Cannabinoids and Neurodegenerative Diseases - IngentaConnect

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CNS & Neurological Disorders - Drug Targets, 2009, 8, 440-450

Cannabinoids and Neurodegenerative Diseases Julian Romero*,1 and Jose Martínez-Orgado*,1,2 1

Laboratorio de Investigación, Hospital Universitario Fundación Alcorcón and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), C/o Budapest 1, 28922, Alcorcón, Spain 2

Servicio de Pediatría, Hospital Universitario Puerta de Hierro, C/o Manuel de Falla 1, 28222, Majadahonda, Madrid, Spain Abstract: Although significant advances have taken place in recent years on our understanding of the molecular mechanisms of different neurodegenerative diseases, its translation into effective therapeutic treatments has not been as successful as could be expected. There is still a dramatic lack of curative treatments for the most frequent disorders and only symptomatic relief for many others. Under this perspective, the search for novel therapeutic approaches is demanding and significant attention and efforts have been directed to studying additional neurotransmission systems including the endocannabinoid system (ECS). The neuroprotective properties of exogenous as well as endogenous cannabinoids have been known for years and the underlying molecular mechanisms have been recently unveiled. As discussed later, antioxidative, antiglutamatergic and antiinflammatory effects are now recognized as derived from cannabinoid action and are known to be of common interest for many neurodegenerative processes. Thus, these characteristics make cannabinoids attractive candidates for the development of novel therapeutic strategies [1]. The present review will focus on the existing data regarding the possible usefulness of cannabinoid agents for the treatment of relevant neurological pathologies for our society such as Alzheimer’s disease, multiple sclerosis, Huntington’s disease and amyotrophic lateral sclerosis.

Keywords: Alzheimer’s disease, ischemia, neuroprotection, glia. CANNABINOIDS AND ALZHEIMER’S DISEASE Alzheimer’s disease (AD) is the most common neurodegenerative process linked to age and accounts for the most frequent form of dementia in the elderly. It is currently estimated that approximately half of the people affected by dementia around the world suffer from AD. Moreover, epidemiological studies predict a significant increase in the number of these patients, reaching 34 million people by the year 2025 [2, 3]. Age is still considered as the principal risk factor so the probability of suffering the disease doubles every 5 years from the age of 65. For all these reasons, AD is estimated to be one of the most important health issues in the near future, including a growing social and economic impact in the next decades [4]. Clinical features of this disease include early loss of memory, specifically of most recent events, as well as changes in cognitive abilities, interfering with mood, reasoning and oral expression. The insidious evolution of the disease allows patients to survive even 20 years after the initial diagnosis, although the median survival time varies between 5 and 10 years. In most cases the etiology of the disease is unknown, although a small percentage shows a hereditary link related to a family of enzymes involved in the processing of a membrane peptide [5]. In any case, the neuropathology of the process is common for the diverse types of AD, *Address correspondence to these authors at the Laboratorio de Investigación, Hospital Universitario Fundación Alcorcón and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), C/o Budapest 1, 28922, Alcorcón, Spain; E-mails: [email protected], [email protected]

1871-5273/09 $55.00+.00

including three essential features [6]: i) formation of extracellular deposits (the so called “neuritic plaques”) constituted mostly by a small protein, the beta amyloid (A), that accumulate preferentially in limbic areas of the brain, such as hippocampus, parahippocampal cortex and amygdala; ii) intraneuronal accumulation of hyperphosphorylated tau, a cytoskeletal protein (leading to the formation of “neurofibrillary tangles”); and iii) loss of functional synapses, thought to be a consequence of the neuronal death triggered by the two former processes. Although recent advances have been produced in the early diagnosis of AD [7, 8], definite diagnosis is still based on postmortem analysis of cerebral tissue samples. This is due, in part, to our lack of knowledge regarding the molecular events behind the disease. It is widely accepted that the aberrant processing of a membrane peptide (the “amyloid precursor protein”, or “APP”) leads to the appearance of pathological forms of A, possessing a higher tendency to aggregate. A concentration in AD brains is approximately of 2 μM, that is, around 10 times higher than that measured in healthy individuals [9]. Neuritic plaques, mostly composed of A1-42 would be the result of this process and also include other forms of A (monomers, dimers and oligomers). These precipitates will in turn damage neighbour neurons and will additionally trigger an inflammatory response in which glial cells will be crucially involved [10]. It has been recently shown that the formation and growth of these plaques is a much faster process than previously thought [11]. Experimental Data As previously mentioned, exogenous and endogenous cannabinoids exhibit neuroprotective properties [1] (see © 2009 Bentham Science Publishers Ltd.

