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Cbd oil for neurodegenerative disorders

From Cannabis sativa to Cannabidiol: Promising Therapeutic Candidate for the Treatment of Neurodegenerative Diseases

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Abstract

Cannabis sativa, commonly known as marijuana, contains a pool of secondary plant metabolites with therapeutic effects. Besides Δ9-tetrahydrocannabinol that is the principal psychoactive constituent of Cannabis, cannabidiol (CBD) is the most abundant nonpsychoactive phytocannabinoid and may represent a prototype for anti-inflammatory drug development for human pathologies where both the inflammation and oxidative stress (OS) play an important role to their etiology and progression. To this regard, Alzheimer’s disease (AD), Parkinson’s disease (PD), the most common neurodegenerative disorders, are characterized by extensive oxidative damage to different biological substrates that can cause cell death by different pathways. Most cases of neurodegenerative diseases have a complex etiology with a variety of factors contributing to the progression of the neurodegenerative processes; therefore, promising treatment strategies should simultaneously target multiple substrates in order to stop and/or slow down the neurodegeneration. In this context, CBD, which interacts with the eCB system, but has also cannabinoid receptor-independent mechanism, might be a good candidate as a prototype for anti-oxidant drug development for the major neurodegenerative disorders, such as PD and AD. This review summarizes the multiple molecular pathways that underlie the positive effects of CBD, which may have a considerable impact on the progression of the major neurodegenerative disorders.

Keywords: Cannabis sativa, oxidative stress, phytocannabinoids, cannabidiol, Alzheimer’s disease, Parkinson’s disease

Introduction

Oxidative stress (OS) plays a crucial role in aging and occurs manly when the activity of the anti-oxidants enzymes is not sufficient to counterbalance the generation of reactive oxygen species (ROS). In the latter condition, high production of ROS can alter the structure of proteins, lipids, nucleic acids, and matrix components leading to programmed cell death (Cassano et al., 2016). Different tissues present different susceptibility to OS. The central nervous system (CNS) is extremely sensitive to this type of damage for several reasons. To this regard, the CNS has a low level of antioxidant enzymes, a high content of oxidizable substrates, and a large amount of ROS produced during neurochemical reactions (Trabace et al., 2004; Uttara et al., 2009). In addition to several other environmental or genetic factors, OS contributes to neurodegeneration since free radicals attack neural cells. Therefore, neurons suffer a functional or sensory loss during the neurodegenerative process. Even if oxygen is indispensable for life, an unbalanced metabolism and an excess production of ROS ends up in a series of pathological conditions, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and many other neural disorders. Free radicals cause lesions to protein and DNA, activate inflammatory process and subsequent cell apoptosis (Cassano et al., 2012).

In the last years, there is an urgent need to discover new drug targets that can effectively combat cell alteration caused by the stress of cell membranes. In this perspective, the endocannabinoid (eCB) system has attracted considerable interest due to the current interplay between eCB and different redox-dependent signaling pathways. The two well-characterized eCBs are N-arachidonoyl-ethanolamine or anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG), which are synthesized on demand in response to elevations of intracellular calcium (Howlett et al., 2002; Di Marzo et al., 2005) and respectively metabolized by fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MAGL) (Piomelli, 2003; Di Marzo, 2008; Kunos et al., 2009). Cannabinoid (CB) receptors exist in two different subtypes: type 1 (CB1) and type 2 (CB2) (Matsuda et al., 1990; Munro et al., 1993; Howlett et al., 2002). The CB1 receptors, first cloned in 1990, are widely distributed in the body and in the CNS are distributed at the level of basal ganglia, cerebellum, hippocampus, caudate nucleus, putamen, hypothalamus, amygdala, and spinal cord (Matsuda et al., 1990). The CB2 receptors, cloned in 1993, are mainly located in cells of the immune system with high density in the spleen, T lymphocytes, and macrophages (Munro et al., 1993). Their anatomical distribution correlates them to the actions for which they are responsible: the activation of the CB1 receptors has euphoric effects and an antioxidant, antiemetic, analgesic, antispasmodic, and appetite stimulating actions. As for CB2 receptors, their stimulation is attributable to the anti-inflammatory and immunomodulatory actions of CB (Cassano et al., 2017).

Converging evidence strongly suggests that eCBs act as retrograde synaptic messengers (Kano et al., 2002; Freund et al., 2003). This phenomenon is initiated postsynaptically by an elevation of cytoplasmic calcium concentration that induces the production and release into the synaptic space of eCBs. Thereafter, eCBs activate CB1 receptors at presynaptic levels and block the release from the terminals of neurons of different transmitters, such as gamma-aminobutyric acid (GABA), glutamate, dopamine (DA), noradrenaline, serotonin, and acetylcholine (Howlett et al., 2002; Pertwee and Ross, 2002; Szabo and Schlicker, 2005). These mechanisms mediated by the activation of presynaptic CB1 receptors are termed depolarization-induced suppression of inhibition (DSI) and excitation (DSE), respectively when are involved the inhibitory (GABA) or excitatory (glutamate) synaptic transmissions (Kano et al., 2002; Freund et al., 2003). Likewise, CB2 receptors can modulate the production and function of certain inflammatory cytokines at multiple levels by activating the immune cells and modulating their migration both within and outside the CNS (Freund et al., 2003; Walter and Stella, 2004). Antioxidant enzymes can be modulated by eCBs, not only acting on the CB1 and CB2 receptors, but also through the transient receptor potential vanilloid-1 (TRPV1), the peroxisome proliferator-activated receptor alpha (PPAR-alpha), and the orphan receptors N-arachidonyl glycine receptor or G-protein-coupled receptors 18 (GPR18) GPR19 and GPR55 (Piomelli, 2003; McHugh et al., 2010; Howlett et al., 2011; McHugh, 2012). Therefore, the direct and/or indirect modulation of pathways through which the eCBs damper the OS may represent a promising strategy for reducing the damage caused by a redox imbalance (Gallelli et al., 2018). Moreover, antioxidants are now seen as a convincing therapy against severe neurodegeneration, as they have the ability to fight it by blocking the OS. Diet and medicinal herbs are an important source of antioxidants. The recognition of antioxidant therapy upstream and downstream of OS has proven to be an effective tool to improve any neuronal damage as well as to eliminate free radicals. Antioxidants have a wide field of application and can prevent OS interacting with the metal ions, which play an important role in the build-up of neuronal plaque (Uttara et al., 2009).

In the last decade there are increasing evidences that secondary plant metabolites, extracted from medicinal herbs, may represent lead compounds for the production of medications against inflammation and OS, protecting from neuronal cell loss (Giudetti et al., 2018). Among these medicinal herbs, Cannabis sativa, commonly known as marijuana, contains a pool of secondary plant metabolites with therapeutic effects (Gugliandolo et al., 2018). In this context, cannabidiol (CBD) the nonpsychotropic CB extract from Cannabis sativa may represent a prototype for anti-inflammatory drug development for those human pathologies where both the inflammation and OS play a key role to their etiology and progression (Izzo et al., 2009). To this regard, therapies that effectively combat disease progression are still lacking in the field of neurodegenerative disorders, and mostly with AD. CBD, which modulates the eCB system, but has also CB receptor-independent mechanism, seems to be a prototype for anti-inflammatory drug development.

Therefore, the present review summarizes the main molecular mechanisms through which CBD exerts its beneficial effects that may have a considerable impact on the progression of the major neurodegenerative disorders.

Cannabis sativa

The medical and psychotropic effects of Cannabis sativa have been well known since long time. A multitude of secondary metabolites was extracted from this plant and most of them were used for therapeutic purpose by many cultures. So far more than 400 chemical compounds have been isolated from Cannabis sativa and among them more than 100 terpeno-phenol compounds named phytocannabinoids have been detected (Mechoulam and Hanus, 2000; Mechoulam et al., 2007). As such Cannabis sativa can be regarded as a natural library of unique compounds. The most abundant phytocannabinoid is the Δ9-tetrahydrocannabinol (delta-9-THC), responsible for the psychotropic effect associated with Cannabis consumption, and then the nonpsychoactive constituent CBD and cannabigerol (CBG) (Mechoulam and Hanus, 2000; Mechoulam et al., 2007; Gugliandolo et al., 2018). Table 1 shows the list of the most abundant nonpsychoactive phytocannabinoids isolated from Cannabis sativa. Phytocannabinoids mimic the effects of eCBs that regulate the transmission of nerve impulses in some synapses of the nerve pathways, causing in particular a reduction in the release of signals between the cells (Piomelli, 2003).

