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Mechanisms of Control of Neuron Survival by the Endocannabinoid

Current Pharmaceutical Design, 2008, 14, 000-000
Mechanisms of Control of Neuron Survival by the Endocannabinoid
Ismael Galve-Roperh*, Tania Aguado, Javier Palazuelos and Manuel Guzmán*
Department of Biochemistry and Molecular Biology I, School of Biology, and Centro de Investigación Biomédica en Red
sobre Enfermedades Neurodegenerativas (CIBERNED), Complutense University, 28040 Madrid, Spain
Abstract: Endocannabinoids act as retrograde messengers that, by inhibiting neurotransmitter release via presynaptic CB1
cannabinoid receptors, regulate the functionality of many synapses. In addition, the endocannabinoid system participates
in the control of neuron survival. Thus, CB1 receptor activation has been shown to protect neurons from acute brain injury
as well as in neuroinflammatory conditions and neurodegenerative diseases. Nonetheless, some studies have reported that
cannabinoids can also exert neurotoxic actions. Cannabinoid neuroprotective activity relies on the inhibition of glutamatergic neurotransmission and on other various mechanisms, and is supported by the observation that the brain overproduces endocannabinoids upon damage. Coupling of neuronal CB1 receptors to cell survival routes such as the phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase pathways may contribute to cannabinoid neuroprotective action. These pro-survival signals occur, at least in part, by the cross-talk between CB1 receptors and growth factor
tyrosine kinase receptors. Besides promoting neuroprotection, a role for the endocannabinoid system in the control of neurogenesis from neural progenitors has been put forward. In addition, activation of CB2 cannabinoid receptors on glial cells
may also participate in neuroprotection by limiting the extent of neuroinflammation. Altogether, these findings support
that endocannabinoids constitute a new family of lipid mediators that act as instructive signals in the control of neuron
Key Words: Cannabinoid, endocannabinoid system, neuron, neuroprotection, neurodegeneration, neurogenesis, neuroinflammation.
Preparations from Cannabis sativa L. (marijuana) have
been used for many centuries both medicinally and recreationally. However, the chemical structure of their active
components - the cannabinoids - was not elucidated until the
early 1960s. Among the approximately 70 cannabinoids produced by marijuana, 9-tetrahydrocannabinol (THC) is the
most relevant owing to its high potency and abundance [1].
Since the early-mid 1990s it is widely accepted that THC
acts in the organism by mimicking endogenous substances the endocannabinoids (eCBs) anandamide (AEA, N-arachidonoylethanolamine; [2]) and 2-arachidonoylglycerol (2AG;
[3, 4]) that bind to and activate specific cell surface cannabinoid receptors, two of which have been cloned and well
characterized from mammalian tissues: CB1 [5] and CB2 [6].
eCB generation occurs by cleavage of plasma membrane
lipid precursors, and is tightly controlled by neuronal activity
(Fig. 1). Thus, engagement of various postsynaptic metabotropic and ionotropic neurotransmitter receptors triggers eCB
production. Once generated, eCBs act retrogradely through
presynaptic CB1 cannabinoid receptors, blunting membrane
depolarization and inhibiting neurotransmitter release [7].
CB1 receptors are highly abundant in discrete areas of the
brain, and their activation lowers the release of neurotransmitters such GABA and glutamate, thereby affecting pro*Address correspondence to these authors at the Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University,
28040 Madrid, Spain; Tel: +34913944668; Fax: +34913944672;
E-mail: and
1381-6128/08 $55.00+.00
cesses such as motor activity, learning and memory [7, 8].
Besides this well established neuromodulatory role of eCBs,
it is becoming evident that these compounds play an important role in the control of neuron survival. A large series of
articles in this Special Issue provides details on the characteristics and therapeutic potential of eCB system-mediated
neuroprotection in many particular neuropathologies related
to acute brain injury, neurodegeneration and neuroinflammation. Hence here we will focus on the general signalling
mechanisms by which the eCB system can protect neurons
from death.
