast, activation of CB2 receptors with the synthetic agonist HU‐308 in the spinal cord of mice with experimental autoimmune encephalomyelitis promotes autophagy, which leads to an inhibition of NLRP3 inflammasome activation, thus alleviating the pathogenesis of this disease in this animal model (Shao et al., 2014). Activation of both CB1 and CB2 receptors by Sativex®, a mixture of THC and cannabidiol, stimulates autophagy in a mouse model of tauopathy, which is associated with decreased levels of tau and amyloid proteins in the brain (Casarejos et al., 2013).

Activation of CB1 and CB2 receptors in different tumour cell lines and animal models of cancer can cause autophagic cell death. The general mechanism involves activation of ER stress‐related proteins such as p8, ATF‐4 and CHOP, which enhances the interaction of tribbles pseudokinase 3 (TRIB3) with Akt, leading to inhibition of the mTOR complex 1 (mTORC1) and the stimulation of autophagy causing cell death (Velasco et al., 2016b). In hepatocellular carcinoma cell lines, activation of the CB2 receptor causes ER stress‐dependent activation of AMP‐activated protein kinase, which inhibits mTORC1 and promotes autophagic cell death in addition to the p8/TRIB3 pathway (Vara et al., 2011).

Neuroimmune interactions of endocannabinoids and neural cell fate decisions

Recent work has highlighted that there is a synergy between the brain immune response and eCB signalling to promote functional recovery, as immune cells help to maintain neurogenesis in germinal centres of the adult CNS even under non‐pathological conditions (Molina‐Holgado and Molina‐Holgado, 2010). Thus, the eCB system, which has neuroprotective and immunomodulatory actions mediated by different signalling cascades in the brain, could assist the process of proliferation and differentiation of embryonic or adult neural stem cells inducing cellular responses by modulating the expression of a number of different genes (Galve‐Roperh et al., 2013). Embryonic/adult neurogenesis is at present one of the most exciting phenomena in neuroscience, but a lack of knowledge about how it works has made it difficult to understand why neurogenesis fails and hence to identify the missing factors that would form the basis for both induction and implantation of cell‐based therapies. Such therapies could be beneficial towards reversing/treating all manner of neurodegenerative diseases as well as providing important insights as to how the brain functions.

Although the role of several cytokines has been examined in neuroinflammation and neurodegeneration, a possible bidirectional interaction between the immune system and brain eCB in cell fate remains to be established. Evidence is emerging that the IL‐1 receptor antagonist (IL‐1ra), an endogenous antagonist for the actions of IL‐1 in the brain, is a potent signal to induce neural stem cell proliferation and migration, enhances neuroblast migration and the number of newly born neurons after cerebral ischaemia (Pradillo et al., 2017). IL‐1ra induces NSC proliferation in vivo and in vitro and mediates anti‐inflammatory and neuroprotective actions of CBs in neurons and glia (Molina‐Holgado et al., 2003; García‐Ovejero et al., 2013).

Similarly, a bi‐directional crosstalk between the TNF‐α and eCB signalling pathways is required to stimulate NSC proliferation (Rubio‐Araiz et al., 2008). However, although TNF‐α is detrimental to neurons after a stroke, it is involved in the repair process, since infusion of anti‐TNF‐α antibodies reduces the survival of newly formed neuroblasts (Heldmann et al., 2005; Katakowski et al., 2007). The above findings support the idea that activation of TNF‐α acting via its receptor TNFR2 leads to 2‐AG synthesis, which may act on the cells' own CB1 and CB2 receptors directing the migration of the progenitor cells to the site of injury. This is consistent with previous findings where DAGLα expression is dramatically down‐regulated when neural stem cells are differentiated (Walker et al., 2010), suggesting that TNF‐α‐induced neural stem proliferation depends on eCB production, release and binding to CB receptors.

The eCB system establishes interactions with other signalling systems that are relevant to the modulation of neural progenitor proliferation or neuritogenesis. Thus, activation of FGF receptors in rat cerebellar granule neurons promotes DAGL synthesis of 2‐AG, which activates CB1 receptors and promotes axonal growth (Williams et al., 2003). Co‐activation of opioid μ receptors and CB1 receptors in Neuro‐2A mouse neuroblastoma cells causes an attenuation of the neurite outgrowth seen upon the activation of each receptor type alone (Rios et al., 2006). Co‐stimulation of CB1 receptor and D2 dopamine receptors induce the formation of heterodimers of both types of receptor, which affects CB1 receptor signalling (Kearn et al., 2005). Finally, eicosapentaenoic acid, an ω‐3 polyunsaturated fatty acid, increases the proliferation of neural stem cells by increasing the levels of 2‐AG, causing the activation of CB1 and CB2 receptors (Dyall et al., 2016).

Conclusions

Cell fate decisions are key in the homeostatic maintenance of the cellular milieu as well as in the survival of tissues and organisms. The eCB network is an important regulator of brain cell fate determination in health and in pathological conditions. Signal transduction via cannabinoid receptors leads to the proliferation, differentiation and cell death events of brain cells, and this has important consequences for neural development and brain repair. Thus, eCB signalling‐mediated maintenance of synaptic plasticity and neuronal cell function provide potential opportunities for endogenous stem cell‐based neuroreparative strategies. The effect of the eCB system on cell death makes it a promising target to treat different brain tumours, although more studies are needed to avoid the pro‐tumoural effects shown in some models, especially when the CB2 receptor is activated. Furthermore, the bi‐directional crosstalk of the brain eCB system with the immune system drives neuroprotective and anti‐inflammatory actions that could assist the process of proliferation and differentiation of embryonic or adult neural stem cells.

Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al., 2018), and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 (Alexander et al., 2017a,b,c,d,e,f,g).

Conflict of interest

The authors declare no conflicts of interest.

Garcia‐Arencibia, M. , Molina-Holgado, E. , and Molina‐Holgado, F. (2019) Effect of endocannabinoid signalling on cell fate: life, death, differentiation and proliferation of brain cells. British Journal of Pharmacology, 176: 1361–1369. 10.1111/bph.14369.

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