Table 1

Most abundant nonpsychoactive phytocannabinoids isolated from Cannabis sativa: chemical structures and pharmacological actions.

Phytocannabinoids Mechanisms Effects References
CB2 inverse agonist Anti-inflammatory effects Thomas et al., 2005
CB1, CB2 antagonist Antispasmodic effect
FAAH inhibition Reduces FAAH expression in the inflamed intestine Ligresti et al., 2006
TRPA1 agonist Analgesic effects De Petrocellis et al., 2008
TRPM8 antagonist Analgesic effects.
Potential role in prostate carcinoma
TRPV1 agonist Antipsychotic and analgesic effects
Adenosine uptake competitive inhibitor Anti-inflammatory effects Carrier et al., 2006
PPARγ agonist Vasorelaxation and stimulation of fibroblasts into adipocytes O’Sullivan et al., 2009
5HT1A agonist Anti-ischemic and anxiolytic properties Campos and Guimarães, 2008
Resstel et al., 2009
Ca 2+ channel Neuroprotective and antiepileptic properties Drysdale et al., 2006
Ryan et al., 2009
Suppressor of tryptophan degradation Potential role in pain, inflammation and depression Jenny et al., 2009
CB1 antagonist Increases central inhibitory neurotransmission Thomas et al., 2005
Dennis et al., 2008
Ma et al., 2008
CB2 partial agonist Stimulates mesenchymal stem cells Scutt and Williamson, 2007
TRPV1 agonist Potential role in analgesia Ligresti et al., 2006
TRPA1 agonist De Petrocellis et al., 2008
TRPM8 antagonist
TRPA1 partial agonist Potential role in analgesia De Petrocellis et al., 2008
TRPM8 antagonist
TRPA1 partial agonist De Petrocellis et al., 2008
TRPM8 antagonist Potential role in analgesia
TRPV1 agonist Ligresti, A., et al., 2006
COX-2 inhibitor Potential role in inflammation Takeda et al., 2008

Due to its high lipophilicity and its affinity for lipid membranes, delta-9-THC was supposed to bind non-specifically variety of cell membranes modifying their fluidity rather than to activate a specific receptor (Hillard et al., 1985). Later this first hypothesis was completely discarded and was demonstrated that delta-9-THC exerts its effects by combining with a selective receptor (Devane et al., 1988; Howlett et al., 1990; Matsuda et al., 1990). In fact, many authors have demonstrated that delta-9-THC exerts its psychoactive effects acting on CB1 receptors, whereas CDB and CBG, two nonpsychoactive CBs, have low affinity for both CB1 and CB2 receptors and inhibit FAAH, resulting in increased levels of eCBs, which in turn further activate the CB1 receptor (Devane et al., 1988; Howlett et al., 1990; Matsuda et al., 1990; Appendino et al., 2011). Among the nonpsychoactive phytocannabinoids, most of the evidences have focused on CBD, which possesses a high antioxidant and anti-inflammatory activity, together with neuroprotective, anxiolytic and anticonvulsant properties (Pellati et al., 2018).

Mechanisms of CBD Action

After delta-9-THC, CBD is the second most abundant phytocannabinoids and is one of the major nonpsychoactive CB constituents in the plant of Cannabis sativa representing up to 40% of Cannabis extract. Adams and colleagues first isolated the CBD, while Mechoulam and colleagues analyzed its structure and stereochemistry (reviewed in Pertwee, 2006). Therapeutically CBD is already available alone and in formulation with delta-9-THC (Booz, 2011). In particular, a drug containing only CBD (Epidiolex) is used for children affected by epilepsy resistant to other treatments, as well as in combination (1:1 ratio) with delta-9-THC (CBD/delta-9-THC, Sativex/Nabiximols) is currently used to treat the spasticity observed in patients affected by multiple sclerosis (Pertwee, 2008; Devinsky et al., 2016). Compared to delta-9-THC, CBD possess a better safety profile and it is well tolerated when administered at animals and patients even at high doses (up to 1,500 mg/day) (Bergamaschi et al., 2011). In fact, authors demonstrated that CBD did not alter cardiovascular parameters, body temperature, psychomotor, and psychological functions, as well as did not induce catalepsy like delta-9-THC (Bergamaschi et al., 2011). Unlike delta-9-THC, CBD does not target directly the CB receptors and this characteristic may justify its better safety profile compared to delta-9-THC (Pertwee, 2006; Thomas et al., 2007).

Although the pharmacodynamics of CBD is not fully clarified, different evidences have been accumulated showing that CBD seems to act throughout different pathways. To this regard, although CBD shows much lower affinity than delta-9-THC for CB1 and CB2 receptors, it is able to antagonize CB1/CB2 receptor agonists in vitro at reasonably low concentrations (nanomolar range) (Thomas et al., 2007). In particular, it has been shown by in vitro studies that CBD is able to act as CB1/CB2 receptors inverse agonist an action that underlies its antagonism of CP55940 and R-(+)-WIN55212 at the CB1/CB2 receptor (Thomas et al., 2007). It has been hypothesized that the anti-inflammatory actions of CBD might be due to its ability to act as a CB2 receptor inverse agonist (Pertwee, 2006). Besides CB receptors, CBD has been profiled also towards other pharmacological substrates. To this regard, CBD showed also affinity to the peroxisome proliferation-activated receptors (PPARs), which are a family of ligand-inducible transcription factors that belong to the nuclear hormone receptor superfamily. In humans, there are three PPAR isoforms PPARα, PPARβ/δ, and PPARγ that are encoded by separate genes and are differently expressed in organs and tissues (Michalik et al., 2006). CBD seems to activate the transcriptional activity of PPARγ, which play a primary role in the regulation of adipocyte formation, insulin sensitivity and activation of inflammatory response (O’Sullivan, 2007; O’Sullivan and Kendall, 2010; Hind et al., 2016; O’Sullivan, 2016). To this regard, CBD activates PPARγ receptors leading to a lower expression of proinflammatory genes, which were inhibited by PPARγ antagonists (Esposito et al., 2007; Esposito et al., 2011; O’Sullivan, 2016).

Moreover, CBD exerts a more potent antioxidant effects than other antioxidants, such as ascorbate or α-tocopherol, in in vitro study where cortical neurons were treated with toxic concentrations of glutamate (Hampson et al., 1998; Campos et al., 2016).

The neuroprotective effect was present regardless of whether the insult was due to the activation of N-methyl-D-aspartate (NMDA) receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, or kainate receptors and, more interestingly, it was not mediated by CB receptors since the CB antagonist was unaffected (Hampson et al., 1998). The latter result suggests that CBD may be a potent antioxidant without psychotropic side effects, which are mediated by the direct action on CB receptors.

The anti-inflammatory effect of CBD is also mediated by the adenosine A2A (A2A) receptor whose activation dampers the immune system, leading to a reduction of the antigen presentation, immune cell trafficking, immune cell proliferation, production of the proinflammatory cytokine, and cytotoxicity (Magen et al., 2009). In fact, it has been shown that CBD enhances A2A receptor signaling by the inhibition of cellular update of an adenosine transporter leading to anti-inflammatory and antioxidant effects (Carrier et al., 2006). Likewise, CGS-21680, which is an agonist of the A2A receptor, mimics the actions of CBD that were suppressed by an A2A antagonist (i.e. ZM241,385) (Martín-Moreno et al., 2011).

The CBD neuroprotective property seems to be due also to the activation of 5-hydroxytryptamine subtypes 1A (5-HT1A) receptors, which are located in pre- and post-synaptic membranes in several brain regions (Hoyer et al., 1986). Russo and colleagues first demonstrated that CBD is able to activate the 5-HT1A receptors (Russo et al., 2005). Further support to this first observation was given by a recent study where the authors found that the effect of CBD was blocked by WAY-100135, a selective 5-TH1A receptor antagonist (Galaj et al., 2019).