The first reports on the ability of eCBs to protect neurons
from death date more than one decade ago, when various
cannabinoids were shown to exert neuroprotection upon
ischemic/excitotoxic injury both in vitro [9, 10] and in vivo
[11]. These observations founded a new area of research
focused on the study of the eCB system as an endogenous
neuroprotective system and the potential of cannabinoid
compounds as new pharmacological tools for the management of various neuropathologies [12]. A number of cannabinergic drugs, including synthetic and endogenous cannabinoid receptor agonists and inhibitors of eCB transport
and degradation, have been used in those studies. Just to
mention a few examples, THC administration reduces neuronal loss and brain damage in excitotoxicity and ischemia
models [13]. Likewise, AEA exerts a neuroprotective action
© 2008 Bentham Science Publishers Ltd.
2 Current Pharmaceutical Design, 2008, Vol. 14, No. 00
Galve-Roperh et al.
Fig. (1). Control of neuronal activity and excitotoxic death by the endocannabinoid system. eCBs act as retrograde neuromodulators that
inhibit glutamatergic signalling and excitotoxicity, thereby preventing intracellular neurotoxic events. A combination of CB1 receptordependent mechanisms may contribute to cannabinoid-evoked neuroprotection. See text for further details.
in excitotoxicity [14, 15] and 2AG protects neurons in traumatic brain injury [16]. In addition, administration of the
synthetic cannabinoid receptor agonist WIN-55,212-2 confers neuroprotection in a model of neonatal hypoxicischemic encephalopathy [17].
A common approach to modulate eCB levels involves the
use of inhibitors of their transport and degradation, which
provides a means of elevating eCB levels and therefore of
activating cannabinoid receptors in a more prolonged fashion
and with higher sensitivity to physiological, on-demand
regulation than acute administration of cannabinoid receptor
agonists [18]. In agreement with the proposed neuroprotective action of the latter agents, administration of inhibitors of
eCB transport or degrading enzymes [fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)] can
prevent behavioural alterations and memory impairment due
to excitotoxic damage in a CB1 receptor-dependent manner
[19, 20]. A similar strategy has proved useful in attenuating
emotional symptoms of anxiety and depression [21].
In addition to the aforementioned pharmacological studies, the use of CB1 receptor knock-out mice has provided
further evidence for a neuroprotective role of the eCB system as those animals are more sensitive to various brain insults and neurodegenerative disorders that their corresponding wild-type controls. Thus, for example, increased excitotoxic injury is observed in CB1 receptor-deficient mice after
brain stroke or kainic acid administration [22, 23]. CB1 receptors can also favour hippocampal neuron survival in the
hippocampus along life, as CB1 receptor-deficient mice show
an enhanced loss of neurons in CA1 and CA3 with aging,
which is accompanied by a decrease in cognitive functions
The eCB system exerts an important control over excessive synaptic activity in different brain areas [7]. In the context of excitotoxicity, functional CB1 receptors are present at
glutamatergic terminals [25] and become activated by eCBs
upon excitatory synaptic transmission, thereby preventing
massive glutamate release (Fig. 1). For example, the eCB
system participates in the regulation of epileptogenic circuits
of the hippocampus [25] and, in excitotoxicity models induced by ionotropic glutamate receptor agonist administration, cannabinoid treatment exerts a neuroprotective action
that relies, at least mostly, on a depression of glutamatergic
signalling [26, 27]. Likewise, dopaminergic neurons are protected by 2AG from ischemia-induced death [28]. In this
context, increased levels of different molecular species of
eCBs, including AEA, other acylethanolamides and 2AG,
have been determined in various models of brain injury, and
this has been widely related to the involvement of those
compounds in neuroprotection [12, 29-32]. Likewise, CB1
receptors have been reported to be up-regulated in stroke and
excitotoxicity [33, 34]. Nonetheless, FAAH-deficient mice,
which have increased brain AEA levels, exhibit increased
seizure severity [35], suggesting again that the notion of eCB
system-mediated neuroprotection, although generally supported, is complex and may be context-dependent.