Cannabinoids and Neurodegenerative Diseases

CNS & Neurological Disorders - Drug Targets, 2009, Vol. 8, No. 6

Table 1 for a summary of cannabinoid compounds and Table 2 for a summary of experimental models cited throughout the text). Regarding A, Milton [12] was the first to show that anandamide (AEA) exerts a powerful protective effect against A-induced toxicity in a human neuronal cell line; furthermore, this effect was cannabinoid receptor type 1 (CB1)-mediated and implied the activation of the mitogen activated protein kinase (MAPK) pathway. More recently, it has also been shown that cannabinoid receptor type 2 (CB2 ) receptors may be potent modulators of microglial response against A, thus providing neuroprotection. Ramírez et al [13] reported that CB1 as well as CB2 agonists, by activating solely microglial cells, were able to prevent the A-induced neuronal damage and to decrease the secretion of inflammatory cytokines by these cells. In addition, non-CB1, non-CB2-mediated effects of cannabidiol on A toxicity have also been shown by Iuvone and coworkers [14]. These authors have provided significant amount of data suggesting a neuroprotective role for this phytocannabinoid through the involvement of several pathways including: p38MAPK, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and Wnt/-catenin [15-18].

receptors and FAAH takes place in glial cells located on the vicinity of A plaques, suggesting a possible interplay among them and involving both microglia (CB2 positive) and astroglia (FAAH positive). Finally, it is important to note that similar modifications in the expression profile of both elements of the ECS have been also observed in tissue samples obtained from patients affected by other neuroinflammatory processes, such as multiple sclerosis or AIDS induced encephalitis [20].

Van der Stelt and colleagues [19] have recently reported data on the modulation of the ECS in an animal model of AD. By administering A1-42 in the cortex of rats and mice, these authors studied i) the effect on hippocampal levels of AEA and 2-arachidonyl glycerol (2-AG); and ii) the effect of the enhancement of the ECS on the evolution of the pathological disease and on memory processing. Their results show that endocannabinoid levels were significantly elevated as a consequence of toxic damage to the brain, although only 2-AG levels were sensitive to A1-42 administration. In addition, a selective CB2 up-regulation seemed to corroborate the inducible nature of this receptor type, as previously suggested. Furthermore, these authors also provided data on the effect of the enhancement of the endocannabinoid tone on A1-42-induced brain damage and memory impairment, by using the uptake inhibitor VDM-11. Their results suggest that early, but not late, potentiation of the endocannabinoid tone leads to neuronal loss prevention (as measured by recovery of calbindin levels) and to an antiinflammatory response (determined by decreases in cyclooxygenase type 2 (COX-2) and inducible nitric oxide synthase (iNOS) expression). Notably, memory impairment was reduced after VDM-11 administration on day 3 after peptide injection into the cortex, while memory was perturbed when the same compound was administered on day 7. Consequently, these authors concluded that a robust and early potentiation of the endocannabinoid tone may be beneficial for the prevention of A1-42-induced neurodegeneration in vivo. Neuropathological analyses of human tissue samples have also provided interesting data on the possible role of the ECS in AD. Briefly, these findings may be summarized as follows (reviewed in [20]): i) A deposition in cerebral parenchyma is linked to dramatic changes in the pattern of expression of CB2 receptors and fatty acid amide hydrolase (FAAH) enzyme; ii) conversely, CB1 expression is decreased in hippocampus and basal ganglia of AD patients, but not in other regions known to be affected by the pathological process, such as the frontal cortex; iii) overexpression of CB2

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These data suggest that CB2 receptors and FAAH might become novel therapeutic targets in the modulation of the inflammatory process triggered by A. CB2 activation, as already mentioned, could exert antinflammatory actions while not triggering undesired psychoactive effects. On the other hand, the modulation of FAAH activity, most probably through its inhibition, could provide some neuroprotection by increasing endocannabinoid levels and, at the same time, decreasing arachidonic levels at the area of inflammation [21]. Clinical Data Few data have been published so far regarding the possible usefulness of cannabinoids in AD. One study showed a positive effect of dronabinol on body weight increase accompanied by improvements in disturbed behaviors, partially due to decreased agitation [22]. More recently, Walther et al. [23] performed a pilot study on five AD patients and reported that a low dose of dronabinol was able to significantly improve several clinical parameters (such as nocturnal motor activity, agitation, etc), without undesired side effects. The psychoactive properties of cannabinoids have deeply limited human studies with these chemicals and related compounds. Passmore [24] has recently published a case report, suggesting the possible usefulness of 9–tetrahydrocannabinol (THC) in a 72-year old woman by reducing the agitation and aggressiveness. Remarkably, this effect was rapid and dramatic, rendering better results than those observed with other nonantipsychotic medications. Undoubtedly, more studies are needed to confirm these observations. CANNABINOIDS AND MULTIPLE SCLEROSIS Multiple Sclerosis (MS) is an inflammatory and demyelinating disease of the Central Nervous System (CNS) of unknown etiology. In general terms, it is currently thought that MS occurs in a genetically prone population that has been in contact with an environmental factor, most probably a viral infection. Recent data put the focus on axonal degeneration as responsible of the neurological impairment observed in these patients and highlighted the need to understand the changes that follow demyelination, as well as axon-myelin interactions and oligodendrocyte differentiation and remyelination [25]. The combination of inflammation and neurodegeneration seems to explain its complexity as well as the current lack of effective treatments for this disease. The characteristic symptoms of MS (such as painful muscle spasms, sleep disorders, tremor, ataxia, weakness or paralysis) are thought to be the result of both newly formed CNS lesions and expansion of old lesions. Neuropathology of MS includes axonal degeneration, oligodendrocyte loss

