Endocannabinoids and neurodegenerative diseases

Endocannabinoids and neurodegenerative diseases

Pharmacological Research 56 (2007) 382–392 Review Endocannabinoids and neurodegenerative diseases Vincenzo Micale, Carmen Mazzola, Filippo Drago ∗ D...

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Pharmacological Research 56 (2007) 382–392

Review

Endocannabinoids and neurodegenerative diseases Vincenzo Micale, Carmen Mazzola, Filippo Drago ∗ Department of Experimental and Clinical Pharmacology, University of Catania, Medical School, Catania, Italy Accepted 5 September 2007

Abstract The cannabinoid CB1 and CB2 receptors, the endogenous endocannabinoid (EC) ligands anandamide (AEA) and 2-arachidonylethanolamide, and the degradative enzymes fatty acid amide hydrolase (FAAH) and monoglyceride lipase (ML) are key elements of the EC system implicated in different physiological functions including cognition, motor activity and immune responses. Thus, both the possible neuroprotective role of ECs and their modulating action on neurotransmitter systems affected in several neurodegenerative diseases such as Alzheimer’s disease (AD), Huntington’s disease (HD) and multiple sclerosis (MS) are currently under investigation. Accumulating data show an unbalance in the EC system (i.e. decrease of neuronal cannabinoid CB1 receptors, increase of glial cannabinoid CB2 receptors and over-expression of FAAH in astrocytes) in experimental models of AD as well as in post-mortem brain tissue of AD patients, suggesting its possible role in inflammatory processes and in neuroprotection. However, the mechanisms of the EC modulation of immune response are not fully understood. By contrast, in HD a reduced EC signaling, given both by the loss of cannabinoid CB1 receptors and decrease of ECs in brain structures involved in movement control as basal ganglia, has been well documented in preclinical and clinical studies. Thus, in the present review we discuss recent data concerning the role of the EC system in the pathophysiology of AD and HD, two neurodegenerative diseases characterized by cognitive deficit and motor impairment, respectively. We focus on the effects of compounds modulating the EC system (agonists/antagonists of cannabinoid CB1 and CB2 receptors, or inhibitors of ECs metabolism processes) on the symptoms and/or progression of neurodegenerative diseases. © 2007 Published by Elsevier Ltd. Keywords: Endocannabinoids; Cannabinoid receptors; Alzheimer’s disease; Huntington’s disease

Contents 1. 2.

3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The EC system and Alzheimer’s disease (AD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. General considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. The cannabinoid receptors and AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. CB1 receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. CB2 receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. ECs and AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The EC system and Huntington’s disease (HD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. The cannabinoid receptors and HD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. The EC system and HD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



Corresponding author at: Department of Experimental and Clinical Pharmacology, Viale A. Doria 6, 95125 Catania, Italy. Tel.: +39 095 7384236; fax: +39 095 7384238. E-mail address: [email protected] (F. Drago). 1043-6618/$ – see front matter © 2007 Published by Elsevier Ltd. doi:10.1016/j.phrs.2007.09.008

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1. Introduction The endocannabinoid (EC) system plays a role in a variety of physiological processes mainly in the central nervous system

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(CNS) where acts as neuromodulator mediating the effects of the psychoactive constituent of cannabis 9 -tetrahydrocannabinol (THC) [1], but also in the immune [2], cardiovascular [3] and gastrointestinal [4] systems. The EC system consists of: (1) the cannabinoid receptors CB1 and CB2, (2) the endogenous ligands, ethanolamines of arachidonic acid, anandamide (AEA) and the 2-arachidonylglycerol (2-AG), (3) the specific uptake mechanisms and (4) the enzymes for their inactivation, the fatty acid amide hydrolase (FAAH) and the monoglyceride lipase (ML) [5]. Despite the strong evidence supporting that AEA is an endogenous ligand for cannabinoid CB1 receptors in the brain, some of the typical cannabimimetic effects of AEA are still present in cannabinoid CB1 receptor knockout mice. These effects may be due to its capability of acting as a full agonist on the transient receptor potential vanilloid 1 (TRPV1), of which capsaicin, ingredient of hot red pepper, is considered the exogenous ligand. Since TRPV1 receptors are expressed both in the periphery and in the CNS, the endovanilloid activity of AEA may influence many physiological brain functions [6]. The pivotal role of ECs in a variety of CNS diseases such as mood disorders and neurodegenerative diseases is confirmed by the high expression of cannabinoid CB1 receptors in brain areas such as cortex, cerebellum, hippocampus and basal ganglia, affecting cognition, motor activity and satiety. Several data suggest an important function of ECs to guard against chronic neurodegenerative disorders such as Alzheimer’s disease (AD) and Huntington’s disease (HD) [7,8]. Both cannabinoid receptor-dependent and independent mechanisms such as the antioxidant activity of cannabinoids, activation of cytoprotective signaling pathways as neurotrophic factors or protein kinase A and B, modulation of immune response through the activation of cannabinoid CB1 and CB2 receptors are involved in the pathophysiology of these diseases [9–14]. Despite a plenty of preclinical data suggesting the involvement of ECs in AD and HD (Table 1), few human studies have been made to assess the possible therapeutic application of cannabinoids in AD or HD patients. Dronabinol, the major plant-derived cannabinoid (9 -THC), showed beneficial effects on appetite stimulation and disturbed behavior of AD patients [15,16]. HD patients treated with cannabidiol (CBD), a natural cannabinoid which lacks psychoactive effects and does not bind to the cannabinoid CB1 or CB2 receptors, failed to show any clinical improvement. Furthermore, nabilone, a synthetic THC analog, showed opposite results in two case reports [17–19].