The mammalian brain shows very limited capacity for
self-repair, but the occurrence of neurogenesis in certain
Mechanisms of Control of Neuron Survival
areas of the adult brain suggests that neural progenitor cells
can participate in structural and functional neurorepair. Under normal conditions, neurogenesis in the adult brain appears to be restricted to discrete germinal areas - the subventricular zone and the hippocampal dentate gyrus [36]. While
some reports indicate that neurogenesis in the adult central
nervous system may be more widespread than previously
thought, improved characterization of these observations is
required [37]. Newly generated cells mature into functional
neurons in the adult mammalian brain; in the hippocampus
they can participate in memory processing [38], while in the
olfactory bulb they can contribute to the control of olfactory
inputs [36].
Within the many signalling systems involved in the instruction of neuronal generation, e.g. trophic factors and cytokines [39], the eCB system has been recently proposed to
cooperate in the regulation of neural cell development and
neurogenesis [40, 41]. Cannabinoid receptors are not only
expressed in differentiated neurons of many brain areas [7,
42], but they are also present in neuroblasts and neural progenitors of the adult brain [40, 41], in which they modulate
cell proliferation [43-45] and differentiation [46, 47]. Regarding proliferation, CB1 receptor-deficient mice show decreased progenitor proliferation in the hippocampus and the
subventricular zone [43, 44]. Regarding differentiation, the
situation seems more complex as, for example, in certain
pharmacological paradigms cannabinoid administration inhibits synaptogenesis via CB1 receptors [48], while in others
it does not affect the absolute number of newly born hippocampal neurons [49] and in others it promotes neurogenesis
and exerts anxiolytic and antidepressant effects [46].
Some studies on neurogenesis have also been conducted
in genetically-modified animals. Thus, in CB1-/- and FAAH-/adult mice no alterations are evident in hippocampal neurogenesis under basal conditions, though hippocampal astrogliogenesis is depressed in the former and enhanced in the
latter animals [47]. In contrast, upon excitotoxic damage CB1
receptor-deficient mice show a strongly depressed neurogenic response [34]. In that situation, activation of CB1 receptors in neural progenitors induce cell proliferation and
contribute to the generation of new neurons by promoting
the production of growth factors such as fibroblast growth
factor-2 (FGF-2) [34]. CB2 receptor activation can also
stimulate adult neural progenitor proliferation [45, 50] and,
accordingly, CB2-/- mice show lower progenitor proliferation
after excitotoxicity than their wild-type controls [45, 50].
Thus, the eCB system may participate in the control of brain
structural plasticity and repair by modulating neural cell proliferation and commitment, although the precise role of CB1
and CB2 receptors in neuronal specification and differentiation remains to be elucidated.
Besides the various non-cell autonomous processes involved in cannabinoid receptor-mediated neuroprotection,
such as the CB1 receptor-dependent reduction of glutamatergic secretion (see above) and the CB2 receptor-dependent
inhibition of proinflammatory-mediator release from acti-
Current Pharmaceutical Design, 2008, Vol. 14, No. 00
vated microglia (see below), it is likely that neuron-cell intrinsic, CB1 receptor-triggered intracellular signal transduction events also contribute to cannabinoid neuroprotective
activity. The precise nature of those mechanisms is not fully
understood, but there is accruing evidence that CB1 receptor
activation can couple to at least two important cell survival
signalling routes: the phosphatidylinositol 3-kinase (PI3K)/
Akt pathway and the extracellular signal-regulated (ERK)
pathway (Fig. 2).
CB1 receptor activation evokes PI3K/Akt stimulation in
primary cortical neurons [51] and in the mouse hippocampus, striatum and cerebellum in vivo [52], and this event has
been related with cannabinoid-mediated neuroprotection.
CB1-mediated PI3K/Akt activation is also observed in cells
heterologously expressing the receptor [53] and in primary
glial cells [54, 55] and astrocytoma cells lines [56, 57], and
is dependent on Gi/o protein dissociation [53]. The downstream targets by which CB1 receptors may signal neuroprotection via Akt are as yet unclear, but one of them could be
glycogen synthase kinase-3, a potentially neurotoxic protein
that is phosphorylated and inactivated by Akt [52, 53].
It is well documented that cannabinoid administration
leads to CB1 receptor-mediated ERK pathway activation in
the brain in vivo, for example in the hippocampus [58], the
striatum [59], the frontal cortex [60] and the cerebellum [61].