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Table 1. Specificity CB1 Agonists

Compound Abbreviation ACEA

Chemical Names N-(2-Chloroethyl)-5Z,8Z,11Z,14Zeicosatetraenamide

Section of the Manuscript Cannabinoids and multiple sclerosis

Cannabinoids and brain ischemia CB2 Agonists

Mixed CB1/CB2 Agonists

JWH015

(2-Methyl-1-propyl-1H-indol-3-yl)-1naphthalenylmethanone

Cannabinoids and multiple sclerosis

JWH133

(6aR,10aR)-3-(1,1-Dimethylbutyl)-6a,7,10,10atetrahydro -6,6,9-trimethyl-6Hdibenzo[b,d]pyran

Cannabinoids and brain ischemia

AM1241

(3-iodo-5-nitrophenyl)-[1-[(1-methylpiperidin-2yl)methyl]indol-3-yl]methanone

Cannabinodis and amyotrophic lateral sclerosis

Anandamide

N-(2-Hydroxyethyl)-5Z,8Z,11Z,14Zeicosatetraenamide

Cannabinoids and Alzheimer’s disease Cannabinoids and multiple sclerosis

2-Arachidonylglycerol

(5Z,8Z,11Z,14Z)-5,8,11,14-Eicosatetraenoic acid, 2-hydroxy-1-(hydroxymethyl)ethyl ester

Cannabinoids and Alzheimer’s disease Cannabinoids and multiple sclerosis Cannabinoids and brain ischemia

Delta-9-Tetrahydrocannabinol

(6aR,10aR)-6a,7,8,10a-Tetrahydro-6,6,9trimethyl-3-pent yl-6H-dibenzo[b,d]pyran-1-ol

Cannabinoids and Alzheimer’s disease Cannabinoids and multiple sclerosis Cannabinodis and Huntington’s disease Cannabinodis and amyotrophic lateral sclerosis

WIN55,212-2

(R)-(+)-[2,3-Dihydro-5-methyl-3-(4morpholinylmethyl)py rrolo[1,2,3-de]-1,4benzoxazin-6-yl]-1-naphthalenylmeth anone mesylate

Cannabinoids and brain ischemia Cannabinoids and multiple sclerosis Cannabinodis and amyotrophic lateral sclerosis Cannabinoids and brain ischemia

CB1 Antagonists

SR141716A

5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)-4methyl-N-(piperidin-1-yl)-1H-pyrazole-3carboxamide


CB2 Antagonists

SR144528

N-[(1S)-endo-1,3,3-trimethyl bicyclo[2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4methylbenzyl)-pyrazo le-3-carboxamide]


Endocannabinoids Uptake Blockers

VDM11

(5Z,8Z,11Z,14Z)-N-(4-Hydroxy-2methylphenyl)-5,8,11,14- eicosatetraenamide

Cannabinoids and Alzheimer’s disease

AM404

N-(4-Hydroxyphenyl)-5Z,8Z,11Z,14Zeicosatetraenamide

UCM707

(5Z,8Z,11Z,14Z)-N-(3-Furanylmethyl)5,8,11,14-eicosatet raenamide

Cannabinoids and multiple sclerosis Cannabinoids and multiple sclerosis



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(Table 1) contd….

Specificity Other Cannabinoids

Compound Abbreviation Cannabidiol

Chemical Names 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2en-1-yl]-5-pentylbenzene-1,3-diol

Section of the Manuscript Cannabinoids and Alzheimer’s disease


Cannabinodis and Huntington’s disease


HU211

(6aS,10aS)-3-(1,1-Dimethylheptyl)6a,77,10,10a-tetrahyd ro-1-hydroxy-6,6dimethyl-6H-dibenzo[b,d]pyran-9-methanol