Finally, it has been demonstrated that CBD has a direct effect on mitochondria (da Silva et al., 2018). To this regard, it has been widely accepted that mitochondrial dysfunction can contribute to neurodegeneration due to the overproduction of ROS and iron accumulation (Mills et al., 2010; Serviddio et al., 2011; Cassano et al., 2012; Cassano et al., 2016; Romano et al., 2017). In particular, iron overload induces several mitochondrial alterations, such as increased mitochondrial DNA (mtDNA) deletions and reduction of epigenetic mtDNA modulation, mitochondrial ferritin levels, and succinate dehydrogenase activity, which may altogether alter cellular viability leading to neurodegenerative process (da Silva et al., 2018). Interestingly, all these iron-induced mitochondrial alterations were completely reversed by CBD, which promotes neural cell survival (da Silva et al., 2018). Moreover, doxorubicin, a broad-spectrum chemotherapeutic drug, induces a dose-dependent cardiotoxicity through the dysregulation of various metabolic signaling pathways, including mitochondrial dysfunction (Hao et al., 2015). In particular, doxorubicin reduces the activity of myocardial mitochondrial complexes (I and II) and glutathione peroxidase leading to an increase of ROS generation (Hao et al., 2015). Interestingly, CBD significantly attenuated doxorubicin-induced cardiotoxicity and cardiac dysfunction by improving mitochondrial complex I activity and enhancing mitochondrial biogenesis (Hao et al., 2015).

Since CBD targets multiple substrates, it may be a good candidate as a multimodal drug for the major neurodegenerative disorders, such as PD and AD. Figure 1 shows the effects of CBD in PD and AD.

Effect of cannabidiol (CBD) in Parkinson’s disease and Alzheimer’ disease (AD). CBD antagonizes the action of cannabinoid receptors (CB1, CB2) acting as a reverse agonist and negative allosteric modulator of both receptors. CBD also inhibits fatty acid amide hydrolase (FAAH), resulting in increased levels of endocannabinoids (ECs). ECs activate the anti-oxidant and anti-inflammatory effects that are partially mediated by the actions of the CBD of transient receptor potential cation channel subfamily V member 1 (TRPV1) [1]. CBD binds the peroxisome proliferator-activated receptors (PPARs), antagonizes the action of nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), and reduces the expression of proinflammatory enzymes such as inducible nitric oxide synthases (iNOS), cyclooxygenase-2 (COX-2), and proinflammatory cytokines [2]. Activation of PPARγ by modulating the expression of proinflammatory mediators such as nitric oxide (NO), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6), iNOS, and COX-2 [3]. The CBD downregulates the β- and γ-secretase genes leading to a reduction in amyloid-β (Aβ) production [4]. CBD is able to reduce the oxidative stress (OS) through the attenuation of mitochondrial dysregulation and reactive oxygen species (ROS) generation or by the decrease of the expression of several ROS generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase isoforms [5]. The stimulation of transient receptor potential vanilloid-1 (TRPV1) by CBD can activate phosphoinositide 3-kinases/protein kinase B (PI3K/Akt) signaling, which in turn inhibits glycogen synthase kinase 3 β (GSK-3β) by phosphorylation of Ser9, thus reducing tau phosphorylation [6]. CBD reduces the activity of p-GSK-3β, the active phosphorylated form of GSK3-β, and causes an increase in the Wnt/β-catenin pathway. The activation of this pathway can protect against OS and Aβ neurotoxicity in AD [7].

CBD and PD

PD is a progressive neurodegenerative disorder characterized manly by motor alterations, such as akinesia, bradykinesia, tremors, postural instability, and rigidity. Although the etiology of PD is still largely elusive, its pathophysiology is characterized by loss of midbrain substantia nigra DA neurons and overwhelming evidence indicates that OS is a central factor in PD pathophysiology (Hirsch et al., 1988; Branchi et al., 2010; Aureli et al., 2014). It has been demonstrated in animal model of PD that CBD exerts a neuroprotective effect as antioxidant compound acting through a mechanism that is CB receptor-independent (Fernández-Ruiz et al., 2013). In fact, in 6-hydroxydopamine-lesioned mice CBD was able to significantly reduce the DA depletion and to attenuate the OS increasing the expression of Cu,Zn-superoxide dismutase (SOD), which is an important endogenous mechanism that defences cell against OS (Fernández-Ruiz et al., 2013; Martinez et al., 2015). The latter evidence indicates that CBs having antioxidant CB receptor-independent properties attenuate the neurodegeneration of nigrostriatal dopaminergic fibers occurring in PD (García-Arencibia et al., 2007). This thesis is reinforced by the observation that CBD reduces the neuronal cell death in the striatum occurring after the administration of 3-nitropropionic acid (3NP), an inhibitor of mitochondrial complex II. In particular, the authors demonstrated that 3NP administration causes a reduction of both GABA levels and striatal atrophy of the GABAergic neurons as indicated by a depletion of mRNA levels of proenkephalin (PENK), substance P (SP), and neuronal-specific enolase (NSE). Moreover, the inhibition of mitochondrial complex II induced by 3NP reduces the mRNA expression of superoxide dismutase-1 (SOD-1) and -2 (SOD-2), which are endogenous defences against the OS. Interestingly, after 3NP administration CBD can completely abolish the atrophy of the GABAergic neurons and significantly increase the mRNA levels of SOD-2, as well as attenuate the reduction of mRNA levels of SOD-1 and PENK. Differently, after 3NP administration the administration of arachidonyl-2-chloroethylamide (ACEA) or HU-308, respectively agonist of CB1 and CB2 receptor, did not revert the striatal atrophy of the GABAergic neurons, as well as did not restore the endogenous defences against the OS induced by 3NP (Sagredo et al., 2007). Taken together, these results suggest that CBD exerts a neuroprotective role on the GABAergic neurons that project from the striatum to the substantia nigra and further confirm that its mechanism is CB receptor-independent (Sagredo et al., 2007). Furthermore, in another study authors explored whether CBD was able to attenuate the pathological symptoms of PD modulating the GPR55. In particular, mice were treated for 5 weeks with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTPp), which induced motor function impairment and loss of tyrosine hydroxylase-positive neurons and DA levels in the brain. This chronic mouse model of PD was treated with abnormal-CBD (Abn-CBD), a synthetic CBD isomer and GPR55 agonist. Authors found that the key features of PD induced by MPTPp were prevented by the pharmacological treatment, suggesting that the activation of GPR55 may be a good strategy for the treatment of PD (Celorrio et al., 2017).

CBD and AD

AD is the most common form of dementia affecting elderly people and its pathology is characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFTs) in the brain (Querfurth and LaFerla, 2010).

Although the etiology of AD appears to be linked to a multitude of mechanisms, inflammation seems to play a crucial role in its pathogenesis (Bronzuoli et al., 2018; Scuderi et al., 2018). Expected benefits of current therapies are limited (Sabbagh, 2009; Neugroschl and Sano, 2010), so that there is pressing demand for discovering new treatments able to slow disease progression or prevent its onset.

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In this contest, the anti-inflammatory properties of CBD were evaluated by both in vitro and in vivo studies in an animal model of Aβ-induced neuroinflammation (Iuvone et al., 2004; Esposito et al., 2006; Esposito et al., 2007; Esposito et al., 2011). In particular, authors demonstrated that CBD reduces the tau protein hyperphosphorylation through the inhibition of Wingless-type MMTV integration site family member (Wnt) pathways and significantly attenuates all the markers of the Aβ-induced neuroinflammation, including the glial fibrillary acidic protein (GFAP) and inducible nitric oxide synthase (iNOS) protein expression, nitrite production, and interleukin 1 β (IL-1β) (Iuvone et al., 2004; Esposito et al., 2006; Esposito et al., 2007; Iuvone et al., 2009; Esposito et al., 2011). CBD pre-treatment induces a reduction of ROS production, lipid peroxidation, caspase-3 levels, and DNA fragmentation in PC12 cells stimulated by Aβ, an in vitro model of AD (Iuvone et al., 2004; Bedse et al., 2014; Gallelli et al., 2018).