This process is also observed in cells heterologously expressing the receptor [62] as well as in primary glial cells [63] and
astrocytoma cells lines [56, 57]. CB1 receptor-dependent
ERK activation relies on Gi/o protein dissociation [62] and
may be dependent, at least in part, on the inhibition of the
adenylyl cyclase/protein kinase A/cAMP pathway [58, 64,
65]. In line with the notion that ERK actions are highly promiscuous, CB1 receptor coupling to this pathway most likely
signals via different context-dependent effectors. For example, induction of various transcription factors such as the
early-response genes c-fos [66, 67] and Krox-24 [58, 68] and
phosphorylation/activation of transcription factors such as
Elk-1 [59] or other targets such as p90 ribosomal S6 kinase
[54] have been implicated in CB1 receptor-evoked ERK effects in neural cells.
Gi/o protein-coupled receptors can conceptually activate
the PI3K/Akt and ERK pro-survival pathways through G
protein subunit release both “directly” - via activation of
targets such as class IB PI3K isoforms - and “indirectly” - via
transactivation of growth factor tyrosine kinase receptors and
subsequent stimulation of the downstream “canonical” class
IA PI3K/Akt and ERK pathways [69] (Fig. 2). Although for
cannabinoid receptors the former process cannot be excluded, and indeed has received some experimental support
[56, 70], the latter possibility has focused much more attention. The phylogenetically ancient eCB system must have
evolved simultaneously with other signalling systems and in
the process established multiple levels of interactions with
cell surface and intracellular proteins at the ligand, receptor
and post-receptor levels. Thus, accumulating evidence suggests that receptor cross-talk may be involved in coordinating the coincident actions of cannabinoids and growth factors in neural cell survival. For example, CB1 receptor activation at low signal inputs promotes the survival of various
cell lines expressing epidermal growth factor (EGF) recep-
4 Current Pharmaceutical Design, 2008, Vol. 14, No. 00
Galve-Roperh et al.
Fig. (2). CB1 receptor-dependent signalling mechanisms involved in neuroprotection. CB1 receptor activation can couple to at least two
important cell survival signalling routes: the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and the extracellular signal-regulated (ERK)
pathway. This is reliant on heterotrimeric G protein dissociation, and can occur both “directly” and “indirectly” - via transactivation of
growth factor tyrosine kinase receptors. See text for further details.
generative response after excitotoxic injury [34], and the CB1
receptor antagonist rimonabant inhibits bFGF-stimulated
axonal growth [76]. Taken together, these data support that
promotion of signalling through transactivation of tyrosine
kinase receptors may constitute a common mechanism involved in CB1 receptor-mediated neuroprotection.
tors [57, 67, 71]. This activates in turn tumor necrosis factor
-converting enzyme (TACE/ADAM17), a member of the
disintegrin-metalloprotease family, through cytoplasmic Src
family member tyrosine kinases [57]. Proteolytic ectodomain
shedding of EGF-like precursors by TACE would liberate
active ligands at the cell surface, thereby inducing rapid EGF
receptor tyrosine phosphorylation and downstream activation
of mitogenic pathways. Other studies in cell lines indicate
that CB1 receptors may also transactivate vascular endothelial growth factor receptors [72].