and subsequent induction of areas of demyelination. Lymphocytes and monocytes infiltrate the white matter surrounding the blood vessels, destroying myelin but usually sparing axons. Finally, cells of monocytic origin are responsible for myelin removal by phagocytosis and contribute to the inflammatory process (for a review, see [25] and [26]). Experimental Data The possible relevance of the ECS in MS has been extensively reviewed elsewhere [27-29]. Most recent data reinforce the notion of a neuroprotective and antiinflammatory role for the ECS in this pathology and, generally speaking, highlight the relevance of CB2 receptors as putative pharmacological targets for its treatment [29]. Cannabinoid agonists as THC or WIN55212 have been demonstrated to improve functional recovery, reduce spasticity, impede the disease progression or even induce remyelinization in experimental models of MS in rodents including: experimental autoimmune encephalomyelitis (EAE), chronic relapsing experimental allergic encephalomyelitis (CREAE), or Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) [30-32]. CB1 receptor expression has been described in neurons and oligodendrocytes in brains from MS patients; abundant CB1 expression was also detected in macrophages located within active plaques [33]. CB1 receptors are thought to play an important role in MS, as highlighted by the earlier development of symptoms such as spasticity in CREAE CB1-/- homozygous knockout mice, together with greater demyelination and mortality [34]. Selective CB1 agonists, such as arachidonyl-2chloroethylamide (ACEA) reduced demyelination and improved functional recovery in TMEV-IDD mice [32]. In addition, the cannabinoid agonist WIN55212 exerts beneficial effects on spasticity in wild type but not CB1-/homozygous knockout CREAE mice [34]. On the other hand, studies performed in human spinal cord and brain MS samples detected strong CB2 immunoreactivity in microglia/macrophages in white matter areas, usually within active plaques or in the periphery of


chronic lesions [33, 35], as well as in perivascular Tlymphocytes, suggesting a possible role of the ECS in MSlinked neuroinflammation mediated by microglia/macrophages and T-cells. More surprisingly, CB2 expression has also been reported in white matter astrocytes in brain from MS patients [33]. Supporting the important role of CB2 receptors in MS, CB2-selective agonists such as JWH-015 have been shown to reduce demyelination and improve functional recovery in TMEV-IDD mice [32]. Recent reports propose that cannabinoid-induced neuroprotection in MS results from the concomitant activation of CB1 in neurons and CB2 in astrocytes [36]. There is some evidence of an important role of ECS in MS. CNS levels of endocannabinoids including AEA from MS patients as well as AEA and 2-AG levels in a mouse experimental model of MS have been reported to be increased [28]. The administration of CB1 or CB2 antagonists such as SR141716 or SR144528 worsens spasticity in CREAE mice (31). In addition, the endocannabinoiddegrading enzyme FAAH is over-expressed in reactive astrocytes, within MS plaques [33]. Altogether, the data not only support a relevant role for the ECS in MS, but also pointed to a possible therapeutic strategy in MS, the pharmacological enhancement of the ECS through the inhibition of endocannabinoid degradation. Thus, anandamide reuptake inhibitors such as AM404, or FAAH inhibitors such as UCM707 improve spasticity and functional recovery in rodent models of MS [28]. These results, however, should be interpreted with particular caution, because some or all of these compounds may also target other components of the endocannabinoid system when administered at a dose that inhibits cellular uptake [28]. Clinical Data The beneficial effect of cannabinoids on the main complaint of MS patients, spasticity, remains a matter of controversy. Different studies testing the objective amelioration of spasticity in MS patients by oral, oromucosal or parenteral preparations of cannabinoids differ in their results as in the dose or interval of study [28]. The first and largest double-blind, placebo-controlled clinical trial of

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Table 2. Disease Model

Species

Compound

Effect

Refs.

Alzheimer’s Disease In vitro Cultured neurons

Human

Anandamide

Protection against amyloid toxicity

[12]

Cultured microglial cells

Human

HU-210, Win55212, JWH133

Blockade of amyloid-induced microglial activation

[13]

Cultured neurons, glial cells

Rats

Cannabidiol

Protection against amyloid toxicity

[14-18]

Rats, mice

VDM-11

Clinical and neurohistological improvement

[19]

Experimental autoimmune encephalomyelitis (EAE)

Rats

THC

[30]

Chronic allergic encephalomyelitis (CREAE)

Mice

WIN55212, THC, JW133

Reduction of inflammation, clinical improvement Improvement of tremor and spasticity

[31,34]

In vivo Cortical A1-42 injection Multiple sclerosis In vivo

AM404, UCM707

Clinical improvement

[28]

Mice

WIN55212, ACEA, JWH015

Histological/clinical improvement, remyelination

[32]

Rats

WIN55212, THC, HU-308, CBD

Clinical improvement, delay of progress

[57]

Mice

THC, AM1241, WIN55212

Clinical improvement, delay of progress

[65-69]

Cultured neurons

Rats

AEA, WIN55212

Decrease of cell death

[76,77]

Forebrain slices

Rats

WIN55212

Decrease of cell death

[78]

Ouabain injection

Rats

THC, AEA

Histological neuroprotection

[81]

Stroke model (middle cerebral artery occlusion)

Rats

WIN55212


[82]

Ipsilateral hypoxia-ischemia (Rice-Vannucci model)

Rats

WIN55212


[83]

Global Hypoxia-Ischemia

Pigs

CBD

Clinical and histological neuroprotection

[84]