The beneficial effects of CBD were further confirmed by another study where mice were chronically treated (for 3 weeks) with CBD after been injected intracerebroventricularly with fibrillar Aβ (Martín-Moreno et al., 2011). CBD counteracts the Aβ-induced microglial activation, the production of proinflammatory cytokine tumor necrosis factor α (TNF-α) and ameliorates the memory alterations observed in a spatial memory task (Martín-Moreno et al., 2011).

Moreover, Aβ can gradually accumulate in mitochondria, where it can cause reduction of both activity of the respiratory chain complexes and the rate of oxygen consumption leading to a free radical generation and oxidative damage (Caspersen et al., 2005; Lin and Beal, 2006; Manczak et al., 2006; Cassano et al., 2012). To this regard, CBD is able to counteract mitochondrial alterations by the reduction of ROS production induced by both the Aβ and nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase (NOX) (Hao et al., 2015; Vallée et al., 2017).

It is well know that tau hyperphosphorylation, mostly at serine (Ser) or threonine (Thr) residues, plays a crucial role in the pathogenesis of AD, thereby molecules that reduce phospho-tau aggregates may represent a good candidate for the AD treatment. To this regard, it has been demonstrated that CBD reduces the expression of genes, which encode kinases (GSK-3β, CMK, and MAPK) responsible for aberrant tau phosphorylation, leading to a reduction of tau hyperphosphorylation and subsequent NFT formation (Libro et al., 2016). Likewise, CBD activates the PI3K/Akt signaling through the TRPV1, which is able to inhibit the kinase GSK-3β, thereby decreasing tau phosphorylation (Libro et al., 2016). Finally, CBD downregulates β- and γ-secretase genes leading to a reduction of Aβ production (Libro et al., 2016).

Conclusion

The present review provided evidence that the nonpsychoactive phytocannabinoids CBD could be a potential pharmacological tool for the treatment of neurodegenerative disorders; its excellent safety and tolerability profile in clinical studies renders it a promising therapeutic agent.

The molecular mechanisms associated with CBD’s improvement in PD and AD are likely multifaceted, and although CBD may act on different molecular targets all the beneficial effects are in some extent linked to its antioxidant and anti-inflammatory profile, as observed in in vitro and in vivo studies. Therefore, this review describes evidence to prove the therapeutical efficacy of CBD in patients affected by neurodegenerative disorders and promotes further research in order to better elucidate the molecular pathways involved in the therapeutic potential of CBD.

Author Contributions

All authors have contributed to the writing, design, and preparation of figures. The senior authors TC and GS have carried out coordination of efforts.

Funding

This article was published with a contribution from the University of Foggia.

CBD For Neurodegeneration: How CBD Protects The Brain As We Age

Neurodegeneration is an umbrella term used to describe any progressive loss of neuron function.

CBD helps protect the brain from natural degeneration in four key ways — antioxidant, anti-inflammatory, immune-modulation, and sleep-support.

Article By

Neurodegenerative disorders are conditions involving a loss of neuron function in the brain and spinal cord. [1]

As neurons are lost, brain function begins to suffer. This produces problems with memory, concentration, attention, muscle coordination, and language. There are many causes of neurodegeneration, but the main risk factor is age.

Can CBD offer support for chronic neurodegenerative disorders?

Learn how CBD is used to support neurodegenerative disorders, and what the research says about its efficacy.

MEDICALLY REVIEWED BY

Carlos G. Aguirre, M.D., Pediatric Neurologist

Updated on October 20, 2021

Table of Contents
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The Benefits of CBD Oil For Brain Health

Neurodegenerative disorders are characterized by a gradual loss of neurons in particular regions of the nervous system. This cell loss causes a decline in cognitive ability and accounts for most of the symptoms experienced with this condition.

How CBD Protects the Brain & Neurons

  • Reducing brain inflammation
  • Preventing T-cell migration across the blood-brain barrier (prevents autoimmunity)
  • Antioxidant support (protects the DNA from damage)
  • Alleviates anxiety
  • May relieve depression
  • May improve muscle control & alleviate muscle tremors
  • My promote recovery of damaged neurons

CBD For Degenerative Brain Disorders

Cannabis may support neurodegenerative disorders including:

  • Alzheimer’s disease
  • Parkinson’s disease
  • Multiple sclerosis (MS)
  • Huntington’s Disease
  • Prion disease (minor improvement)
  • Lou Gehrig’s Disease (ALS)
  • Spinocerebellar Ataxia (SCA)
  • Spinal Muscular Atrophy (SMA)

1. Alzheimer’s Disease

Alzheimer’s disease is the most common form of neurodegeneration. It involves the buildup of toxic metabolites (TAU proteins or beta-amyloid plaque) around the neurons. Eventually, this results in neuron death and gradual cognitive debility. Alzheimer’s disease, like most other neurodegenerative disorders, is associated with excessive neuroinflammation [11, 12].

CBD offers benefits to this condition primarily through its anti-inflammatory effects.

2. Parkinson’s Disease

Parkinson’s disease is a neurodegenerative disorder affecting the basal ganglia where dopamine is manufactured. The result is a gradual loss of dopamine in the brain, causing muscle tremors, mood changes, and a gradual loss of cognitive function.

Like Alzheimer’s disease, Parkinson’s is considered to rely on excessive inflammatory processes in the brain [11, 12].

CBD, therefore, offers relief from this condition through its anti-inflammatory and neuroprotective actions.

3. Multiple Sclerosis (MS)

Multiple sclerosis is an autoimmune-driven neurodegenerative disorder. Widespread neuroinflammation causes immune cells to attack the myelin sheath on the nerve cells, causing a gradual loss of neuron function.

CBD is very beneficial to this condition through its immunomodulatory and anti-inflammatory effects — both of which are primary factors involved with the progression of MS [15].

Additionally, CBD may provide direct benefits to some of the most common side-effects of MS, including muscle spasticity [16] and loss of bladder control [17].

4. Huntington’s Disease

Huntington’s disease is a neurodegenerative disorder with similar characteristics to Alzheimer’s disease. It’s a genetic disorder involving dysfunction in the gene encoding for a protein called huntingtin. People with Huntington’s disease manufacture huntingtin proteins that are too long. They fracture into smaller pieces and become tangled around the neurons — leading to their gradual death. As Huntington builds up, it causes widespread inflammation throughout the brain and loss of cognitive function over time.

There is no cure for Huntington’s disease, but CBD has been shown to offer significant benefits — slowing progression and alleviating many of the most common symptoms [14].

5. Creutzfeldt-Jakob Disease (CJD) and Other Prion Diseases

Prion diseases such as CJD aren’t common but bring devastating side effects as the disease progresses. It involves a misfolded, protease-resistant protein (PrPres) entering the brain and replicating. Being resistant to protease means that the brain cells cannot break down and remove this protein from the brain. Therefore, as these proteins replicate and build up in the brain, they begin to interfere with healthy brain function. Currently, there’s no cure for prion diseases.

Although inflammation is a primary factor involved with prion disease progression, CBD has only been shown to have minor benefits on the condition by resisting the buildup of PrPres [13].

6. Amyotrophic Lateral Sclerosis (ALS)

Lou Gehrig’s Disease (ALS) is a neurodegenerative disease causing gradual — and ultimately fatal — disruption in signals controlling voluntary muscles throughout the body.

There is no cure for ALS, but CBD has been shown to offer significant benefits.

7. Spinocerebellar Ataxia (SCA)

SCA is a progressive, inherited neurodegenerative disease affecting the cerebellum — the part of the brain associated with coordination and muscle movement. There is no cure for the disease, and it’s often fatal.

Treatment is focused on alleviating symptoms such as muscle tremors, depression, and insomnia — all of which CBD is well-known to help.

8. Spinal Muscular Atrophy (SMA)

SMA is a rare neurodegenerative disorder affecting the motor neurons controlling the muscles. Eventually, the disease causes loss of muscle function and muscle wasting. Like many other neurodegenerative disorders, the condition is caused by a dysfunction in producing a particular protein in the brain. Over time, these dysfunctional proteins build-up, resulting in the death of the neurons. There is no cure for this condition.