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Thus, the aim of present review is to discuss the recent data concerning the role of ECs in the pathophysiology of AD and HD, and possibly to suggest a new therapeutic challenge with ECs in neurodegenerative diseases. 2. The EC system and Alzheimer’s disease (AD) 2.1. General considerations AD is the most common form of dementia, affecting more than 4,000,000 people only in the United States. The pathogenesis of AD is characterized by the deposition of ␤-amyloid (A␤) within the neuritic plaques, fibrillary tangles, gliosis and a neuroinflammatory response involving astrocytes and microglia activation [20]. Neuronal degeneration induced by A␤ affects important brain structures (i.e. the hippocampus, amygdala, temporal, parietal and frontal cortex) and various neurotransmitter systems including acetylcholine (ACh), norepinephrine (NA), dopamine (DA) and serotonin (5-HT) [21,22]. The loss of ACh neurons is one of the major neurochemical deficits in AD, correlated with a loss of cognitive function and the current therapeutic approach is to provide a stimulation of the ACh system. However, cholinergic agents such as the inhibitors of acetyl-cholinesterase (i.e. donepezil, rivastigmine and galantamine) have shown only limited clinical efficacy in AD due to the multifactorial nature of the disease and poorly understood etiology of it. Novel therapeutic approaches are aimed to preserve the surviving neurons by reducing their degeneration. Since the NMDA-receptor mediated glutamate excitotoxicity is a major factor responsible for A␤-induced neuronal death, actually memantine a non-competitive NMDAreceptor antagonist, is used to prevent the progression of AD [23,24]. In vivo and in vitro effects of compounds acting on the elements of the EC system in experimental models of AD are summarized in Table 2. The EC system plays a dual role on pathophysiology of AD, the first linked to its inhibitory action on ACh release and the second to its anti-inflammatory function in the CNS [14,25,26]. The active ingredient of marijuana, 9 -THC, and ECs are known to affect memory as well as neurochemical substrates of memory acquisition and consolidation such as long-term potentiation. The acute activation of cannabinoid CB1 receptors causes cognitive deficits in rodents, counteracted by the cannabinoid CB1 receptor antagonist rimonabant (SR141716) [26–29]. On the other hand, since microglia

Table 1 Schematic representation of the changes in the endocannabinoid (EC) system elements in preclinical an clinical studies of Alzheimer’s Disease (AD) and in Huntington’s disease (HD) AD

HD

Experimental models

Human brain

Experimental models

Hunan brain

CB1

↔ (van der Stelt et al. [41])

↓ (Westlake et al. [39]; Ramirez et al. [34]) ↔ (Benito et al. [33])

↓ (Lastres-Becker et al. [102])

↓ (Glass et al. [99,100])

CB2 EC FAAH

↑ (van der Stelt et al. [41]) ↑ (van der Stelt et al. [41]) ND

↑ (Benito et al. [33]; Ramirez et al. [34]) ↑ (Farooqui et al. [40]) ↑ (Benito et al. [33])

ND ↓ (Lastres-Becker et al. [101]) ND

ND ND ND

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Table 2 In vivo and in vitro effects of compounds acting on the elements of endocannabinoid (EC) system in experimental models of Alzheimer’s disease AD Compound

Function

Effect

References

Noladin WIN55,212-2 JWH-015 Rimonabant Cannabidiol VDM-11

CB1 agonist CB1 and CB2 agonist CB2 agonist CB1 antagonist TRPV1 agonist >CB1 and CB2 EC reuptake inhibitor

To counteract A␤ neurotoxicity To counteract A␤-induced microglial activation To counteract A␤-induced microglia activation To counteract amnesia induced by A␤ peptides To counteract A␤-induced neuroinflammatory responses To counteract amnesia and neuronal damage by A␤ peptides

Milton [52] Pacher et al. [35] Ehrhart et al. [73] Mazzola et al. [29] Esposito et al. [38] van der Stelt et al. [41]

activation results in neurodegeneration both in vitro and in vivo and transegic mouse models of AD also develop plaques characterized by A␤ deposits and activated microglia, recent studies have focused on the possible neuroprotective role of ECs to limit microglia activation and inflammation in AD [30–34]. Increasing evidence supports the important role of ECs in the modulation of immune function and inflammation. Cannabinoid receptors are localized on immune cells, where their expression is modulated by stimuli inducing immune activation, even though a cannabinoid-independent mechanism has been also suggested [35]. McGeer et al. [36] hypothesize the role of inflammatory neurodegeneration in AD showing an association between the disease and polymorphisms in genes encoding some cytokines or acute phase proteins. This hypothesis has been further supported by Zandi et al. [37] showing the protective effects exerted by anti-inflammatory agents in AD. Recently, Esposito et al. [38] showed that CBD is able to attenuate A␤ evoked neuroinflammatory responses in a model of A␤ neurotoxicity, by suppressing IL-1␤ and inducible nitric oxide synthase (iNOS). Few and controversial clinical data are available concerning possible changes of the EC system in AD patients. Westlake et al. [39] found a reduction of the cannabinoid CB1 receptors in the hippocampus of AD patients, not attributable to the pathologic process. These data were not confirmed by Benito et al. [33] showing that the expression of cannabinoid CB1 receptors remained unchanged in neuritic plaque of astrocytes and microglia, while cannabinoid CB2 receptors and FAAH were abundantly and selectively expressed. In contrast, Ramirez et al. [34] found a decrease of cannabinoid CB1 receptors in the frontal cortex of AD patients. Concerning the ECs content in AD brain tissue, Farooqui et al. [40] showed elevated enzymatic activity of 2-AG-biosynthesizing enzyme DAGL␣ in the hippocampus of patients with AD, suggesting that a tissue selective up-regulation of 2-AG levels occurs during this disorder in humans. These findings were recently confirmed by van der Stelt et al. [41] showing enhanced levels both of mRNA encoding for DAGL␣ and 2-AG in the hippocampus of rodents after an A␤ peptide (BAP) analog injection. Walter and Stella [14] have found increased levels of EC in the brain after inflammatory events and in neurodegenerative disorders associated with inflammation. Although many doubts remain, all the elements of the EC system (ECs, cannabinoid receptors and FAAH) acting on different neural cells as neurons, astrocytes may play a role in normal and pathological conditions [2].