Theiler’s murine encephalomyelitis (TMEV-IDD) Huntington’s Disease In vivo Striatal toxic injection Amyotrophic Lateral Sclerosis In vivo Genetic model (SOD1 G93A) mutant Brain Ischemia In vitro

In vivo

cannabinoids in MS patients, the CAMS study, started in 2003 in the UK, failed to demonstrate after 15 weeks of treatment a significant improvement in spasticity associated with multiple sclerosis as measured with the Ashworth scale [37]. Despite its known limitations, the Ashworth scale remains as the usual tool to quantify spasticity in clinical trials on MS patients [38]. The negative results of the early CAMS study, however, could be due at least in part to the interval of study, as it has been demonstrated that cannabinoid-induced amelioration in spasticity and other symptoms of MS reach significance after 10 weeks of treatment and remains over one year [39]. In agreement, the

continuation of the CAMS study revealed that patients treated with oral THC do demonstrate a small but significant improvement on muscle spasticity as measured by change in Ashworth score from baseline to 12 months [40]. In addition, the CAMS study tested cannabinoids administered per os, which is unpredictable [38] and at modest doses to avoid significant side effects [37]. Finally, it is worthwhile to note that, using the same power calculations in the CAMS study, other medications currently tested in MS offer very modest if any improvement in Ashworth scale, with no benefits demonstrated on sleep disorders or pain [37].



Cannabinoids more consistently improved other symptoms of MS, including mobility, pain or urinary dysfunction. Oral THC in the CAMS study improved 10 m walking time [37]. A meta-analysis of cannabinoids for neuropathic pain in MS reported that oral THC, cannabidiol, or oromucosal Sativex, successfully reduced pain more than 1.5 points in an 11-point pain scale, which meets the goal standard for analgesic treatments [41]. Finally, most of the clinical trials on cannabinoids in MS patients agree on the substantial cannabinoid-induced improvement of urinary function, mainly of urgency, urge incontinence, and hesitancy [28, 39].

Experimental Data

Another point of agreement of all studies is that cannabinoids, whatever the dose or route of administration, lead to a subjective improvement of spasticity-related symptoms (pain, sleep quality, spasms), as well as a selfreported moderate to complete relief of many other symptoms such as shaking, tremor, weakness, depression, anxiety, energy, and tiredness [28, 38, 39]. Thus, overall, patients felt that these drugs were helpful in treating their disease [40], being willing to continue the treatment more frequently than with placebo [28, 39]. As a consequence, it is known that the risk of illicit cannabis use among MS patients increased with greater disability and dysfunction of the lower and upper limbs [39]. Reported side effects of cannabinoids use in MS are usually mild and tended to decline as the treatment continues: the most common side effect is dizziness/lightheadedness, affecting one-third to one-half of patients receiving oral THC or Sativex, followed by dry mouth, tiredness, weakness, myalgia or palpitations [28, 42]. By contrast, a recent report describes that patients with MS who regularly smoke cannabis have more extensive cognitive abnormalities and greater lifetime psychopathology than those who do not use cannabis [43]; this might reflect that cannabis further deteriorates the cognitive impairment present in almost a half of MS patients, but alternatively may indicate that those patients with psychiatric or cognitive problems were more likely to use cannabis as a way of self-medicating. CANNABINOIDS AND HUNTINGTON’S DISEASE Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a mutation in the IT15 gene encoding the protein huntingtin, resulting in an abnormal expansion of the N-terminal region of this protein [44]. The disease presents in midlife and has fatal consequences. One important effect of the mutation is the formation of protein aggregates in striatal and striato-fugal neurons subsequently leading to their death. As in the case of AD, it is currently under debate whether these aggregates are toxic or whether smaller (oligomeric) aggregates are more toxic than larger ones [45]. Symptoms of the disease include motor disturbances (chorea) with hyper- and hypokinetic phases, as well as cognitive and psychiatric symptoms (dementia). There is currently no curative treatment for HD and novel therapeutic approaches, such as the use of antiexcitotoxic compounds, the enhancement of brain-derived neurotrophic factor expression or the reduction of the expression of mutant protein, are under study [45].

