Modulation of the Cannabinoid System: A New Perspective for the Treatment of the Alzheimer’s Disease
Department of Human Neuroscience, Sapienza, University of Rome, Rome, Italy
*Address correspondence to this author at the Department of Human Neuroscience, Viale dell’Università 30, 00185 Rome, Italy; Tel: +39 0649914988; Fax: +39 0649694216; E-mail: giuseppina.talarico@uniroma1.itAbstract
The pathogenesis of Alzheimer’s disease (AD) is somewhat complex and has yet to be fully understood. As the ef-fectiveness of the therapy currently available for AD has proved to be limited, the need for new drugs has become increas-ingly urgent. The modulation of the endogenous cannabinoid system (ECBS) is one of the potential therapeutic approaches that is attracting a growing amount of interest. The ECBS consists of endogenous compounds and receptors. The receptors CB1 and CB2 have already been well characterized: CB1 receptors, which are abundant in the brain, particularly in the hip-pocampus, basal ganglia and cerebellum, regulate memory function and cognition. It has been suggested that the activation of CB1 receptors reduces intracellular Ca concentrations, inhibits glutamate release and enhances neurotrophin expression and neurogenesis. CB2 receptors are expressed, though to a lesser extent, in the central nervous system, particularly in the mi-croglia and immune system cells involved in the release of cytokines. CB2 receptors have been shown to be upregulated in neuritic plaque-associated microglia in the hippocampus and entorhinal cortex of patients, which suggests that these receptors play a role in the inflammatory pathology of AD. The role of the ECBS in AD is supported by cellular and animal models. By contrast, few clinical studies designed to investigate therapies aimed at reducing behaviour disturbances, especially night-time agitation, eating behaviour and aggressiveness, have yielded positive results. In this review, we will describe how the manipulation of the ECBS offers a potential approach to the treatment of AD.
1Alzheimer’s disease
Dementia is a leading cause of ill health. Alzheimer’s disease (AD) is the most common form of dementia, accounting for 50-60% of all cases. The prevalence of AD increases exponentially with age, affecting between 24% and 33% of all people over 80 years of age [1]. The number of cases of dementia is expected to rise dramatically over the next 50 years owing to the increase in life expectancy and will consequently present a growing medical challenge.
Clinically, AD is a neurodegenerative disorder characterized by an impairment in cognitive abilities, a dysfunction in activities of daily living and behavioural disturbances. Although the pathogenesis of this disease is still unclear, it has been postulated that Abeta (Aβ) aggregation and deposition, associated with neuritic plaque formation, and tau hyperphosphorylation, associated with the development of neurofibrillary tangles, play important roles in the development of this disease. Other mechanisms known to be involved in the pathogenesis of AD are synapsis dysfunction, inflammation oxidative stress and mitochondrial metabolism alterations [2].
The pathophysiological process underlying AD is believed to start many years before the disease is diagnosed. Therefore, in order to provide an overview of the biomarkers and epidemiological and neuropsychological evidence collected on AD over the last 20 years, the National Institute on Aging and the Alzheimer’s Association developed recommendations to determine the factors that best predict the risk of progression from “normal” cognition to mild cognitive impairment and AD dementia [3]. This “preclinical” phase of AD may benefit from new therapeutic interventions, particularly disease-modifying drugs. The ability of the drugs currently available to modify the clinical symptoms of AD has, however, been limited and relatively short-lasting.
The main therapeutic approach adopted in recent years has been to increase the availability of acetylcholine by inhibiting acetylcholinesterase. The cholinergic hypothesis in AD is based on the degeneration of cholinergic neurons in the basal forebrain, which causes a dysfunction in cholinergic neurotransmission, particularly in the hippocampus and neocortex [4]. Donepezil and galantamine are selective acetylcholinesterase inhibitors, whereas rivastigmine inhibits both acetylcholinesterase and butyrylcholinesterase.
Another current therapeutic strategy in AD consists in modulating glutamate neurotransmission and consequently reducing excitotoxicity [5]. Memantine, a non-competitive N-methyl-D-aspartate (NMDA) receptor, is the only such drug used in AD.
Translating the pathogenetic findings of AD into potential therapeutic strategies based on disease-modifying drugs has been the target of researchers in recent years. Inhibiting Aβ production and aggregation or increasing Aβ clearance from the brain as a means of acting on tau hyperphosphorylation have been the main strategies adopted to date.
Epidemiological and observational studies have also laid the bases for testing various substances in randomized controlled clinical trials, though with often disappointing results.
1.1The Endogenous Cannabinoid System
A novel approach in AD consists in exploiting the endogenous cannabinoid system (ECBS) insofar as this system has been shown to modulate the main pathological process that occurs during the neurodegeneration process (Fig. 1) [6].