2.2. The cannabinoid receptors and AD 2.2.1. CB1 receptors Two cannabinoid receptors, CB1 and CB2 have been identified by molecular cloning and are unambiguously established as mediators of the biological effects induced by cannabinoids, either plant-derived, synthetic, or endogenously produced. Cannabinoid CB1 and CB2 receptors are 7 transmembrane Gi/ocoupled receptors that share 44% protein identity and display different pharmacological profiles and patterns of expression, a dichotomy that provides a unique opportunity to develop pharmaceutical approaches [42,43]. The cannabinoid CB1 receptors are more expressed in CNS, and their distribution in the brain has been documented in detail using highly specific antibodies and CB1−/− tissue controls. The current picture depicts abundant presynaptic expression in the adult mammalian brain, even though they are also present on the dendrites and soma of neurons but less than their presynaptic counterparts [44]. Cannabinoid CB1 receptors are also expressed at low levels by various astrocytes, oligodendrocytes, and neural stem cells [45]. They are coupled to Gi/o proteins and, under specific conditions (i.e. only when other Gi/o protein-coupled receptors are concomitantly activated) also to Gs proteins [46]. By coupling to Gi/o proteins, cannabinoid CB1 receptors regulate the activity of many plasma membrane proteins and signal transduction pathways, including ion channels, enzymes producing cyclic nucleotide second messengers, and various kinases. Thus, depending on the coupling and cell type expressing cannabinoid CB1 receptors, cannabinoids may regulate distinct cell functions. For example, activation of presynaptic cannabinoid CB1 receptors inhibits N-type calcium channels, thus reducing synaptic transmission [44]. It is likely that THC induces most – if not all – of its acute cognitive and intoxicating effects through this molecular mechanism [47]. Whether THC produces its effect by partially activating cannabinoid CB1 receptors or antagonizing the action of ECs on this receptor remains an open question [48]. Activation of cannabinoid CB1 receptors expressed on the soma of neurons increases Erk activity and induces brain-derived neurotrophic factor (BDNF) expression [49]. It is likely that the neuroprotective properties of cannabinoids are in part mediated by this mechanism. Recent evidence shows that cannabinoid CB1 receptor may also control the fate of neural stem cells, the outgrowth of neurites and the formation of functional synapses, emphasizing the importance of this receptor in the remodeling of neuronal networks [45]. Since the blood-derived leukocytes also express cannabinoid CB1 receptors, it has been suggested

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that under neuropathological conditions, whereby the blood brain barrier is affected, the ECs accumulation in the CNS could activate cannabinoid CB1 receptors expressed by invading leukocytes and thereby modulate the development of neuroinflammation [50,51]. The neuroprotective role of ECs through the activation of cannabinoid CB1 receptors is supported by the finding that agonists of cannabinoid CB1 receptors, AEA and noladin prevented A␤-induced neurotoxicity in an in vitro model of AD. This effect was reversed by CB1 blockade, suggesting that the activation of cannabinoid CB1 receptors located on neurons may counteract A␤-induced neurotoxicity [52]. However, these data are not supported by other studies showing that the CB1 blockade is accompanied by neuroprotective effects that could be related to cannabinoid CB1 receptor-independent mechanisms [53–55]. In culture of rat microglia cells, the activation of cannabinoid CB1 receptors inhibited the release of nitric oxide, a major component implicated in the neurotoxic effects of A␤ peptides [56]. Recently, Ramirez et al. [34] have found that in senile plaques of AD patients expressing both cannabinoid receptors, the CB1 are reduced in areas of microglia activation. The high concentration of cannabinoid CB1 receptors and the presence of AEA and 2-AG in brain regions involved in memory processes are in line with the notion that ECs modulate cognitive processes. The activation of these receptors reduces ACh levels in the hippocampus followed by cognitive impairment, suggesting a modulating function on ACh release of the presynaptic cannabinoid CB1 receptors [25,57–59]. Administration of the cannabinoid CB1 receptor antagonist rimonabant showed a cognition enhancing-activity across a range of tasks [60–63]. Rimonabant also improved the cognitive deficits in rodents subjected to amnesia induced by BAP administration, probably increasing hippocampal ACh levels. This model is characterized by progressive ␤-amyloid plaque deposition, extensive hippocampal neuronal damage, and subsequent loss of retention of newly acquired memory, as also occur during AD in humans [29,41]. To confirm that EC and ACh systems play integrated roles in cognition, combined administration of subliminal doses of rimonabant and donezepil improve cognitive performance of rats in spatial memory tests [64]. In agreement with the role of cannabinoid CB1 receptors in cognitive processes, CB1 receptor knockout mice performed better than wild type in learning and memory tasks [59]. Furthermore, these receptors may be also involved in aversive memory, since cannabinoid CB1 receptors deficient mice exhibited impaired extinction of aversive memory, but not of memory acquisition and consolidation, in fear-conditioning test [65]. Analyses of brain tissue samples obtained from AD patients showed a decrease of cannabinoid CB1 receptors in the hippocampus, even though this reduction was not correlated or localized to areas showing histopathology [39]. By contrast, van der Stelt et al. [41] did not find any change in the expression of cannabinoid CB1 receptors in hippocampus of rats subjected to BAP injection. The importance of cannabinoid CB1 receptor is given by its modulator action on ACh release, since several data show that cannabinoid CB1 blockade by rimonabant, is followed both by enhancement of ACh neurotransmission and by improvement of cognitive performance.