It’s unclear whether CBD is beneficial to those with SMA. The majority of side-effects of this condition involve muscle weakness — something CBD isn’t thought to improve.

How to Use CBD Oil For Brain Health

Tips for Getting the Most Out of Using CBD for Neurodegenerative Disorders:

  1. Use a full-spectrum extract (THC also offers benefits for these conditions)
  2. Incorporate improvements of diet and lifestyle choices at the same time as CBD supplementation
  3. If there is an environmental cause (such as heavy metal exposure), make sure this is removed immediately
  4. Be consistent with dosing — it can take up to three months before any changes are experienced when it comes to neurodegenerative disorders

What’s Are The Best CBD Products For Brain Health?

Neurodegenerative disorders are a combination of many different neurological and systemic issues working together to produce a gradual loss of neurons.

Therefore, treating these conditions isn’t as straightforward as just addressing one of these issues at a time — it relies on addressing several of them at the same time.

CBD oils and other cannabis products should, therefore, be combined with other treatments and lifestyle and dietary changes for best results.

So, when searching for the best oils for neurodegenerative disorders, there are two things to consider:

  1. Has the CBD product been proven to be free from contaminants such as heavy metals or pesticides?
  2. Does the potency of the CBD product match the recommended dose? In the case of neurodegenerative disorders, this usually means using a high-potency extract.

It’s also useful to opt for a full-spectrum CBD extract rather than an isolate if you want to leverage the neuroprotective benefits of some of the other cannabinoids. However, if this isn’t possible, or you’ve decided you like a company selling CBD isolates, that’s okay. It will still work but just isn’t the best CBD oil for the job.

What Dose Of CBD Should I Use For Neurodegenerative Disease?

Most of the research involving CBD and other cannabinoids for neurodegenerative disorders involve very high doses — usually in the realm of around 500 mg per day.

Although it may not be totally necessary to use a dose this high, it does suggest that the heavy end of the dosage range is the most beneficial.

Use our CBD oil dosage calculator below to find the best dose for you based on your weight.

Remember to start low and build up over time. Everyone reacts differently to CBD, so it’s therefore important that you take a conservative approach to find the right dose to avoid any negative side effects.

Recommended strength for neurodegenerative disorders: medium to high strength

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How Long Will It Take To Notice Improvement?

Neurodegenerative disorders are long-term medical conditions — and most of them have no cure. CBD can be used to slow the progression of the disease and alleviate common side effects but isn’t going to cure the condition.

Therefore, it’s helpful to track the progress of the disease over time to identify whether the CBD is working or if the dose needs to be increased.

You can do this by taking detailed notes about your symptoms. Then, you can go back and see if there have been any improvements over time. Additionally, in the case of progressive neurodegenerative disorders, you can track the rate of progression of the disease.

What Is Neurodegenerative Disease?

Neurodegeneration is an umbrella term for a series of unrelated medical conditions that result in a loss of neuron function.

The primary cause for this condition is dementia, including Alzheimer’s disease — accounting for up to 70% of cases around the world, according to JPND Research.

These disorders are generally progressive, worsening in severity and rate of degeneration over time. This can take any time from a few months to a few decades. However, the process of neurodegeneration usually begins long before symptoms start to appear.

Evidence in recent years has pointed the finger at inflammation in the brain as one of the primary drivers of neurodegeneration [8]. The problem with this is that it’s also necessary for resisting neurological damage — prompting researchers to regard neuroinflammation as the “double-edged sword” of neurodegeneration.

When something causes damage to the neurons in the brain — for which there are too many potential causes to count — local immune cells start the inflammatory process.

In the early stages, this is beneficial — even necessary — for eliminating toxic materials. This is because inflammation speeds the recovery of the neurons by boosting blood flow to the area and bringing in defensive immune cells to remove any infectious materials.

The problem is that, in many cases, this inflammation goes out of control, causing a cascade of devastating, long-term inflammation in the brain. Excessive inflammation causes the microglia to release toxic substances into the brain, ultimately leading to the death of the neurons. These microglia are tasked with keeping the neurons safe [9, 10].

The whole process goes from a typical inflammatory response to a devastating, self-perpetuating process of degeneration and loss of neurons.

What Causes Degenerative Brain Disease?

When to Avoid Using CBD or Cannabis-Related Products

Even though CBD is very safe, there are some instances when you must first consult with an experienced medical professional before taking it:

  • If you have psychosis
  • If you have bipolar disorder (caution advised)
  • Whenever taking antipsychotics or certain antidepressants

Key Takeaways: How Does CBD Support Brain Health?

Researchers are still disputing exactly how CBD and other cannabinoids are effective for slowing the progression of neurodegenerative disorders.

The interaction between CBD and the nervous system is complex — involving multiple separate processes going on at the same time.

However, the general idea is that CBD supports the homeostasis of the nervous system. This means it supports the balance of various factors involved with neurological function, including inflammation, pain transmission, nerve excitability, and immune function.

Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?

Professor Javier Fernández-Ruiz PhD, Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad Complutense, Ciudad Universitaria s/n, 28040-Madrid, Spain. Tel.: +34 91 394 1450, Fax: +34 91 394 1691, E-mail: [email protected]

Abstract

Cannabidiol (CBD) is a phytocannabinoid with therapeutic properties for numerous disorders exerted through molecular mechanisms that are yet to be completely identified. CBD acts in some experimental models as an anti-inflammatory, anticonvulsant, anti-oxidant, anti-emetic, anxiolytic and antipsychotic agent, and is therefore a potential medicine for the treatment of neuroinflammation, epilepsy, oxidative injury, vomiting and nausea, anxiety and schizophrenia, respectively. The neuroprotective potential of CBD, based on the combination of its anti-inflammatory and anti-oxidant properties, is of particular interest and is presently under intense preclinical research in numerous neurodegenerative disorders. In fact, CBD combined with Δ 9 -tetrahydrocannabinol is already under clinical evaluation in patients with Huntington’s disease to determine its potential as a disease-modifying therapy. The neuroprotective properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like Δ 9 -tetrahydrocannabinol, i.e. CB1 and CB2 receptors, as CBD has negligible activity at these cannabinoid receptors, although certain activity at the CB2 receptor has been documented in specific pathological conditions (i.e. damage of immature brain). Within the endocannabinoid system, CBD has been shown to have an inhibitory effect on the inactivation of endocannabinoids (i.e. inhibition of FAAH enzyme), thereby enhancing the action of these endogenous molecules on cannabinoid receptors, which is also noted in certain pathological conditions. CBD acts not only through the endocannabinoid system, but also causes direct or indirect activation of metabotropic receptors for serotonin or adenosine, and can target nuclear receptors of the PPAR family and also ion channels.

Keywords: cannabidiol, cannabinoid signalling system, Huntington’s disease, neonatal ischaemia, neuroprotection, Parkinson’s disease

