Neurodegenerative disorders carry a significant social and economic burden, and the effective treatment of such illnesses remains a challenge for neuroscientists and neurologists. Although significant advances have been made on our understanding of the molecular mechanisms underlying neurodegenerative diseases, the translation of this knowledge into effective therapeutic treatments has been limited. There is still a dearth of curative treatments for most neurodegenerative disorders, with symptomatic relief being the principal target for drug action. Endocannabinoids belong to an evolutionary conserved neuro-signaling system and certain endogenous and exogenous components of this system are emerging as clinically promising neuroprotective agents due to their anti-oxidative, anti-excitotoxic, and anti-inflammatory properties. The cannabinoid system is, therefore, a potential target for several neurodegenerative conditions, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Research on the therapeutic potential of drugs that modulate endogenous cannabinoid tone is intense. Recent evidence implicates the endocannabinoid system as a potential pharmacological target to circumvent neurodegenerative disease pathology. WIREs Membr Transp Signal 2012, 1:633–639. doi: 10.1002/wmts.64
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Several neurodegenerative disorders display alterations in components of the cannabinoid system and a cannabinoid-based approach has proven efficacious in the reversal of certain neurodegenerative events. Common features of neurodegenerative diseases include neuronal loss, oxidative stress, and neuroinflammation, which can contribute to the disease symptomatology (Figure 1). In this article, three neurodegenerative diseases, namely Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease, are discussed in the context of disease-related alterations in the cannabinoid system and the potential benefit that may be achieved by targeting the cannabinoid system to alleviate various features of the pathologies. Although these diseases differ in their etiology, they share certain common features, particularly neuroinflammation and neuronal loss, which the cannabinoid system can impact upon.
CANNABINOIDS AND ALZHEIMER'S DISEASE
AD is a multifactorial age-related neurodegenerative condition characterized by progressive cognitive decline as a result of chronic synaptic loss and neuronal death. The key neuropathological hallmarks of AD include deposition of amyloid beta (Aβ) plaques and the presence of neurofibrillary tangles composed of the hyperphosphorylated form of the microtubule associated protein, tau. As AD is a neurodegenerative cognitive disorder with an inflammatory component, the cannabinoid system, which influences both the immune system and cognition, may have relevance in the treatment of AD. Lately, the endocannabinoid system has attracted interest as a novel target for AD, as well as other neurodegenerative disorders, due to the potential neuroprotective, anti-inflammatory, and neurotrophic properties of cannabinoid compounds.1,2
The use of Dronabinol, a preparation of the phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC), has been shown to reduce anorexia, increase body weight, and improve behavior in elderly patients.3 More recently, in a pilot study performed on five AD patients, a low dose of Dronabinol significantly improved several clinical parameters, such as nocturnal motor activity and agitation, without undesired side effects.4 A recent case report also describes the ability of Δ9-THC to reduce agitation and aggression in a 72-year-old woman. Remarkably, this effect was rapid and dramatic, rendering better results than those observed with other antipsychotic medications.5 Cannabinoid-based medications may, therefore, assist in the management of the behavioral symptoms of AD. The focus of this review is on the potential of cannabinoids to target the processes involved with the disease pathology.