The ECBS consists of lipid compounds, specific receptors and several enzymes responsible for their synthesis and degradation (fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL) and diacylglycerol lipase (DAGL) [7].
The best-known endocannabinoids (CB) are arachidonoylethanolamine (AEA), also referred to as anandamide, and 2-arachidonoylglycerol (2-AG), both of which are eicosanoids derived from the hydrolysis of membrane phospholipids. They are synthesized in the post-synaptic terminal and work as retrograde messengers on presynaptic CB receptors [6-8]. Following the activation of CB receptors, endocannabinoids are removed by means of enzymatic hydrolysis from the synaptic junction; anandamide is hydrolysed by FAAH in post-synaptic neurons, while 2-AG is hydrolysed prevalently by MAGL in pre-synaptic neurons [9].
Other endocannabinoids have been identified more recently (virodhamine and 2-arachidonylglyserylether (2-AGE), among others), though their action is still unclear [10].
The cannabinoid receptors CB1 and CB2 are G protein-coupled receptors. CB1 receptors, which are the most abundant cannabinoid receptors, are expressed mainly in neurons in the central nervous system, as well as in glial cells, and thus regulate important brain functions, including cognition and memory, emotion, motor control, feeding and pain perception [11]. The activation of these receptors is believed to inhibit adenylate cyclase activity and calcium influx into the axon terminal [12]. CB1 is also expressed in peripheral tissue, i.e. in heart, uterus, testis, liver and small intestine, as well as in immune cells and adipose tissue [13].
CB2 receptors are expressed to a lesser extent in the central nervous system but are located above all in microglia and in immune system cells that act on the release of cytokines [14], their expression being significantly increased following stressful conditions [15]. Recent experimental studies have detected CB2 receptor activity in neural progenitor cell proliferation, axon guidance and synaptic transmission [16-17]. CB2 receptors can act through the initiation of the phospholipase C (PLC) and inositol 1 4 5-triphosphate (IP3) signalling pathway, which results in increased levels of intracellular calcium [18]. Like CB1 receptors, CB2 receptors can inhibit adenylyl cyclase, thereby reducing intracellular cAMP levels [7]. Activation of CB2 receptors is coupled with other cellular pathways, including PKA, ERK1/2 and P38. Besides being found in cells of the immune and hematopoietic system, CB2 receptors have also been found in peripheral organs such as muscle, liver, intestine and testis [19].
4Clinical evidence
Few clinical studies have tested cannabinoids on AD patients, and the majority of those that do exist were conducted on populations in the late stages of the disease and were based on a short-lasting treatment [58-60]. A first attempt to determine whether cannabinoids are clinically effective in the treatment of dementia was made by the Cochrane Dementia and Cognitive Improvement Group (CDCIG) in 2009 [61]. Only one study met the selection criteria, which only allowed the inclusion of double blind and single (rater)-blind randomized placebo-controlled trials [59]. The participants (15 severe, hospitalised, AD patients) were randomly assigned to two groups to receive either dronabinol (2.5 mg twice daily) or placebo for six weeks before treatment was crossed over for a further six weeks. The authors suggested that dronabinol is a promising agent for the treatment of anorexia and other behavioural disturbances such as agitation and aberrant nocturnal motor activity. However, the authors of the review also concluded that more randomized double-blind placebo-controlled trials are needed to determine whether cannabinoids are clinically effective as a means of treating dementia.
Some years later, another systematic review [62] sought to extend the evidence on the indications, efficacy, safety and pharmacokinetics of medical cannabinoids in older subjects. PubMed, EMBASE, CINAHL and Cochrane Library were used as a source of research and only controlled studies or data reporting only including subjects over 65 years of age, who did not need to be affected by AD, were selected. Only two studies [58, 59] have shown that THC might be useful in the treatment of anorexia and behavioural symptoms in dementia. The adverse events linked to cannabinoid treatment are sedation-like symptoms. The authors concluded that, despite the fascinating therapeutic potential, adequately powered trials are needed to assess the efficacy and safety of cannabinoids in older subjects [62].
In a more recent retrospective systematic review on 40 demented inpatients with behavioural and appetite disturbances, dronabinol intake, at a mean dose of 7.03 mg/day, was found to lead to a significant decrease in all domains of the Pittsburgh Agitation Scale (PAS) and an improvement in Clinical Global Impression (CGI) scores, sleep duration and meal consumption, as well as being well tolerated [63].