Another connection of cannabinoids with cell survival
mediators is that of neuronal CB1 receptors with the brainderived neurotrophic factor (BDNF) signalling system. Thus,
CB1 receptors are involved in BDNF production, and this
process plays a pivotal role in the neuroprotective response
elicited by endocannabinoids upon excitotoxic damage in
brain areas such as the hippocampus and the striatum [23,
73, 74]. In addition, studies on the cooperativity of cannabinoid- and BDNF-induced migration of cortical GABAergic
interneurons have revealed that CB1 receptors promote neuronal differentiation through transactivation of BDNF TrkB
receptors in a Src kinase-dependent fashion [75]. Likewise,
CB1 receptors might cross-talk to the bFGF signalling system. Thus, for example, increased production of bFGF may
be involved CB1 receptor-mediated hippocampal neurore-
Cannabinoids are known to improve the symptoms of
several models of neuroinflammatory disorders such as experimental autoimmune encephalomyelitis (EAE) at least in
part by their ability to modulate microglial cell activation
[77, 78]. Here we will focus on this topic, as the ability of
cannabinoids to regulate other aspects of glial cell biology in
various neuropathologies is discussed elsewhere in this Special Issue. Amelioration of EAE motor symptoms can occur
at different levels and involves both CB1 and CB2 receptors
[79-81]. Genetic and pharmacological studies support that
neuronal CB1 receptors are majorly involved in preventing
inflammation-induced neuron death [79]. Nonetheless, the
absence of CB2 receptors significantly exacerbates EAE pathology, and the administration of CB2 receptor-selective
agonists exerts beneficial symptomatic effects [80, 82]. In
Mechanisms of Control of Neuron Survival
this context, CB2 receptor activation decreases leukocyte
rolling, leukocyte/endothelial interactions and leukocyte infiltration into the nervous system [83], contributes to the
attenuation of excitotoxic damage during demyelination and
ischemic injury [84, 85] and inhibits microglial activation
[86]. Microglial cells express CB2 receptors (Fig. 3), which
are strongly up-regulated during neuroinflammation [87] and
in plaques of multiple sclerosis [88] and Alzheimer’s disease
patients [89]. Microglia also synthesize and degrade eCBs
such as 2AG, the levels of which are negatively controlled
by the IFN- released by primed T-cells invading the central
nervous system during EAE, thus indicating that impaired
2AG production may be associated with neurodegeneration
in this disorder [90]. In addition, cannabinoids down-regulate the production of proinflammatory cytokines as well as
nitrogen and oxygen reactive species by microglial cells and
autoreactive T cells [86]. Overall, this attenuation of microglial activation is considered to participate in cannabinoidinduced neuroprotection under neuroinflammatory conditions and in excitotoxicity [86, 91]. Additionally, brain microglia can be replenished from bone marrow-derived progenitors during inflammation and brain injury [92, 93], and
myeloid progenitors mobilize through the bloodstream and
target the inflamed central nervous system in a process that
is under the negative control of CB2 receptors [82]. In summary, eCBs can contribute to neuron survival by their CB2
receptor-dependent central and peripheral immunomodulatory actions (Fig. 3).
Current Pharmaceutical Design, 2008, Vol. 14, No. 00
In addition to the CB receptor-dependent promotion of
neuron survival, some cannabinoids can also exert neuroprotective actions by receptor-independent mechanisms. On the
one hand, the intrinsic antioxidant properties of phenolcontaining cannabinoids as cannabidiol and THC are well
known [94, 95] and, for example, cannabidiol administration
protects neurons from ischemic damage [96] and in a Parkinson’s disease model [97] independently of CB receptors. On
the other hand, eCBs are actively metabolized in the brain,
and the resulting products constitute a variety of bioactive
lipids that may control neuron survival. For example, cyclooxygenase-2-mediated metabolism of eCB substrates [98]
generates different neuroactive prostaglandins [99] and
prostamides [100], and AEA hydrolysis by FAAH yields
ethanolamine, that is protective for neuroblastoma cells
[101]. During brain injury, alterations in eCBs levels are not
restricted to AEA and 2AG species, and other fatty acid
ethanolamides – including various putative eCBs - are also
affected [12]. Among them, palmitoylethanolamide exerts
anti-inflammatory effects that are most likely mediated by
peroxisome proliferator-activated receptor- [102]. Microglial cells produce palmitoylethanolamide and their motility
is increased after focal cerebral ischemia, a situation in
which palmitoylethanolamide levels raise [31]. Hence, under
certain circumstances cannabinoid-mediated neuroprotection
Fig. (3). CB2 receptor-dependent mechanisms involved in neuroprotection. Cannabinoids can contribute to neuron survival by their CB2
receptor-dependent central and peripheral immunomodulatory actions. These include for example inhibition of microglial activation, leukocyte infiltration and myeloid progenitor-derived microglial replenishment. See text for further details.