The status of CB1 receptors in the AD brain has been the issue of some debate.6–8 Recent reports suggest that CB1 receptor expression remains intact in the postmortem cortex of AD patients.7 However, it is also reported that neuronal CB1 receptors in the hippocampus and basal ganglia are reduced in AD and become nitrosylated, thus hampering G-protein coupling and rendering the receptors functionally impaired.8 Given that functional CB1 receptors are associated with neuronal survival, a reduction in the CB1 receptor system would be expected to reduce the pro-survival capability of neurones. Recent lipidomic analyses have revealed that levels of the endocannabinoid anandamide (AEA) and its precursor 1-stearoyl, 2-docosahexaenoylsn-glycerophosphoethanolamine-N-arachidonoyl (NA rPE), are significantly reduced in the AD brain and that this may be due to plaque burden, since Aβ1-42 prevents the synthesis and mobilization of AEA.9 The reduction in cortical AEA levels correlate with the reduction in cognitive performance, psychomotor speed, and language function in AD patients. Interestingly, apart from AEA and its precursor NArPE, no other endocannabinoid-related lipid species was altered in the cortex of AD patients. The reduced AEA levels correlate specifically with Aβ1-42 load and not with the less toxic Aβ1-40 amyloid species nor with neurofibrillary tangles or ApoE4 genotypes. However, the molecular mechanisms engaged by Aβ1-42 to affect AEA bioavailability remain to be resolved. Thus, the combination of possible alterations in CB1 receptors and endocannabinoid tone in the AD brain may contribute to changes in glutamatergic synaptic function and cell viability.10 Furthermore, it has been reported that both fatty acid amide hydrolase (the endocannabinoid metabolizing enzyme) and cannabinoid CB2 receptors are upregulated in neuritic plaque-associated astrocytes and microglia respectively, thus linking the endocannabinoid system to the destructive inflammatory process accompanying AD.11
The Aβ burden in the AD brain can induce excitotoxicity through reduced glutamate re-uptake by astrocytes. The synthetic phytocannabinoid, HU-211, has been shown to act as a stereoselective inhibitor of N-methyl-D-aspartate (NMDA) receptors and thereby protect rat forebrain cultures12 and cortical neuronal cultures from excitotoxicity.13 Cannabinoids can also upregulate the brain-derived neurotrophic factor (BDNF) to confer neuroprotection against excitotoxicity.14 Given that CB1 receptors are abundant at glutamatergic terminals,10 the ability of cannabinoids to thwart excitotoxicity represents one aspect of cannabinoid function that may confer neuroprotection. Recent work by Haghani and co-workers15 has demonstrated that a bilateral injection of Aβ into the prefrontal cortex of Wistar rats reduces evoked neural activity in hippocampal CA1 pyramidal neurons. This deleterious effect of Aβ treatment was almost completely prevented when the rats were co-treated with ACEA, a selective CB1 receptor agonist, suggesting that activation of the CB1 receptor can overcome changes in neural activity evoked by Aβ. Given the role of the hippocampal formation in learning and memory, such an impact of ACEA on neural activity in this brain region may have the potential to restore cognitive function in AD.
Targeting the cannabinoid system can also interfere with downstream signaling events associated with neuronal cell death. In this regard, the destabilization of the neuronal lysosomal membrane induced by Aβ is an early signaling event in apoptosis which leads to the release of cathepsins and subsequent demise of the cell. The upregulation of endocannabinoid tone has been shown to prevent the Aβ mediated lysosomal destabilization in cultured neurons to confer neuroprotection.16 While CB1 cannabinoid receptor activation may restore cognitive function by inhibiting Aβ-induced neuronal apoptosis, CB1 cannabinoid receptor agonist administration during advanced neurodegeneration may worsen the Aβ-induced neuronal demise by inhibiting residual neuronal activity.17 New concepts are also emerging regarding the role of the endocannabinoid system in driving the disease process in AD. Evidence suggests that errant retrograde 2-AG signaling impairs synaptic neurotransmission in AD and that disease progression alters 2-AG signaling thereby contributing to synaptic silencing in AD.18
Chronic low-grade neuroinflammation plays a central role in driving the progression of AD. The Aβ plaques are a well established trigger for microglial activation which, upon activation, release a range of pro-inflammatory cytokines and chemokines that exacerbate the ongoing neuroinflammation, contribute to cell damage and may also drive amyloidogenesis.19,20 Microglial CB2 receptors can suppress the microglial activation evoked by Aβ.21,22 In fact, upregulation of both CB1 and CB2 receptors have been observed on microglia within amyloid plaques,8 possibly in an attempt to reduce neuroinflammation, since CB2 receptor activation in-vitro has the proclivity to reduce the production of pro-inflammatory cytokines.23 Administration of the selective CB2 receptor agonist, JWH-133, for 4 months to the Tg APP transgenic mouse model of AD reduces microglial activation, COX-2 protein expression, TNF-α mRNA expression and cortical Aβ levels, and subsequently prevents the deterioration in performance in a novel object recognition task.24 Therefore a cannabinoid-mediated reduction in neuroinflammation translates into an improvement in cognition which would be a useful combination of properties for the treatment of AD.
One of the beneficial properties of the phytocannabinoid, cannabidiol (CBD), as a therapeutic agent is its lack of psychoactive effects.25 CBD can decrease the phosphorylation of the stress-activated protein kinase, p38 mitogen activated protein kinase (MAPK) induced by Aβ, thus preventing the translocation of nuclear factor (NF)-κB into the nucleus and the subsequent transcription of pertinent pro-inflammatory genes.26 In a mouse model of AD, which received an intrahippocampal administration of Aβ1-42, CBD prevented reactive gliosis and the release of proinflammatory mediators.27 CBD has also been shown to dampen Aβ-induced GSK-3β activation thereby preventing tau hyperphosphorylation and the subsequent formation of neurofibrillary tangles.28 CBD thus impacts upon a number of useful targets of relevance to AD pathology.