Overview on the therapeutic properties of CBD

Cannabidiol (CBD) is one of the key cannabinoid constituents in the plant Cannabis sativa in which it may represent up to 40% of cannabis extracts [1]. However, contrarily to Δ 9 -tetrahydrocannabinol (Δ 9 -THC), the major psychoactive plant-derived cannabinoid, which combines therapeutic properties with some important adverse effects, CBD is not psychoactive (it does not activate CB1 receptors [2]), it is well-tolerated and exhibits a broad spectrum of therapeutic properties [3]. Even, combined with Δ 9 -THC in the cannabis-based medicine Sativex® (GW Pharmaceuticals Ltd, Kent, UK), CBD is able to enhance the beneficial properties of Δ 9 -THC while reducing its negative effects [4]. Based on this relatively low toxicity, CBD has been studied, even at the clinical level, alone or combined with other phytocannabinoids, to determine its therapeutic efficacy in different central nervous system (CNS) and peripheral disorders [3]. In the CNS, CBD has been reported to have anti-inflammatory properties, thus being useful for neuroinflammatory disorders [5], including multiple sclerosis for which CBD combined with Δ 9 -THC (Sativex®) has been recently licenced as a symptom-relieving agent for the treatment of spasticity and pain [6]. Based on its anticonvulsant properties, CBD has been proposed for the treatment of epilepsy [7–9], and also for the treatment of sleep disorders based on its capability to induce sleep [10]. CBD is also anti-emetic, as are most of the cannabinoid agonists, but its effects are independent of CB1 receptors and are possibly related to its capability to modulate serotonin transmission (see [11] and below). CBD has antitumoural properties that explain its potential against various types of cancer [12, 13]. Moreover, CBD has recently shown an interesting profile for psychiatric disorders, for example, it may serve as an antipsychotic and be a promising compound for the treatment of schizophrenia [14–17], but it also has potential as an anxiolytic [18] and antidepressant [19], thus being also effective for other psychiatric disorders. Lastly, based on the combination of its anti-inflammatory and anti-oxidant properties, CBD has been demonstrated to have an interesting neuroprotective profile as indicated by results obtained through intense preclinical research into numerous neurodegenerative disorders, in particular the three disorders addressed in this review, neonatal ischaemia (CBD alone) [20], Huntington’s disease (HD) (CBD combined with Δ 9 -THC as in Sativex®) [21–23] or Parkinson’s disease (PD) (CBD probably combined with the phytocannabinoid Δ 9 -tetrahydrocannabivarin, Δ 9 -THCV) [24, 25], work that has recently progressed to the clinical area in some specific cases [26]. The neuroprotective potential of CBD for the management of certain other neurodegenerative disorders, e.g. Alzheimer’s disease, stroke and multiple sclerosis, has also been investigated in studies that have yielded some positive results [27–33]. However, these data will be considered here only very briefly.

Overview on the mechanisms of action of CBD

The therapeutic properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like Δ 9 -THC, i.e. CB1 and CB2 receptors. CBD has in general negligible activity at these cannabinoid receptors [2], so it has been generally assumed that most of its pharmacological effects are not a priori pharmacodynamic in nature and related to the activation of specific signalling pathways, but related to its innate chemical properties, in particular with the presence of two hydroxyl groups (see below) that enables CBD to have an important anti-oxidant action [2]. However, in certain pathological conditions (i.e. damage of immature brain), CBD has shown some activity at the CB2 receptor exerted directly ([20], see also Table 1 ) or indirectly through an inhibitory effect on the mechanisms of inactivation (i.e. transporter, FAAH enzyme) of endocannabinoids [34, 35], enhancing the action of these endogenous molecules at the CB2 receptor but also at the CB1 and at other receptors for endocannabinoids, i.e. TRPV1 [35] and TRPV2 [36] receptors.

Table 1

A selection of receptors, ion channels, enzymes and cellular uptake processes that CBD has been reported to activate, antagonize or inhibit in vitro

CBD concentration Pharmacological target and effect Reference
Receptors and channels
CB1 receptor (−) [40]
CB2 receptor (−) [40]
GPR55 (−) [41] †
5-HT3A ligand-gated channel (−) * [42]
TRPM8 cation channel (−) [36]
TRPA1 cation channel (+) [36]
1–10 µ m PPARγ nuclear receptor (+) [41] †
CaV3 T-type Ca 2+ channels (−) [43]
TRPV1 cation channel (+) [36]
TRPV2 cation channel (+) [36]
>10 µ m 5-HT1A receptor (+) [44] †
µ and δ opioid receptors (−) * [44] †
α1 and α1β glycine ligand-gated channels (+) * [45]
Enzymes
CYP1A1 (−) [46]
1–10 µ m CYP1A2 & CYP1B1 (−) [46]
CYP2B6 (−) [47]
CYP2D6 (−) [48]
CYP3A5 (−) [49]
Mg 2+ -ATPase (−) [44] †
Arylalkylamine N-acetyltransferase (−) [50]
Indoleamine-2,3-dioxygenase (−) [51]
15-lipoxygenase (−) [52]
Phospholipase A2 (+) [44] †
Glutathione peroxidase (+) [13, 53]
Glutathione reductase (+) [13, 53]
>10 µ m CYP2A6 (−) [47]
CYP3A4 and CYP3A7 (−) [49]
Fatty acid amide hydrolase (−) [36]
5-lipoxygenase (−) [52]
Superoxide dismutase (−) [53]
Catalase (−) [53]
NAD(P)H-quinone reductase (−) [53]
Progesterone 17α-hydroxylase (−) [54, 55]
Testosterone 6β-hydroxylase (−) [54]
Testosterone 16α-hydroxylase (−) [54]
Transporters and cellular uptake
Adenosine uptake by cultured microglia and macrophages (−) [44] †
Calcium uptake by synaptosomes (−) [44] †
1–10 µ m NE, DA, 5-HT and GABA uptake by synaptosomes (−) [44] †
Anandamide and palmitoylethanolamide cellular uptake (−) [36]
P-glycoprotein (drug efflux transporter) (−) [56]
>10 µ m Choline uptake by rat hippocampal homogenates (−) [44] †

5-HT, 5-hydroxytryptamine; DA, dopamine; GABA, γ-aminobutyric acid; NE, norepinephrine.

However, the anti-oxidant profile of CBD, as well as the few effects it exerts through targets within the endocannabinoid system in certain pathophysiological conditions, cannot completely explain all of the many pharmacological effects of CBD, prompting a need to seek out possible targets for this phytocannabinoid outside the endocannabinoid system. There is, indeed, already evidence that CBD can affect serotonin receptors (i.e. 5HT1A) [18, 19, 28], adenosine uptake [37], nuclear receptors of the PPAR family (i.e. PPAR-γ) [38, 39] and many other pharmacological targets (see Table 1 including references [40–56]). In part, this information derives from numerous studies directed at identifying the pharmacological actions that CBD produces in vitro. This phytocannabinoid has been found to display a wide range of actions in vitro some at concentrations in the submicromolar range, and others at concentrations between 1 and 10 µ m or above 10 µ m . Its pharmacological targets include a number of receptors, ion channels, enzymes and cellular uptake processes (summarized in Table 1 ). There is evidence too that CBD can inhibit delayed rectifier K + and L-type Ca 2+ currents and evoked human neutrophil migration, activate basal microglial cell migration, and increase membrane fluidity, all at submicromolar concentrations, and that at concentrations between 1 and 10 µ m it can inhibit the proliferation of human keratinocytes and of certain cancer cells (reviewed in [44]). At concentrations between 1 and 10 µ m , CBD has also been reported to be neuroprotective, to reduce signs of oxidative stress, to modulate cytokine release and to increase calcium release from neuronal and glial intracellular stores (reviewed in [44]), and at 15 µM to induce mRNA expression of several phosphatases in prostate and colon cancer cells [57].

As will be discussed in the following section, the question of which of these many actions contributes most towards the beneficial effects that CBD displays in vivo in animal models of neurodegenerative disorders such as PD and HD remains to be fully investigated. Also still to be explored is the possibility that CBD may ameliorate signs and symptoms of such disorders and others (i.e. psychiatric disorders), at least in part, by potentiating activation of 5-HT1A receptors by endogenously released serotonin. Thus, although CBD only activates the 5-HT1A receptor at concentrations above 10 µ m ( Table 1 ), it can, at the much lower concentration of 100 n m enhance the ability of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin to stimulate [ 35 S]-GTPγS binding to rat brainstem membranes [58]. Furthermore, there is evidence first, that activation of 5-HT1A receptors can ameliorate specific symptoms in PD [59, 60] and second, that beneficial effects displayed by CBD in vivo in animal models of ischaemic injury [27, 28], hepatic encephalopathy [61], anxiety, stress and panic [18, 62–64], depression [19], pain [65] and nausea and vomiting [66] are all mediated by increased activation of the 5-HT1A receptor. Importantly, the dose–response curve of CBD for the production of its effects in several of these models has been found to be bell-shaped [19, 28, 62, 65, 67, 68]. This is a significant observation since it strengthens the hypothesis that CBD can act in vivo to potentiate 5-HT-induced activation of 5-HT1A receptors. Thus, the concentration–response curve of CBD for its enhancement of 8-hydroxy-2-(di-n-propylamino)tetralin-induced stimulation of [ 35 S]-GTPγS binding to rat brainstem membranes is also bell-shaped [58].