6 Current Pharmaceutical Design, 2008, Vol. 14, No. 00
comprises various components that include CB receptordependent and independent actions. Nonetheless, it is plausible that at least some of those receptor-independent actions
will be ascribed in the future to membrane receptors such as
GPR55 - recently proposed as a new metabotropic cannabinoid receptor [103] - or intracellular targets such as peroxisome proliferator-activated receptors and [104].
In contrast to the large number of reports showing cannabinoid-mediated neuroprotection, some other studies have
shown that high eCB levels can be deleterious to neurons.
Thus, for example, AEA can induce brain damage by a
mechanism that depends, at least in part, on the activation of
TRPV1 vanilloid receptors [105, 106]. It is therefore conceivable that, besides the intrinsic differences in the pharmacokinetics of synthetic, plant-derived and endogenous cannabinoid agonists, an important factor that determines the
balance of protective versus toxic actions of these compounds is their distinct ability to engage (neuroprotective)
metabotropic CB1 receptors or (neurotoxic) ionotropic
TRPV1 receptors [105, 107]. Nonetheless, the situation may
be more complex as, under certain experimental conditions,
administration of the CB1 receptor antagonist SR141716
(rimonabant) has been shown to exert neuroprotection from
excitotoxic/ischemic damage [108-110]. Various cell signalling mechanisms have been proposed for cannabinoid-
Galve-Roperh et al.
evoked neuron killing, including prostanoid synthesis and
generation of free radicals by cyclooxygenase [111], stimulation of the pro-apoptotic c-Jun N-terminal kinase [112] and
p38 mitogen-activated protein kinase [113] cascades, activation of calpains [106, 114] and increase of p53-dependent
lysosomal permeability [115]. Finally, different cannabinoid
agonists are known to induce cyclooxygenase-2 expression
[116, 117], which may also contribute to the final balance
between neuronal protection and death.
Research conducted during the last decade and summarized here provides support for a neuroprotective action of
cannabinoids in which various cells types and both CB1 and
CB2 receptors are most likely involved (Fig. 4). However,
while in several animal models cannabinoids have shown
promising symptomatic relief together with decreased neuron damage, data from human studies are still very scarce,
except perhaps for the alleviation of multiple sclerosisassociated symptoms such as spasticity, tremor, neuropathic
pain and nocturia. Besides exerting neuroprotection by acting on differentiated neural cells, the functionality of the
eCB system in neurogenic areas prompts the study of its potential contribution to endogenous processes of neurorepair.
This may be of importance not only in the adult brain but
perhaps more in the younger, immature brain, which possesses higher plasticity and thus potential of repair. Much
Fig. (4). Summary of cannabinoid receptor-dependent processes involved in neuroprotection. Cannabinoid receptors and their endogenous ligands are present in undifferentiated and differentiated neural cells. Neurons can be protected by cannabinoids through a combination
of cell-autonomous and indirect actions. Cannabinoids also promote astrocyte and oligodendrocyte survival and inhibit microglial activation.
In addition, the eCB system controls neural progenitor cell proliferation and lineage commitment. See text for further details.
Mechanisms of Control of Neuron Survival
Current Pharmaceutical Design, 2008, Vol. 14, No. 00
more research is nonetheless required to define in detail the
molecular mechanisms of the control of neuron generation
and survival by the eCB system and the pathophysiological
consequences of cannabinoid-evoked neuroprotection.
T.A. and J.P. are supported by Comunidad Autónoma de
Madrid (Spain) and Ministerio de Educación y Ciencia (FPI
Program; Spain), respectively. Research in our laboratory is
financially supported by Comunidad de Madrid (S-SAL2006/261 and 950344), Picasso Program (HF2005-0017),
Fundación de Investigación Médica Mutua Madrileña Automovilística and Ministerio de Educación y Ciencia
N-arachidonoylethanolamine (anandamide)
Brain-derived neurotrophic factor
Fibroblast growth factor-2
Experimental autoimmune encephalomyelitis
Epidermal growth factor
Extracellular signal-regulated kinase
Fatty acid amide hydrolase
Monoacylglycerol lipase
Phosphatidylinositol 3-kinase
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