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2.2.2. CB2 receptors Under non-pathological conditions, cannabinoid CB2 receptors are primarily expressed by leukocytes (with a rank order of B cells > natural killer [NK] cells  monocytes/macrophages > neutrophils > CD8 + T cells > CD4 + T cells) [43]. Recently, they were also localized in the brain, endocrine pancreas and bone [66–69]. Most neurodegenerative diseases are associated with chronic inflammation resulting from the activation of microglia cells. Since an increased proliferation of microglia cells, in brain of patients with AD, has deleterious effects on the surrounding neurons, several studies have focused on factors mediating activation of microglia [70,71]. Among these, the cannabinoid CB2 receptors seem to play a pivotal role in inflammatory processes affecting the brain [72]. The cannabinoid CB2 receptors, but not cannabinoid CB1 receptors, are over-expressed both in the brain of A␤-treated rats and in the brain of AD patients [33,34,41]. Thus, it has been hypothesized that the over-expression of cannabinoid CB2 receptors in microglial cells could be considered as an anti-inflammatory response of the CNS to protect neurons from degeneration. It is well accepted that cannabinoid CB2 activation elicits immunomodulatory effects, leading to several changes in the production of inflammation-related substances [73]. The ability of cannabinoid CB2 receptorselective compounds to reduce inflammation could be explained by increased proliferation and recruitment of immune cells involved in the immune-mediated repair of damaged tissue. Thus, cannabinoid CB2 receptors expressed on leukocytes in the CNS could be activated by EC, modulating the development of neuroinflammation [70]. These results are in agreement with the immunosuppressive effects of marijuana and its active constituent 9 -THC mediated by cannabinoid CB2 receptors [2]. To further confirm this hypothesis, 9 -THC failed to show any immunosuppressive response in cannabinoid CB2 knockout mice [74]. The above data suggest the pivotal role of cannabinoid CB2 receptors in the immune responses of the brain. 2.3. ECs and AD The first substance recognized as an EC was AEA, identified by Devane et al. [75] binding with high affinity to cannabinoid CB1 receptors. Furthermore, it fulfilled the three criteria necessary to be considered a bona fide EC: activity-dependent production, functional activation of cannabinoid receptors and biological inactivation [76]. Injection of AEA in rodents mimics most of the effects produced by 9 -THC, although inactivation of its degradation is often necessary to see biological effects [77,78]. Since AEA acts as a partial agonist or antagonist of cannabinoid CB2 receptors, this action could have some relevance in modulating inflammation [79]. Although evidence exists that FAAH metabolizes AEA, other enzymes as cyclooxygenases and lipooxygenases are involved in the AEA inactivation, although their action is almost irrelevant [78,80]. Mechoulam et al. [81] and Sugiura et al. [82] simultaneously reported a second endogenous ligand of cannabinoid CB1 and

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Table 3 In vivo and in vitro effects of compounds acting on the elements of the endocannabinoid (EC) system in experimental models of Huntington’s disease (HD) Compound

Function (references)

Effect

CP55,940 Arvanil Cannabidiol Capsaicin AM404 UCM707

CB1 and CB2 agonist (Lastres-Becker et al. [103]) CB1 and TRPV1 agonist (de Lago et al. [124]) antioxidant properties (Aiken et al. [107]; Sagredo et al. [122]) TRPV1 agonist (Lastres-Becker et al. [123]) EC reuptake inhibitor and TRPV1 agonist? (Lastres-Becker et al. [109]) EC reuptake inhibitor (de Lago et al. [126])

Anti-hyperkinetic effects Anti-hyperkinetic effects neuroprotective action and reverse GABAergic damage Anti-hyperkineticeffects, improvement DAergic and GABAergic system Anti-hyperkinetic effects improvement DAergic and GABAergic system Anti-hyperkinetic effects