CBD as a neuroprotective agent

In contrast to the neuroprotective properties of cannabinoid receptor agonists [69, 70], those of CBD do not seem to be attributable to the control of excitotoxicity via the activation of CB1 receptors and/or to the control of microglial toxicity via the activation of CB2 receptors. Thus, except in preclinical models of neonatal ischaemia (see below and [20]), CBD has been found not to display any signs of CB1 or CB2 receptor activation, and yet is no less active than cannabinoid receptor agonists against the brain damage produced by different types of cytotoxic insults ([71–75], reviewed in [76]). What then are the cannabinoid receptor-independent mechanisms by which CBD acts as a neuroprotective agent? Finding the correct answer to this question is not easy, although data obtained in numerous investigations into different pathological conditions associated with brain damage indicate that CBD does normalize glutamate homeostasis [71, 72], reduce oxidative stress [73, 77] and attenuate glial activation and the occurrence of local inflammatory events [74, 78]. Furthermore, a recent study by Juknat et al. [79] has strongly demonstrated the existence of notable differences in the genes that were altered by CBD (not active at CB1 or CB2 receptors) and those altered by Δ 9 -THC (active at both these receptors) in inflammatory conditions in an in vitro model. These authors found a greater influence of CBD on genes controlled by nuclear factors known to be involved in the regulation of stress responses (including oxidative stress) and inflammation [79]. This agrees with the idea that there may be two key processes underlying the neuroprotective effects of CBD. The first and the most classic mechanism is the capability of CBD to restore the normal balance between oxidative events and anti-oxidant endogenous mechanisms [69] that is frequently disrupted in neurodegenerative disorders, thereby enhancing neuronal survival. As has been mentioned above [73, 77], this capability seems to be inherent to CBD and structurally-similar compounds, i.e. Δ 9 -THC, cannabinol, nabilone, levonantradol and dexanabinol, as it would depend on the innate anti-oxidant properties of these compounds and be cannabinoid receptor-independent. Alternatively, or in addition, the anti-oxidant effect of CBD may involve intracellular mechanisms that enhance the ability of endogenous anti-oxidant enzymes to control oxidative stress, in particular the signaling triggered by the transcription factor nuclear factor-erythroid 2-related Factor 2 (nrf-2), as has been found in the case of other classic anti-oxidants. According to this idea, CBD may bind to an intracellular target capable of regulating this transcription factor which plays a major role in the control of anti-oxidant-response elements located in genes encoding for different anti-oxidant enzymes of the so-called phase II-anti-oxidant response (see proposed mechanism in Figure 1 ). This possibility is presently under investigation (reviewed in [69]).

Mechanisms proposed for the neuroprotective effects exerted by CBD in neurodegenerative disorders.

The second key mechanism for CBD as a neuroprotective compound involves its anti-inflammatory activity that is exerted by mechanisms other than the activation of CB2 receptors, the canonic pathway for the anti-inflammatory effects of most of cannabinoid agonists [70]. Anti-inflammatory effects of CBD have been related to the control of microglial cell migration [80] and the toxicity exerted by these cells, i.e. production of pro-inflammatory mediators [81], similarly with the case of cannabinoid compounds targeting the CB2 receptor [70]. However, a key element in this CBD effect is the inhibitory control of NFκB signalling activity and the control of those genes regulated by this transcription factor (i.e. iNOS) [31, 81]. This inhibitory control of NFκB signalling may be exerted by reducing the phosphorylation of specific kinases (i.e. p38 MAP kinase) involved in the control of this transcription factor and by preventing its translocation to the nucleus to induce the expression of pro-inflammatory genes [31]. However, it has been recently proposed that CBD may bind the nuclear receptors of the PPAR family, in particular the PPAR-γ[38, 39] ( Table 1 ) and it is well known that these receptors antagonize the action of NFκB, reducing the expression of pro-inflammatory enzymes (i.e. iNOS, COX-2), pro-inflammatory cytokines and metalloproteases, effects that are elicited by different cannabinoids including CBD (reviewed in [9, 39]). Therefore, it could well be that CBD may produce its anti-inflammatory effects by the activation of these nuclear receptors and the regulation of their downstream signals although various aspects of this mechanism are pending further research and confirmation (see proposed mechanism in Figure 1 ).

Other mechanisms proposed for the neuroprotective effects of CBD include: (i) the contribution of 5HT1A receptors, e.g. in stroke [27, 28], (ii) the inhibition of adenosine uptake [37], e.g. in neonatal ischaemia ([20], see below) and (iii) specific signalling pathways (e.g. WNT/β-catenin signaling) that play a role in β-amyloid-induced GSK-3β activation and tau hyperphosphorylation in Alzheimer’s disease [82].

CBD in specific neurodegenerative disorders: from basic to clinical studies

Although the neuroprotective properties of CBD have been already examined in numerous acute or chronic neurodegenerative disorders, we will address here only three disorders, i.e. neonatal ischaemia, HD and PD, in which a clinical evaluation of CBD, as monotherapy or in combination with other phytocannabinoids, is already in progress or may be developed soon. CBD has demonstrated significant effects in preclinical models of these three disorders, but, in some cases, its combination with other phytocannabinoids (i.e. Δ 9 -THC for HD, Δ 9 -THCV for PD) revealed some interesting synergies that may be extremely useful at the clinical level.

CBD and neonatal ischaemia

Brain damage by hypoxia-ischaemia (HI) affects 0.3% subjects over 65 years old in developed countries leading to more than 150 000 deaths per year in the USA (for review see [83]). Although less prevalent, newborn hypoxic-ischaemic brain damage (NHIBD) is of great importance too. Approximately 0.1–0.2% live term births experience perinatal asphyxia with one third of them developing a severe neurological syndrome. About 25% of severe NHIBD leads to lasting sequelae and about 20% to death. Energy failure during ischaemia provokes the dysfunction of ionic pumps in neurons, leading to accumulation of ions and excitotoxic substances such as glutamate. The consequent increase in intracellular calcium content aggravates the neuron dysfunction and activates different enzymes, starting different processes of immediate and programmed cell death. During post ischaemic reperfusion, inflammation and oxidative stress aggravate and amplify such responses, increasing and spreading neuron and glial cell damage. Excitotoxicity, inflammation and oxidative stress play, therefore, a particularly relevant role in HI-induced brain cell death in newborns [83].

Unfortunately, the therapeutic outcome in NHIBD is still very limited and there is a strong need for novel strategies. We have solid evidence that CBD may be a good candidate to be tested in NHIBD at the clinical level. Using forebrain slices from newborn mice subjected to glucose-oxygen deprivation, a well-known in vitro model of NHIBD, we have already reported that CBD is able to reduce necrotic and apoptotic damage [20]. This neuroprotective effect is related to the modulation of excitotoxicity, oxidative stress and inflammation, as CBD normalizes the release of glutamate and cytokines as well as the induction of iNOS and COX-2 [20]. Surprisingly, we found that co-incubation of CBD with the CB2 receptor antagonist AM-630 abolished all these protective effects, suggesting that CB2 receptors are somehow involved in neuroprotective effects of CBD in immature brain [20]. In addition, adenosine receptors, in particular A2A receptors, seem to be also involved in these neuroprotective effects of CBD in the immature brain as revealed by the fact that the effect of CBD in this model was abolished by co-incubation with the A2A receptor antagonist > SCH58261 [20]. CBD has been tested further in an in vivo model of NHIBD in newborn pigs, which closely resembles the actual human condition. In this model, the administration of CBD after the HI insult also reduces immediate brain damage by modulating cerebral haemodynamic impairment and brain metabolic derangement, and preventing the appearance of brain oedema and seizures. These neuroprotective effects are not only free from side effects but also associated with some beneficial cardiac, haemodynamic and ventilatory effects [84]. These protective effects restore neurobehavioural performance in the following 72 h post HI [85].