In a recent open label study on 11 AD patients with behavioural and psychological symptoms, medical cannabis oil (1.65% THC) administered up to 7.5 mg twice daily over 4 weeks proved to be both safe and well tolerated. A significant reduction in the CGI severity score, in caregiver distress and in the NeuroPsychiatric Inventory (NPI) domains, particularly in delusions, agitation/aggression, irritability, apathy and sleep disturbances, were observed, as were good safety and tolerability profiles [64].
In another study, a phase 2, randomized, multi-center, double-blind, parallel group trial was designed to explore the efficacy and safety of THC in tablet form (dose of 4.5 mg daily) to treat behavioural disturbances and pain in patients with mild to severe dementia. Behavioural disturbances were defined as a score of ≥10 on the NPI, which also served as the primary outcome measure. THC showed no benefit over placebo, though it was well tolerated. The authors suggested that the target dose might have been too low to detect any psychomimetic effects and the treatment period too short (3 weeks) [65].
Two studies are currently being conducted (clinicaltrial.gov) to evaluate the safety and efficacy of cannabinoids (nabilone in one and dronabinol in the other) in the treatment of AD, particularly of agitation, pain, weight, sleep and memory. The first study is a 14-week crossover pilot study designed to compare a 2 mg daily dose of nabilone for 6 weeks with placebo in 40 patients with AD. The second is a 3-week pilot study designed to compare a 5 mg daily dose of dronabinol with placebo in 160 in-patients with AD. See Table 1 for a better overview.
Conclusion
Manipulation of the cannabinoid system may offer a novel pharmacological approach to the treatment of AD. Manipulation should be aimed prevalently at inhibiting neuroinflammation through CB2r activation so as to prevent ROS formation and cytokine release from microglia, on the one hand, and at reducing neurotoxicity by CB1 receptor activation so as to inhibit glutamate release and enhancing neurotrophin expression and neurogenesis, on the other.
It has also been demonstrated that the ECBS reduces tau phosphorylation and Delta9-THC inhibits AchE, which result in enhanced cholinergic transmission and reduced amyloidogenesis. However, since the potential value of the ECBS on cognitive and behavioural performances remains unclear, randomized controlled trials are warranted to evaluate whether the ECBS may modify disease development or progression.
ACKNOWLEDGEMENTS
All the authors made a significant contribution to this study. Talarico Giuseppina wrote the article. Trebbastoni Alessandro contributed to the drafting of the clinical evidence paragraph and prepared the figure. Bruno Giuseppe and de Lena Carlo were involved in revising the draft and reviewing the article from a linguistic point of view.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or otherwise.
| References | Numbers of Partecipants | Type of eCB | Type of Study | Duration of Treatment | Clinical Evidences |
|---|---|---|---|---|---|
| Volicer L, 1997 [55] | 15 severe AD patient hospitalised | dronabinol (2.5 mg twice daily) or placebo | placebo controlled study (double blind and single-rater blind randomized | six week and crossover of treatment for a further six week. | Improvement on anorexia, agitation and aberrant nocturnal motor activity |
| Walther S, 2006 [54] | 6 demented patients (5AD, 1 VaD) | Dronabinol (2,5 mg daily) | Open label pilot study | 2 weeks | Reduction of night-time agitation |
| Koppel J, 2009 [56] | 19 late-onset AD subjects and 12 controls | No drugs | A case-control and cohort study | No significant differences in AEA and 2AG plasma concentration between AD and CTR | |
| Woodward M.R, 2014 [59] | 40 inpatients with severe dementia | Dronabinol | Retrospective study | 1 week | Significant decreases in all domains of PAS, significant improvements in CGI scores and in sleep duration |
| Shelef, A, 2016 [60] | 11 AD patients | THC oil up to 7.5 mg twice daily | an open label, add-on, pilot study | 4 weeks | Improvement on delusions, agitation/aggression, irritability, apathy, and sleep disturbances. Reduction in CGI severity score and in caregiver distress |
| Van den Elsen G.A.H, 2015 [61] | patients with mild to severe dementia (24 with TCH and 26 with placebo) | THC in tablet form (dose of 1.5 mg 3 times daily) | a phase 2, randomized, double-blind, placebo-controlled study | 3 weeks | No benefit in NPS |
| clinicaltrial.gov NCT02351882 | 40 AD patients | nabilone at 2 mg daily dose versus placebo | randomized placebo controlled study | 14 weeks: participants take nabilone for 6 weeks, placebo for 6 weeks (order randomized) with 1 week between treatments | Estimated Study Completion Date: march 2018 |
| clinicaltrial.gov NCT02792257 | 160 AD patients | 2.5 mg per dose (5mg daily) during Week 1, then 5 mg per dose (10mg daily) for Weeks 2 and 3 versus placebo | randomized placebo controlled study | 3 weeks | Estimated Study Completion Date: august 2020 |