CB2 receptors, the 2-AG. It is primarily inactivated by ML, but also additional enzymes as FAAH and cyclooxygenases are involved in this process [83,84]. It has been found that neuronal activity enhanced 2-AG synthesis, reaching levels 100 times higher than that of AEA [85]. The FAAH enzymes, mediating the termination of the signal of AEA, 2-AG and of several noncannabinoid fatty acid amides (FAAs), are key elements in the regulation of the EC system, as confirmed by FAAH knockout mice possessing higher levels of ECs in the brain and other areas than wild type mice [86,87]. Thus, the pharmacological block of FAAH activity, as well as FAAH (−/−) mice represent a useful tool to evaluate the physiological function of ECs. FAAH is present in neuronal and glial elements and shows a significant overlap with cannabinoid CB1 receptors, mainly in areas related to cognitive processes, where they are involved in the extinction learning [88]. FAAH enzymes, with cannabinoid CB2 receptors, modulated the inflammation since FAAH protein and activity, together to cannabinoid CB2 receptors are over-expressed in glial cells linked to the inflammatory processes typical of AD [33]. Since AEA and, partially, 2-AG are substrates for FAAH and are converted into arachidonic acid, the higher presence of FAAH in astrocytes surrounding neuritic plaques suggests that astrocytes, via FAAH, could be a significant source of arachidonic acid and related pro-inflammatory substances in the vicinity of these plaques. Thus, the inhibition of FAAH activity could be beneficial in preventing the inflammatory process associated with A␤ deposition. This is in line with the use of antiinflammatory compounds in AD, confirmed by the beneficial effects of cycloooxygenase inhibitors treatment [37]. Among several central properties of ECs, particular attention has been devoted recently to their possible neuroprotective actions in vitro, as well as in animal models of neuronal damage [35]. In particular, in experimental models of A␤ neurotoxicity, in which rodent brain is injected with A␤ fragments, van der Stelt et al. [41] have found an enhancement of 2-AG, in the hippocampus due to its enhanced synthesis. These findings are in agreement with previous report of elevated DAGL enzymatic activity in the hippocampus of patients with AD, suggesting a tissue-selective enhancement of 2-AG levels [40]. In line with the hypothesis that elevated EC levels exert neuroprotective functions, repeated treatment (12 days) with the selective inhibitor of EC cellular reuptake, VDM-11 reversed hippocampal damage and the loss of memory retention in passive avoidance tasks induced by A␤ fragments administration. By contrast, when the inhibitor was administered only for 5 days, starting 7 days after A␤ treatment, no significant amelioration

of the histological, biochemical and behavioral parameters was found, suggesting that EC elevation should be induced early in the neurodegenerative process in order to achieve neuroprotection [41]. These results are in agreement with those of Iuvone et al. [89] showing that the non-psychotropic cannabinoid, CBD, which was previously found to inhibit ECs inactivation, also reduced A␤ cell toxicity. These data suggest that a prolonged action of ECs, through the block of their inactivation or reuptake, may be applied in the future as a novel therapeutic target against ␤-amyloid-induced neurotoxicity. 3. The EC system and Huntington’s disease (HD) HD is an autosomal dominant, progressive neurodegenerative disorder, caused by a mutation in the IT15 gene of chromosome 4 coding for huntingtin (htt). This mutation is followed by an unstable expanded trinucleotide cytosine-adenine-guanine (CAG) repeat, which encodes for the amino acid glutamine. Normally IT15 gene contains between 9 and 35 repeats of the DNA sequence CAG, whereas in family with HD, the gene has 40 and 60 CAG repeats leading to a mutant form of htt where glutamine is repeated dozens of times [90]. The polyglutamines causes degeneration of medium spiny striato-efferent GABAergic neurons and atrophy of the caudate nucleus. The mode of neuronal death in HD continues to be debated, although considerable evidence suggests that apoptosis plays an important role [91]. Clinically, HD is characterized by motor disturbances, such as chorea (involuntary movements) and dystonia, demetia and other cognitive deficits [92]. Actually, the therapy of HD is limited to the use of antidopaminergic drugs to decrease hyperkinesias and antiglutammatergic drugs to reduce excitotoxicity, but no treatment is yet available to prevent the onset or to block the progression of the disease [93]. It has been demonstrated that synthetic, plant-derived and endogenous cannabinoids have mostly inhibitory effects on motor activity (Table 3). The magnitude of this inhibition seems to depend on the dose used and time after the administration at which the effects were tested. This effect may be explained by GABAergic, DAergic and glutamatergic neurotransmission changes, all of which are involved in the control of movements [94]. Increasing evidence suggests the involvement of ECs in movement disorders as HD and Parkinson’s disease (PD), given both by its regulatory action on motor activity and by neuroprotective properties in the CNS. Since the cannabinoid CB1 receptors and ECs are localized, as well as are altered in brain

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areas involved in motor regulation as the basal ganglia and cerebellum, the decreased activity or the hyperactivity of the EC system could be compatible with the hyperkinesia or hypokinesia typical of HD and PD, respectively [95,96]. Thus, since cannabinoid affected movement in line with the presence of cannabinoid CB1 receptors in the basal ganglia, these findings have encouraged the study on the possible therapeutic application of cannabinoids to improve hyper- or hipokinetic disorders. The relationship between ECs and HD has been studied both in experimental models of HD induced by the toxin 3-nitropropionic acid (3-NP) and in transegic mouse models of HD expressing mutated forms of the huntingtin. The HD rat models were generated by lesions of the striato-efferent GABAergic neurons, caused by the administration of 3-NP. This is a mitochondrial toxin that inhibiting succinate dehydrogenase produces the same phenomena proposed for the etiology of the human disease, i.e. failure of energy metabolism, glutamate excitotoxicity, oxidative stress, leading to progressive neuronal death [97,98]. All these experimental models exhibit histological, neurochemical and behavioral phenotypes closely resembling HD symptoms, such as early choreiform-like movements followed by a late motor depression, stereotypies and cognitive decline. Although extrapolation to humans is hard to be made, the biphasic pattern observed in rats might be in line with the progression of motor disturbances observed in HD patients. Interestingly, both in animal models and in post-mortem brain of HD patients, reduced cannabinoid CB1 receptor density and lower ECs levels were found, suggesting a low function of the EC system in HD [99–103]. In addition to brain functions, such as the control of nociception, motor activity, emesis, body temperature, and memory and learning, the EC system has recently been implicated in the control of the cell survival/death decision both in the CNS and the periphery. This finding is based, among other things, on the observation that cannabinoids may protect neurons from toxic insults such as glutamatergic excitotoxicity, ischemia, oxidative damage and others. Most of these protective effects are likely to be mediated by the activation of cannabinoid CB1 and CB2 receptors, although the contribution of other different mechanisms (i.e. antioxidant and/or anti-inflammatory properties of cannabinoids) cannot be ruled out [104]. 9 -THC showed neuroprotective effects against striatal neurodegeneration of rats after exposure to 3-NP, but not in the model of HD induced by intrastriatal injection of malonate [103]. This different effect (protective or pro-apoptotic) seems to be due to the bimodal influence of cannabinoids on biochemical mechanisms underlying cell death in these two models [105,106]. CBD, a non-psychotropic cannabinoid, also exhibited protective effects in cultured neuronal (PC12) cells from death caused by an expanded polyglutamine (poly Q) form of huntingtin exon 1, with no evidence of toxicity. Since PC12 cells lack cannabinoid CB1 receptors, it has been supposed that CBD acting through a receptor-independent pathway, could exhibit antioxidant properties [107]. This property of CBD was further confirmed by Sagredo et al. [122] in an animal model of HD. By contrast, Consroe et al. [17] in a small clinical trial showed that CBD is ineffective in patients with HD. Furthermore, case