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Several studies have clearly demonstrated that the brains of advanced HD patients exhibit an almost complete disappearance of CB1 receptor binding in the substantia nigra, lateral part of the globus pallidus and, to a lesser extent, in the putamen [46-48]. This loss of CB1 receptors is concordant with the characteristic neuronal loss observed in HD, that predominantly affects medium-spiny GABAergic neurons [49], which contain most of CB1 receptors present in basal ganglia structures [50, 51] and that also affects other receptor types. This is also consistent with the fact that other phenotypic markers for those neurons, such as substance P, enkephalin, calcineurin, calbindin, and adenosine and dopamine receptors, are also depleted in HD [52]. Interestingly, data in postmortem tissue have revealed that the loss of CB1 receptors occurred in advance to other receptor losses and even before the appearance of major HD symptoms. This suggests that losses of CB1 receptors might be involved in the pathogenesis and/or progression of the neurodegeneration in HD [47]. This observation has been recently corroborated in animal models of this disease, although with subtle differences related to the animal model employed. Thus Dowie et al [53] have reported that only a slight decrease in CB1 expression is detected in the R6/1 mouse, making it as a suitable model for cannabinoid treatment. More dramatic decreases have been shown for other mice models of HD (see 54 for review). In addition, it has been suggested that defects in CB1 signaling could render neurons more vulnerable to the degenerative process associated with HD and, conversely, that a robust CB1–mediated activity could be beneficial [54]. In this sense, it is interesting to note that environmental stimulation slowed the degree of CB1 loss in the R6/1 transgenic model of the disease [55]. On the other hand, R6/2 mice exhibit a severe impairment in the sensitivity of striatal GABAergic synapses to cannabinoid stimulation [56]. Very recently, that the early activation of these receptors could be a promising therapeutic target in R6/2 mice has been confirmed (M Guzmán et al, personal communication). Finally, it has been also postulated that cannabinoids may exert neuroprotection on striatal neurons not only through CB1- but also through CB2-mediated mechanisms (see [54], for review). Briefly, activation of CB1 receptors would reduce excitotoxic events by normalizing glutamate homeostasis while CB2 receptors would control the role that microglia play in the inflammatory process linked to neuronal death in HD. In addition, other non-receptor mediated actions of cannabinoids and, remarkably, their antioxidant properties would also cooperate in these beneficial effects. Thus, in vivo data indicate that THC may be effective against the toxicity of 3-nitropropionic acid, a mitochondrial toxin that replicates the complex II deficiency characteristic of HD patients. Striatal injury in this animal model progresses by mechanisms that involve non-apoptotic pathways. More recently, Sagredo et al. [57] have found that cannabidiol also exerts neuroprotection against this toxin-induced striatal lesion. This suggests that both THC and cannabidiol may protect striatal neurons through an antioxidant action mediated by cannabinoid receptor-independent mechanisms, possibly as scavengers of free radicals.

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Interestingly, Battista et al [58] have recently reported that FAAH activity in lymphocytes may be a good index in relation to the metabolic alterations that are present in HD patients. These authors performed a study with 78 HD patients in which they found a dramatic and specific reduction of FAAH activity linked to the disease. Other elements of the ECS remained constant among HD and control groups. These results allowed these authors to postulate FAAH as a possible index of HD pathology and of huntingin toxicity. Clinical Data A double-blind randomized study of cannabidiol in 15 neuroleptic-free patients with HD reported that this treatment was well tolerated by patients, but failed to report any beneficial effect of cannabidiol on chorea severity [59]. Nabilone at 1.5 mg per day increased choreic movements in one patient with HD [60], whereas at 1 mg per day improved behavior and reduced chorea in another patient [61]. CANNABINOIDS AND AMYOTROPHIC LATERAL SCLEROSIS Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease and is the result of the degeneration of motor neurons in the brain, spinal cord and peripheral nervous system [62]. The clinical features include weakness of arms, legs and face and difficulties with speech, swallowing and breathing and its progression usually leads to death within 3 to 5 years after onset. Although 90% of cases are sporadic, ten percent of ALS cases are familial forms resultant from monogenic mutations that cause the disease [63]. About 2% of ALS cases are due to the mutation in the gene encoding superoxide dismutase 1 protein (SOD1), an enzyme that scavenges superoxide radicals. Mice with mutations in SOD1 have become a remarkable model for this disease. Unfortunately, many therapeutic approaches for ALS have so far failed to translate into clinical practice, and only riluzole has been recently added as possible treatment for ALS patients [64]. With only modest efficacy, approximately 15-18% of patients taking riluzole experienced significant adverse effects, so the need for additional treatments is critical. Experimental Data The SOD1 G93A mice have become a useful tool for the study of the role of cannabinoids in ALS. Raman et al [65] reported that THC was able to delay the progression of the disease in these animals. Furthermore, early administration of this cannabinoid delayed the motor disturbances while prolonging their survival. This effect was also seen in motor neurons in vitro. Interestingly, the beneficial effect of an early treatment with cannabinoid-related chemicals has been also raised by other authors [19]. Conversely, Weydt et al [66] did not find a beneficial effect of cannabinol on the survival although onset of the disease was also significantly delayed. Interestingly, Bisland et al. [67] found that the early enhancement of the endocannabinoid tone exerted a dramatic neuroprotective effect on SOD1G93A mice. These authors postulated that this effect could not be mediated by