A growing body of evidence therefore supports the role of cannabinoids in alleviating some of the major neuropathological features of AD, including neuroinflammation, neuronal loss and tau phosphorylation.
CANNABINOIDS AND PARKINSON'S DISEASE
Parkinson's disease (PD) is a neurodegenerative illness characterised by the selective loss of dopaminergic neurons in the substantia nigra pars compacta and the deposition of α-synuclein aggregates in a portion of the surviving nigral neurons. Thus, PD shares certain overarching features with AD; namely neuronal cell loss, neuroinflammation and an accumulation of protein aggregates. However, in PD the neurodegeneration is restricted to the dopaminergic innervation of the striatum which is responsible for the motor dysfunction symptomatic of the disease, for example bradykinesia, rigidity and tremor.29
The potential causes of PD have not yet been rigidly defined. A wealth of evidence would suggest a key role for oxidative stress and neuroinflammation in the progression of the disease. A recent microarray study demonstrated an increased expression of genes encoding pro-inflammatory cytokines and subunits of the electron transport chain, and decreased expression of anti-oxidative glutathione-related genes in the brains of PD patients.30 Furthermore, increased microglial activation, as well as higher levels of pro-inflammatory cytokines, were detected in the brains of mutant mice in which the gene for α-synuclein was overexpressed.31 Microglial activation can play a causal and exacerbating role in both neuroinflammation and oxidative stress. Recent in vivo and in vitro studies have shown that superoxide anions (O produced by microglial NADPH oxidase can promote dopaminergic cell damage both alone and in concert with nitric oxide (in this case generating the free radical peroxynitrite, ONOO−). The oxidative stress elicited by these events can promote neuroinflammation.31 A number of environmental factors that are associated with idiopathic PD, such as head trauma, systemic infection and exposure to heavy metals and neurotoxins, have also been shown to induce a neuroinflammatory and oxidative response. Direct evidence that these responses have important roles to play are presented by the following observations; midbrain dopaminergic neurons are particularly sensitive to the deleterious effects of cytokines on neuronal survival, and this area of the brain also been reported to have the highest density of microglia.30
The cannabinoid system presents a promising target for the treatment of degenerative, inflammatory disorders of the central nervous system. Several studies have shown that CB1 receptor expression and availability is reduced in both the true disease state32 and in the 6-hydroxydopamine (6-OHDA)-induced nigrostriatal terminal lesion animal model of PD.33 Evidence suggests that elements of the cannabinoid system may play a neuroprotective role in PD via inhibition of oxidative and inflammatory processes. The phenolic ring moieties that cannabinoids contain display anti-oxidant properties and have been shown to protect against glutamate excitotoxicity in vitro.31 The CB1 receptor has also been shown to protect nigrostriatal dopaminergic neurons against the deleterious effects of the neurotoxin MPTP through the inhibition of microglia-mediated oxidative stress.34 Interestingly, the neuroprotective action of cannabinoids does not seem to be entirely dependent on cannabinoid receptor activation. The phytocannabinoid cannabidiol and the synthetic cannabinoid, AM404, have little or no affinity for cannabinoid receptors and have been shown to attenuate the reduction of mRNA levels of the anti-oxidant superoxide dismutase following 6-OHDA administration.31 Furthermore, CBD and Δ9-THC have been shown to reduce the production of the pro-inflammatory cytokines interleukin-1β, interleukin-6 and interferon-β from BV-2 microglial cell lines, and CBD alone was shown to reduce the activity of the pro-inflammatory NF-κB pathway, all independently of CB1 or CB2 receptor involvement.35 This may prove advantageous in the treatment of PD, as it has been found that long-term agonism of the CB1 receptor in particular can exacerbate motor dysfunction. Aside from developing cannabinoid therapies that are CB1 receptor independent, the CB2 receptor presents another target in the treatment of the disease. An lipopolysaccharide insult in mice has been shown to upregulate CB2 receptor expression in nigral parenchyma, and selective activation of these receptors protects dopaminergic neurons from resulting inflammation.36 These data suggest that exploitation of the anti-oxidant and anti-inflammatory elements of the cannabinoid system may present a promising pharmacological target in the treatment of PD, with particular focus on the CB2 receptor subtype.