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reports on the effects of nabilone, a synthetic THC analog in patients with HD showed opposite results. M¨uller-Vahl et al. [18] found an increase in choreic movement in HD patients, while Curtis and Rickards [19] reported an improvement in the behavior and a reduction of choreic movement in a woman with HD after nabilone treatment. Since ECs also modulate GABA and DA neurotransmission, and a lower function in cannabinoid transmission affecting GABA and DA signalling has been implicated in HD, all the substances increasing the activity of EC neurotransmission (receptors agonists or inhibitors of uptake and/or metabolism processes) might be useful in the treatment of HD. 3.1. The cannabinoid receptors and HD Most of the data concerning ECs in HD have been obtained analyzing the cannabinoid CB1 receptors in basal ganglia. Among the brain structures that contain cannabinoid CB1 receptors, the basal ganglia exhibit the highest density. They are localized presynaptically in striatonigral and striatopallidal projection neurons, which contain GABA as neurotransmitter [108]. However, there are controversial data concerning the effects of cannabinoid CB1 receptor activation on GABAergic neurotransmission. Lastres-Becker et al. [109] showed that the administration of cannabinoids did not affect GABA synthesis or release in the basal ganglia of na¨ıve animals, whereas it increased both parameters in experimental models of HD with lesion of GABAergic neurons. More recently, Centonze et al. [110] showed that in transgenic mouse model of HD, but not in control animals, cannabinoids stimulate GABA release when there was no striatal neurodegenerative processes yet. The mechanisms by which HD affects the sensitivity of GABA synapse to cannabinoid CB1 receptor stimulation are unknown. However, an early down-regulation of cannabinoid CB1 receptors and of EC observed in HD patients and in several animal models of HD might reflect a compensatory mechanism aimed to counteract, through an increased release, the initial excitotoxic damage of striatal neurons. Stimulation of cannabinoid CB1 receptors also enhanced GABA neurotransmission by inhibition of GABA uptake, as well as the blockade of cannabinoid CB1 receptors with SR141716A reduced the inhibitory GABAergic tone, allowing an increased firing of nigrostriatal dopaminergic neurons [111,112]. Thus, the EC neurotransmission might increase the action of striatal GABAergic neurons in the substantia nigra, producing a decrease of the stimulation of nigral dopaminergic neurons. Conversely, Chan et al. [113] and Szabo et al. [114] showed an inhibition of GABA neurotransmission by cannabinoids in the striatum. Further studies are needed to elucidate the interaction of cannabinoids with GABA neurotransmission in the basal ganglia. The first evidence of a correlation between HD and a dysregulation of the EC system was provided by Glass et al. [99] who showed a loss (∼97%) of cannabinoid CB1 receptors in the substantia nigra of human brain from HD. Furthermore, the same authors suggested an involvement of these receptors in the pathogenesis and/or progression of the neurodegeneration in HD, since their loss occurred in advance of other receptor losses