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cannabinoid receptors of the CB1 type, as deletion of this receptor did prolong the life span of the mice. These data raise the interesting hypothesis that other receptors, most probably CB2, could also participate in the beneficial effects of the enhancement of the endocannabinoid tone. In concordance with this line of reasoning, Kim et al [68] and Shoemaker et al. [69] have recently highlighted the possible relevance of CB2 receptors for the treatment of ALS. Thus, these reports show that administration of the specific CB2 agonist AM-1241 to SOD1 G93A mutant mice significantly delays the progression of the disease as well as prolongs their survival. Kim et al. [68] provided behavioral data showing that mice exhibited improved rotarod activity when treated with a specific CB2 agonist; interestingly, this effect was only observed in male mice. The study from Shoemaker et al [69] represents an interesting effort to unveil the molecular mechanisms involved in cannabinoid-induced protection in ALS. These authors found a significant pro-survival effect of the specific CB2 agonist AM-1241 on ALS mutant mice. Coincident with other pathologies, CB2 receptors seem to upregulate as a consequence of the chronic inflammatory environment in the spinal cord of these animals, while at the same time the density of CB1 receptors is clearly decreased. These data reinforce the notion of an inducible nature for the CB2 receptor and postulate it as a possible therapeutic target, free of undesired psychotropic effects. The authors suggest that CB2 upregulation may be a protective response of the CNS against injury. Clinical Data In a descriptive survey, 10% of patients with ALS responding to the survey consumed cannabis, reporting some moderate relief in symptoms of appetite loss, depression, pain, spasticity, and drooling; cannabis, however, failed to reduce difficulties with speech and swallowing, and sexual dysfunction [70]. CANNABINOIDS AND BRAIN ISCHEMIA Ischemic brain damage in adults, known as stroke, is a prevalent condition affecting 3/1000 people over 65-yearsold in developed countries; it is responsible for more than 150,000 deaths per year in USA, and this number will probably increase in the future [71]. Although less prevalent, newborn hypoxic-ischemic brain damage is of great importance too. Approximately 1-2 per 1000 live term births experience perinatal asphyxia; with one third of them developing a severe neurological syndrome, the neonatal hypoxic-ischemic encephalopathy (NHIE), and about 25% of severe NHIE leads to lasting sequelae, and about 20% to death [72]. Energy failure during ischemia provokes the dysfunction of ionic pumps in neurons, leading to changes in polarity and accumulation of ions and excitotoxic substances as glutamate. The consequent increase in intracellular calcium content aggravates the neuron dysfunction and activates different enzymes including proteases, lipases, endonucleases, nitric oxide synthase and others, starting different processes of immediate and programmed cell death [71]. During post-ischemic reperfusion, inflammation and



oxidative stress aggravate and amplify such responses, increasing and spreading neuron and glial cell damage [71].

damage, in a manner that can be attributed to a cannabidiolinduced reduction of cerebral hemodynamic impairment, improvement of brain metabolic activity postinsult, reduction of brain oedema and reduction of seizures. These neuroprotective effects are not only free from side effects but also associated with some cardiac, hemodynamic and ventilatory benefits, which makes cannabidiol a serious candidate for future clinical trials with asphyxiated newborns [84].

Experimental Data Cannabinoids show several neuroprotective properties: the activation of cannabinoid receptors induces the closure of Ca++ channels, inhibits the transcriptional activity of the NFB, reduces cytokine and glutamate release, and modulates the induction of NOS and COX; in addition, cannabinoids are immunomodulators, antioxidants, vasodilators and stimulate neuroproliferation and remyelination [36, 72, 73-75]. Several studies have demonstrated that cannabinoids reduce hypoxic-ischemic brain injury. In vitro studies have demonstrated that cannabinoids prevent cellular death in incubated neurons [76, 77] or newborn rat forebrain slices exposed to oxygen-glucose deprivation [78]. In the latter model, neuroprotection by the CB1-CB2 agonist WIN55212 is related to the decrease of glutamate and cytokines release as well as of iNOS expression [78]. Interestingly, all these effects were abolished by either a CB1 or CB2 receptor antagonist, suggesting that WIN55212 is neuroprotective by acting simultaneously on both kinds of receptors [78]. Moreover, the effect of WIN55212, a combined CB1 and CB2 agonist, is superior to the effect of a pure CB1 agonist (ACEA) or a pure CB2 agonist (JWH133) [78]. These data suggest that the simultaneous activation of both CB1 and CB2 receptors offers more benefits than CB1 or CB2 activation alone. A number of in vivo experiments supported the neuroprotective effect of cannabinoids [73-75, 79, 80]. This effect varies according to the species, age, and the type and/or severity of brain insult [73, 79]. In adult rats, WIN55212 reduced brain injury after global or focal ischemia [76]. In adult and newborn rats it has been reported that cannabinoids (HU211 or 2-AG) reduce brain damage induced by closed cranial trauma [79]. Besides, the administration of THC [81] affords neuroprotection in a newborn rat model with excitotoxic neuronal injury. We analyzed the neuroprotective value of WIN55212 (WIN) in newborn rats after acute severe anoxia [82] or a standard hypoxic-ischemic insult [83]. In these models, post-insult administration of WIN55212 0.1 mg/kg dramatically reduces early and delayed neuronal death in cortex and hippocampus. In the hypoxic-ischemic model, we observed by magnetic resonance imaging that despite the fact that the severity of early brain damage was similar in rat pups treated with vehicle or WIN55212 24 hr after hypoxia-ischemia, one week after hypoxia-ischemia the area of damage evolved to necrosis in vehicle-treated pups, but to healing in WINtreated pups, supporting a strong neuroprotective effect for WIN [83]. Again in this in vivo model, co-administration of WIN with either a CB1 or a CB2 receptor antagonist abolished the beneficial effect of WIN [83]. The importance of these results may be highlighted by the fact that WIN was useful when administered after the HI insult, which renders this strategy feasible in actual clinical conditions, where NHIE is almost unpredictable [75]. Recently, we have demonstrated in a model of hypoxic-ischemic brain damage in newborn piglets that the post-insult administration of the cannabinoid agonist cannabidiol reduces short term-brain