CBD and Huntington’s disease

HD is an inherited neurodegenerative disorder caused by a mutation in the gene encoding the protein huntingtin. The mutation consists of a CAG triplet repeat expansion translated into an abnormal polyglutamine tract in the amino-terminal portion of huntingtin, which due to a gain of function becomes toxic for specific striatal and cortical neuronal subpopulations, although a loss of function in mutant huntingtin has been also related to HD pathogenesis (see [86] for review). Major symptoms include hyperkinesia (chorea) and cognitive deficits (see [87] for review). At present, there is no specific pharmacotherapy to alleviate motor and cognitive symptoms and/or to arrest/delay disease progression in HD. Thus, even though a few compounds have produced encouraging effects in preclinical studies (i.e. minocycline, coenzyme Q10, unsaturated fatty acids, inhibitors of histone deacetylases) none of the findings obtained in these studies have yet led on to the development of an effective medicine [88]. Importantly, therefore, following on from an extensive preclinical evaluation using different experimental models of HD, clinical tests are now being performed with cannabinoids, and this includes the use of CBD combined with Δ 9 -THC [26]. To get here, CBD was first studied in rats lesioned with 3-nitropropionic acid, a mitochondrial toxin that replicates the complex II deficiency characteristic of HD patients and that provokes striatal injury by mechanisms that mainly involve the Ca ++ -regulated protein calpain and generation of ROS. Neuroprotective effects in this experimental model were found with CBD alone [21] or combined with Δ 9 -THC as in Sativex®[22], and in both cases, these effects were not blocked by selective antagonists of either CB1 or CB2 receptors, thus supporting the idea that these effects are caused by the anti-oxidant and cannabinoid receptor-independent properties of these phytocannabinoids. It is possible, however, that this anti-oxidant/neuroprotective effect of phytocannabinoids involves the activation of signalling pathways implicated in the control of redox balance (i.e. nrf-2/ARE), as mentioned before. CBD has also been studied in rats lesioned with malonate, a model of striatal atrophy that involves mainly glial activation, inflammatory events and activation of apoptotic machinery. CBD alone did not provide protection in this model as only CB2 receptor agonists were effective [89], but the combination of CBD with Δ 9 -THC used in Sativex® was highly effective in this model, by preserving striatal neurons, and this protective effect involved both CB1 and CB2 receptors [23]. It is interesting to note that Δ 9 -THC alone produced biphasic effects in this model whereas CB1 receptor blockade aggravated the striatal damage [90]. We are presently studying the efficacy of this phytocannabinoid combination in a transgenic murine model of HD, i.e. R6/2 mice, in which the activation of both CB1 and CB2 receptors has already been found to induce beneficial effects [91, 92]. This solid preclinical evidence has provided substantial support for the evaluation of Sativex®, or equivalent cannabinoid-based medicines, as a new disease-modifying therapy in HD patients. Previous clinical studies had already used CBD, but they concentrated on symptom relief (i.e. chorea) rather than on disease progression and they did not show any significant improvement [93, 94]. We are presently engaged in a novel phase II-clinical trial with Sativex® as a disease-modifying agent in presymptomatic and early symptomatic patients [26], the outcome of which will be known soon.

CBD and Parkinson’s disease

PD is also a progressive neurodegenerative disorder whose aetiology has been, however, associated with environmental insults, genetic susceptibility or interactions between both causes [95]. The major clinical symptoms in PD are tremor, bradykinesia, postural instability and rigidity, symptoms that result from the severe dopaminergic denervation of the striatum caused by the progressive death of dopaminergic neurons of the substantia nigra pars compacta[96]. CBD has also been found to be highly effective as a neuroprotective compound in experimental models of parkinsonism, i.e. 6-hydroxydopamine-lesioned rats, by acting through anti-oxidant mechanisms that seem to be independent of CB1 or CB2 receptors [24, 25, 97]. This observation is particularly important in the case of PD due to the relevance of oxidative injury to this disease, and because the hypokinetic profile of cannabinoids that activate CB1 receptors represents a disadvantage for this disease because such compounds can acutely enhance rather than reduce motor disability, as a few clinical data have already revealed (reviewed in [98]). Therefore, major efforts are being directed at finding cannabinoid molecules that may provide neuroprotection through their anti-oxidant properties and that may also activate CB2 receptors, but not CB1 receptors, or that may even block CB1 receptors, actions which may provide additional benefits, for example by relieving symptoms such as bradykinesia. One interesting example of a compound with this profile is the phytocannabinoid Δ 9 -THCV, which is presently under investigation in preclinical models of PD [25]. Thus, there could well be clinical advantages to administering Δ 9 -THCV together with CBD as this might induce symptomatic relief (due to the blockade of CB1 by Δ 9 -THCV) and neuroprotection (due to the anti-oxidant and anti-inflammatory properties of both CBD and Δ 9 -THCV). The combination of CBD with Δ 9 -THCV (rather than with Δ 9 -THC) would merit investigation in parkinsonian patients (reviewed in [9, 99]), as previous data obtained in clinical studies have indicated that CBD was effective in the relief of some PD-related symptoms such as dystonia, although not in others like tremor [100], but its combination with Δ 9 -THC, which can activate CB1 receptors, failed to improve parkinsoniam symptoms or to attenuate levodopa-induced dyskinesias [101].

Concluding remarks and futures perspectives

The experimental evidence presented in this review supports the idea that, from a pharmaceutical point of view, CBD is an unusually interesting molecule. As presented above, its actions are channeled through several biochemical mechanisms and yet it causes essentially no undesirable side effects and its toxicity is negligible [2]. It has shown valuable activities in numerous pharmaceutically important areas: (i) it is a potent anti-oxidant [73], which may partly explain its neuroprotective effects in PD [24, 25], and possibly in cerebral ischaemia-reperfusion (reviewed in [83]), (ii) it has been evaluated in human epileptic patients with very positive results [7–9], (iii) it has shown activity in mice with several autoimmune diseases, i.e. type-1 diabetes [102] and rheumatoid arthritis [103], (iv) it lowers the effects of myocardial ischaemic-reperfusion injury in mice [104], (v) it reduces microglial activation in mice and hence may slow the progression of Alzheimer’s disease [78], (vi) it protects against hepatic ischaemia/reperfusion injury in animals [105] and has shown considerable activity in an animal model of hepatic encephalopathy [106], (vii) it even lowers anxiety (in humans) [107] and (viii) it is already in use, together with Δ 9 -THC, in a buccal spray (Sativex®) to lower symptoms of multiple sclerosis [6]. The presence of CBD in Sativex® enhances the positive effects of Δ 9 -THC whilst reducing its adverse effects, in concordance with previous data that indicated that CBD alters some of the effects of Δ 9 -THC, i.e. it lowers the acute memory-impairing effects and anxiety produced by Δ 9 -THC [108]. In addition, cannabis with high CBD content presumably leads to fewer psychotic experiences than cannabis with a highest proportion of Δ 9 -THC [17].

It is possible that CBD has not become a licensed medicine (except in Sativex®) because of patenting problems. However, commercial issues apart, CBD has tremendous potential as a new medicine. Thus, because the mechanisms that underlie its anti-inflammatory effects are different from those of prescribed drugs, it could well prove to be of considerable benefit to a large number of patients, who for various reasons are not sufficiently helped by existing drugs. In type 1-diabetes, we have shown that in mice CBD very significantly lowers the number of insulin-producing cells that are affected even after the disease has advanced [102]. Its neuroprotective effects are extremely valuable as no drugs exist that have similar properties. Surprisingly very few CBD derivatives have been evaluated and compared with CBD. At least one of them, CBD-dimethylheptyl-7-oic acid, is more potent than CBD as an anti-inflammatory agent [109]. Aren’t we missing a valuable new pathway to a family of very promising new therapeutic agents?

Acknowledgments

The experimental work carried out by our group and that has been mentioned in this review article, has been supported during the last years by grants from CIBERNED (CB06/05/0089), MICINN (SAF2009-11847), CAM (S2011/BMD-2308) and GW Pharmaceuticals Ltd. The authors are indebted to all colleagues who contributed in this experimental work and to Yolanda García-Movellán for administrative support.

Competing Interests

JFR, OS and CG are supported by GW Pharma for research on phytocannabinoids and motor disorders. JMO and MRP have received funds for research from GW Pharma, Ltd. RP’s research is supported in part by funding from GW Pharmaceuticals. RM is a consultant of GW Pharma.

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