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such as the dopamine D1 and D2 receptors and even before the appearance of the major symptoms [100]. These findings are in line with the characteristic neuronal loss observed in HD that predominantly affects medium-spiny GABAergic neurons, which contain most of the cannabinoid CB1 receptors present in basal ganglia structures [115]. The same results were supported by Latsres-Becker et al. [109] and Naver et al. [116] in two different transgenic mouse models of HD and by Page et al. [117] in experimental model of HD induced by the 3-NP toxin. These mice developing many features of HD such as striatal atrophy, intraneuronal aggregates and progressive dystonia, showed a decrease in cannabinoid CB1 mRNA levels in basal ganglia, before the development of either neuropsychiatric symptoms or neuronal degeneration. Although the mechanisms are not fully understood, Glass et al. [118] showed that a delayed loss of cannabinoid CB1 receptors was followed by a delayed onset of motor symptoms in transgenic animal models of HD. This finding suggested that a loss of these receptors may render the cells more susceptible to excitotoxicity and that the progression of the disease could be delayed counteracting the loss of these receptors. This hypothesis is in line with the data of Sa˜nudo-Pe˜na et al. [119] showing that the activation of cannabinoid CB1 receptors in the basal ganglia inhibited the glutamate release, suggesting a therapeutic value in neurodegenerative diseases as HD with impairment of the basal ganglia and excitotoxicity as a part of the neuropathology. Recently, Curtis et al. [120] identifying a novel population of progenitor cell expressing cannabinoid CB1 receptors in the subependymal layer of the normal and HD human brain, supposed that these cells could be a source of replacement of cells lost due to neurodegeneration. Additionally, also vanilloid TRPV1 receptors seem to be involved in HD symptomatology. These receptors are also located in the nigrostriatal dopaminergic neurons of basal ganglia and their stimulation induced hypokinetic effects in rats [121]. CBD, a plant-derived cannabinoid with low affinity for cannabinoid CB1 and CB2 receptors, was able to activate the vanilloid TRPV1 receptors and exhibited protective effects on cultured neuronal cells against an polyglutamine [107]. Recently Sagredo et al. [122] showed that CBD reversed the reduction of GABA content of the striatum in the experimental model of HD induced by 3-NP by mechanisms independent of the activation of cannabinoid, vanilloid TRPV(1) and adenosine A (2A) receptors, suggesting that this effect is based exclusively to its antioxidant properties. Furthermore, Lastres-Becker et al. [123] showed that CP55,940, a cannabinoid CB1 receptor agonist with no activity on vanilloid TRPV1 receptors, reduced hyperkinesias but was unable to cause recovery from any of the neurochemical deficits observed in 3-NP-injected rats. However, preclinical data concerning the effects of CBD were not confirmed in a small clinical trial, probably due to dosing issues or to the advanced stage of the disease [17]. To further confirm the role of vanilloid receptors in HD, capsaicin and arvanil, a selective TRPV1 agonist and a hybrid EC/endovanilloid compound respectively, reduced hyperkinesia in an experimental model of HD. These findings suggest that vanilloid TRPV1 receptor agonists alone or in combination with cannabinoid CB1 receptor agonists could be a promis-

ing molecules for a novel symptomatic and or/neuroprotective therapy in HD [123,124]. 3.2. The EC system and HD Most of the studies to characterize the reduced EC tone in HD showed a decrease of cannabinoid CB1 receptor activity and density in the basal ganglia [99,116]. However Latsres-Becker et al. [101] found a significant reduction of AEA in the striatum in a rat model of HD, in addition to a loss of cannabinoid CB1 receptors, suggesting that the EC transmission, at the level of both receptors and their endogenous ligands, is decreased in this region. Thus, compounds able to directly or indirectly activate EC signaling may be a reasonable alternative since they combine both anti-hyperkinetic and neuroprotective effects [35]. In contrast to the agonists of cannabinoid CB1 receptors, these compounds act on the mechanism of EC uptake called AEA transporter (AMT) and on the FAAH, responsible for the degradation of AEA. These compounds termed “indirect agonist”, act by potentiating the action of endogenous ligands and, hence, they may be used in diseases where an increase of EC neurotransmission has been postulated to be of therapeutic value. The use of these compounds may reduce the unwanted effects produced by the direct activation of cannabinoid CB1 receptors, through the control of ECs levels in a concentration range to avoid psychoactive side effects [125]. In agreement to this hypothesis, the AMT inhibitor, AM404 was able to reduce hyperkinesia and to lead to recovery from GABAergic deficits in a rat model of HD, suggesting that the inhibition of AMT enhances the activation of the remaining cannabinoid CB1 receptors [109]. At the first, the anti-hyperkinetic effect of AM404 was attributed to its inhibitory action on AMT, but this hypothesis was not fully confirmed, since the ameliorative effects of AM404 on hyperkinesia were counteracted by capsazepine, a selective antagonist of TRPV1, but not by SR141716A, an antagonist of cannabinoid CB1 receptor. The inhibitor of AMT, VDM11 also failed to ameliorate ambulation of a rat model of HD, suggesting that the ameliorative effects of AM404 could be due to its action on TRPV1 rather than the its inhibitory action on AMT [123]. Recently, de Lago et al. [126,127] showed that the potent and selective AMT inhibitor with no activity on vanilloid TRPV1 receptors, UCM707 exhibited a notable anti-hyperkinetic activity in a rat model of HD induced by the 3-NP toxin. This effect was associated to an amelioration of GABA and glutamate deficits induced by the toxin in the globus pallidus and the substantia nigra, respectively. Interestingly, the anti-hyperkinetic activity of UCM707 was very surprising if compared to the lack of efficacy as a anti-hyperkinetic agent of VDM11, an inhibitor of AMT with pharmacodynamic and pharmacokinetic characteristics similar to those of UCM707. These differences could be related to the higher potency of UCM707 than VDM11 as AMT inhibitor, with following higher and longer increase of ECs levels. The higher potency of UCM707 could compensate the progressive decrease of cannabinoid CB1 receptors during the progression of the disease [128]. Although the ameliorative symptomatic effects, UCM707 failed to protect GABAergic neurons in rat