447

Clinical Data Cannabinoids have not been used so far in treating acute neurodegenerative diseases in humans, with the exception of an attempt of using the cannabinoid HU-211 after brain trauma in adults [85]. In a phase II trial, this approach offered promising preliminary results, as the treated patients achieved significantly better intracranial pressure/cerebral perfusion pressure control without systemic side effects, and the percentage of patients achieving good neurologic outcome at 3 and 6 months was 21% and 14% higher, respectively in the drug-treated group [85]. However, in a subsequent phase III trial, HU211 treatment failed to demonstrate any benefit on neurologic outcome or survival at 6 months [86]. CONCLUSION Nowadays, it is generally accepted that cannabinoids may be neuroprotective in several diseases. However, it is still premature to predict their actual relevance in future clinical practice. Several lines of work fully support the use of cannabinoid chemicals for, for instance, appetite stimulation or motor disturbances and even some pharmaceutical preparations are under study in MS and other diseases. But perhaps the most exciting aspect of current research on cannabinoids may be their possible interest not only at the symptomatic level, but also as possible curative or disease-modifying agents. CB1 receptors are still on the front line of cannabinoid research, mostly due to their wellknown distribution as well as to the effects derived from their activation. More recently, however, other elements of the ECS have been raised as putative relevant therapeutic targets for several neurological diseases. Among them, CB2 receptors and the enzyme FAAH are being increasingly studied. First, expression of CB2 receptors seems to be subjected to selective induction under inflammatory conditions and might play a role in microglia-mediated effects [13, 87, 88] by reducing the production of cytotoxic factors, such as nitric oxide, reactive oxygen species and proinflammatory cytokines. On the other hand, FAAH inhibition could provide beneficial effects [89] by several mechanisms, such as increases in AEA levels and, at the same time, decreases in arachidonic acid, a precursor molecule for pro-inflammatory mediators. Further research is needed to understand the functional significance of the disease-related changes observed in the ECS as well as to unveil the therapeutic potential of cannabinoid chemicals. ACKNOWLEDGEMENTS Financial support is provided by CIBERNED (CB06/05/1109), Ministerio de Ciencia e Innovación Tecnológica (SAF2007-61565), FIS (PI061085 and

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PI060839) and Comunidad Autónoma de Madrid (SSAL/0261/2006). ABBREVIATIONS 2AG

= 2-Arachidonoyl Glycerol

AD

= Alzheimer’s Disease

ACEA

= Arachidonyl-2-Chloroethylamide

AEA

= Anandamide

ALS

= Amyotrophic Lateral Sclerosis

CB1

= Cannabinoid Receptor Type 1

CB2

= Cannabinoid Receptor Type 2

COX-2

= Cyclooxygenase Type 2

CREAE

= Chronic Relapsing Experimental Allergic Encephalomyelitis

EAE

= Experimental Autoimmune Encephalomyelitis

ECS

= Endocannabinoid System

FAAH

= Fatty Acid Amide Hydrolase

HD

= Huntington’s Disease

iNOS

= Inducible Nitric Oxide Synthase

[9]

[10] [11]

[12] [13]

[14]

[15]

[16]

MAP-Kinase = Mitogen Activated Protein Kinase MS

= Multiple Sclerosis

NHIE

= Neonatal Hypoxic-Ischemic Encephalopathy

NF-kB

= Nuclear Factor kappa-Light-ChainEnhancer of Activated B Cells

p38MAPK

= p38 Mitogen Activated Protein Kinase

SOD

= Superoxide Dismutase

THC

= 9–Tetrahydrocannabinol

TMEV-IDD

= Theiler’s Murine Encephalomyelitis Virus-Induced Demyelinating Disease

[17]

[18]

[19]

[20]

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Received: October 10, 2009

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Revised: October 17, 2009

Accepted: October 18, 2009