THE CANNABINOID SYSTEM AND HUNTINGTON'S DISEASE
Huntington's disease (HD) is an autosomal dominant, inherited, progressive, neurodegenerative disorder, characterized by motor disturbances, cognitive loss and psychiatric manifestations. HD is caused by a mutation in exon 1 of the IT15 gene coding the huntingtin protein on chromosome 4. This mutation affects a specific region of neurons in the striatum and cerebral cortex resulting in motor dysfunction and cognitive loss, respectively.
Several studies have reported a loss of CB1 receptors and reduced endocannabinoid levels in animal models of HD.37,38 Rats injected with 3-nitropropionic acid (3-NP), a toxin which selectively damages striatal GABAergic efferent neurons, produces an animal model of HD, with a decrease in striatal levels of AEA and 2-AG.39
A study by Blazquez and colleagues40 investigated the impact of the loss of CB1 receptors in the basal ganglia in an animal model of HD and found that receptor deletion exacerbates the HD-like symptoms and neuropathology,40 whilst administration of Δ9-THC ameliorated the disease-related events.39 BDNF has been implicated in the pathophysiology of HD and is crucial for sustaining neuronal survival. In vitro and in vivo studies in HD models support a CB1 receptor-dependent upregulation of striatal BDNF expression whilst a deficiency in CB1 receptors correlates with a reduction in BDNF.40
Scotter and co-workers41 have reported that CB1 receptor activation by the synthetic cannabinoid agonists, HU210 and WIN55212-2, protects against mutant huntingtin-induced cell death. The CB1 receptor may, therefore, represent a therapeutic target in HD, however, its protective potential may be limited by promiscuous coupling to Gs, the stimulation of cAMP formation and increased huntingtin aggregate formation, therefore suggesting that therapies selective to the Gi/o, ERK pathway may be of most benefit in HD.
Administration of Δ9-THC and CBD-enriched botanical extracts attenuates the down-regulation of the CB1 receptor induced by 3-NP, in addition to attenuating 3-NP-induced GABA deficiency, loss of Nissl-stained neurons, reduced IGF-1 expression, and up-regulation of calpain expression.42 Additional effects included an attenuation of pro-inflammatory markers, such as inducible nitric oxide synthase, and the actions of Δ9-THC and CBD occurred in a CB1 and CB2 receptor-independent manner. This study provides preclinical evidence that cannabis-based medicine, in particular Sativex, has a neuroprotective effect in an animal model of HD, encouraging the commencement of clinical trials in the area.
Owing to the down-regulation of CB1 receptors in striatal neurons in HD and the fact that CB1 agonists can trigger undesirable psychoactive effects, alternative targets such as CB2 receptors may possess further potential. In contrast to neuronal CB1 receptors, microglial CB2 receptors are upregulated in HD transgenic mouse models and patients, and administration of CB2 receptor selective-agonists reduces neuroinflammation, brain edema, striatal neuronal loss, and motor symptoms.43 Furthermore, CB2 receptor ablation exacerbates microglial activation and accelerates the manifestation of HD-like symptoms.43 The discovery of increased CB2 expression in active striatal microglia is in agreement with previous findings of an innate inflammatory response occurring in the early stages of HD. These results suggest a role for CB2 receptors in attenuating microglial activation and possibly conferring neuroprotection in HD.
Neurodegenerative disorders can arise as a consequence of genetic, environmental, or sporadic factors. Despite these diverse etiologies, common features include neuroinflammation and neuronal loss. The evidence presented herein supports a role for the cannabinoid system in reducing neuroinflammation, most likely via the CB2 receptor, and creating an environment which supports neuronal survival by reducing excitotoxicity, promoting growth factor production and directly interfering with the cell death cascade. Apart from the typical cannabinoid receptors, the discovery that the novel cannabinoid receptor, GPR55 and the putative abnormal cannabidiol (Abn-CBD) receptor, GPR18 in microglia regulates their cellular responses to excititoxicity, cell migration and cytokine release holds promise.44,45 These multiple actions of the cannabinoid system are likely to be advantageous to several neurodegenerative conditions and open the possibility for a successful cannabinoid-based medication for neurodegenerative disease, akin to the recent clinical benefit obtained by the prescription of Sativex for patients with multiple sclerosis.