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model of HD induced by malonate, which is believed to be the most useful test for neuroprotective effects. The lack of neuroprotective effects of UCM707 in this model was supposed to be due to inability of this compound to activate the cannabinoid CB2 receptors directly, since several data indicate that the activation of these receptors in microglia cells reduced striatal damage by decreasing local inflammatory processes [126]. Since a reduced activity of the cannabinoid neurotransmission is a key element in the pathophysiology of HD, compounds increasing cannabinoid signaling through the block of AMT could be useful the treatment of HD. The other target of the so called “indirect agonists” could be the FAAH enzymes, which mediate the termination of the AEA signal [78,79]. Thus, the hypoactivity of the EC signaling in HD could be counteracted through the block of FAAH activity. However, the only study conducted using the selective FAAH inhibitor, AM374 in rat model of HD failed to find any improvement of hyperkinesia [123]. However, these data suggest to investigate further the role of FAAH inhibitors in different stages of HD, using different experimental models. The studies on the therapeutic effects of drugs targeting EC metabolism is supported by the evidence showing altered levels of ECs in several pathological conditions of CNS [35]. 4. Conclusion Data discuss in the present review clearly support the hypothesis that ECs could play a crucial role in the pathogenesis of neurodegenerative diseases such as AD and HD, as well as in PD and multiple sclerosis as reported in literature. Concerning the role of ECs in AD, we have reviewed the pharmacological and biochemical bases that support the involvement of the EC neurotransmission in this neurodegenerative disease. In brain damage induced by A␤ deposition, ECs released from neurons and glia increase Erk activity and induce brain-derived neurotrophic factor (BDNF), activating CB1-mediated neuroprotective pathways [47,49]. Additionally, ECs modulate the release of inflammatory mediators in microglia through cannabinoid CB2 receptors. In fact, activated microglia cells, such as those in AD, but not microglia present in healthy CNS tissue, express significant levels of cannabinoid CB2 receptors, suggesting that ECs could trigger CB2-dependent cytokine production, which has favorable effects on AD pathogenesis [33,71,105]. Since ECs (AEA and 2-AG) are substrates for FAAH and both are converted into arachidonic acid, the higher presence of FAAH in astrocytes surrounding neuritic plaques, suggests that astrocytes, via FAAH, could be a significant source of arachidonic acid and related pro-inflammatory substances near these plaques. Thus, the inhibition of FAAH activity could be beneficial in preventing the inflammatory process associated with A␤ deposition [70]. Since the current approach focused on cholinergic agents, such as the inhibitors of acetyl-cholinesterase (i.e. donepezil, rivastigmine and galantamine) have shown only limited clinical efficacy in AD, cannabinoid CB1 and CB2 agonists as well as FAAH inhibitors showing beneficial effects on the inflammatory process linked to A␤ deposition, could be a novel therapeutic approach. Further studies are needed to clarify this hypothe-

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sis since ECs affect ACh neurotransmission contributing to the synaptic dysfunction in AD. Preclinical and clinical data show a lower function of the EC system in HD, as described both by the loss of cannabinoid CB1 receptors and by decreased levels of ECs [99,101]. Thus, compounds able to directly or indirectly activate cannabinoid CB1 receptors in the basal ganglia could be used in diseases such as HD. This is crucial point since the treatment of HD lacks of novel pharmacological therapies with symptomatic and/or neuroprotective efficacy. Therefore, compounds like direct agonists of cannabinoid CB1 receptors or indirect agonists, as AMT or FAAH inhibitors, elevating ECs brain levels could improve motor deterioration seen in HD. These compounds might also act reducing the excessive activity of the nigrostriatal DAergic neurons that are responsible for many neurological symptoms of HD. Despite the influence of cannabinoid signaling on motor activity, other key element in their action could be given by an antioxidant capability. It could prevent neuronal death in HD where production of free radicals has been found as a consequence of mitochondrial dysfunction [95]. Further studies could be necessary to well understand how the EC system modulation could be therapeutically implicated in degenerative diseases, considering also the evidence that cannabinoids can modulate synaptic neurotransmission and immune system through mechanisms not involving cannabinoid CB1 or CB2 receptors, and that an additional independent EC signaling system might exist. References [1] Isbell H, Gorodetzsky CW, Jasinski D, Claussen U, von Spulak F, Korte F. Effects of (9 ) delta-9-trans-tetrahydrocannabinol in man. Psychopharmacologia 1967;11:184–8. [2] Klein TW. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol 2005;5:400–11. [3] Randall MD, Harris D, Kendall DA, Ralevic V. Cardiovascular effects of cannabinoids. Pharmacol Ther 2002;95:191–202. [4] Mul`e F, Amato A, Baldassano S, Serio R. Evidence for a modulatory role of cannabinoids on the excitatory NANC neurotransmission in mouse colon. Pharmacol Res 2007;56:185–92. [5] Lambert DM, Fowler CJ. The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications. J Med Chem 2005;48:5059–87. [6] Mackie K, Stella N. Cannabinoid receptors and endocannabinoids: evidence for new players. AAPS J 2006;8:E298–306. [7] Glass M, Felder CC. Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors augments cAMP accumulation in striatal neurons: evidence for a Gs linkage to the CB1 receptor. J Neurosci 1997;17:5327–33. [8] Mechoulam R, Spatz M, Shohami E. Endocannabinoids and neuroprotection. Sci STKE 2002;129:RE5. [9] Hampson RE, Mu J, Deadwyler SA. Cannabinoid and kappa opioid receptors reduce potassium K current via activation of G(s) proteins in cultured hippocampal neurons. J Neurophysiol 2000;84:2356–64. [10] Marsicano G, Moosmann B, Hermann H, Lutz B, Behl C. Neuroprotective properties of cannabinoids against oxidative stress: role of the cannabinoid receptor CB1. J Neurochem 2002;80:448–56. [11] Molina-Holgado E, Vela JM, Arevalo-Martin A, Almazan G, Molina-Holgado F, Borrell J, et al. Cannabinoids promote oligodendrocyte progenitor survival: involvement of cannabinoid receptors and phosphatidylinositol-3 kinase/Akt signaling. J Neurosci 2002;22:9742–53.

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