The presence of both CB₁ and CB₂ receptors on immune cells [13], and the evidence that cannabinoids inhibit adenylyl cyclase in such cells through a pertussis toxin-sensitive mode, first suggested a role for cannabinoid receptors in the modulation of the immune system [15]. Moreover, activation of immune cells by a range of inflammatory stimuli modulates the expression of CB₁ and CB₂ by these cells, a fact that has been linked to the immune-regulatory effects of cannabinoids [20, 47]. In vitro experiments have reported that cannabinoids may act as immunomodulators by (1) induction of apoptosis, (2) inhibition of cell proliferation as well as cytokine and chemokine production, and (3) expansion of regulatory T cells [48, 49]. In addition, there is also evidence of endocannabinoid production as metabolites of activated immune cells [50, 51].

It has been reported that cannabinoids suppress the production of a variety of pro-inflammatory cytokines in both human cell cultures and animal models, an effect that has been thought to be mediated mainly by CB₂ receptors [52, 53]. When activated, CB₂ receptors can modulate immune cell migration and cytokine release both outside and within the brain [54]. Furthermore, through CB₂ receptors, cannabinoids may inhibit the production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and the p40 subunit of IL-12 and IL-23 by microglia and macrophages [55-57]. Moreover, CB₂ receptors also seem to play an important role in regulating cell migration of neutrophils, macrophages, NK and B cells [20]. Also, it has been suggested that cannabinoids are able to decrease IL-2 production and T cells proliferation [20] and may alter the cytokine profile from a T helper (Th)1 to a Th2 phenotype in a CB₂-dependent manner [53, 58]. However, CB₁ receptors have also been related to neuroinflammation regulation. Notably are the data from Mestre et al. [59], showing that anandamide, through CB₁ receptor activation, inhibits the expression of Theiler’s virus-induced vascular cell adhesion molecule (VCAM)-1, an endothelial receptor that plays a key role in leukocyte transmigration in multiple sclerosis [60, 61]. Zoppi et al. [62] also demonstrated that CB₁ receptors activation by a synthetic selective CB₁ agonist (arachidonyl-2'-chloroethylamide; ACEA) modulates stress-induced conditions and neuroinflammation by preventing the decrease in glutamate uptake and glutamate astroglial transporter excitatory amino acid transporter 2 (EAAT2) expression, the increase in pro-inflammatory molecules (cytokines, nuclear factor kappa B – NF-κB) and enzymatic sources, such as inducible nitric oxide synthase (NOS-2) and cyclooxygenase-2 (COX-2), in addition to the increase in lipid peroxidation.

Toll-like receptors (TLRs), considered as pattern recognition receptors (PRRs) that recognize molecular signatures of microbes known as pathogen-associated molecular patterns (PAMPs) have been emerged as central keys in the innate immune and neuroimmune responses [63-64]. Indeed, TLRs have been found to be expressed on glial cells and neurons [65-70]. Such receptors after being activated by PAMPs lead to intracellular signaling cascades that culminate in NF-κB translocation to the nucleus and the consequent synthesis of pro-inflammatory molecules [71]. Interestingly, as discussed above, cannabinoid receptors are also present on glial cells and a large body of evidence suggests that cannabinoids (phyto-, synthetic and endocannabinoids) can negatively modulate TLR4-induced neuroinflammation in these cells [72-76]. Moreover, as recently published by Downer et al. [77], the synthetic cannabinoid WIN-55,212-2 inhibits the pro-inflammatory signaling axis triggered by TLR3 and TLR4, while selectively augmenting TLR3-induced expression of IFN-β.

Thus, due to a myriad of neuro-protective, anti-neuro-inflammatory and anti-oxidant actions, cannabinoids have been cogitated as possible therapeutic agents for neurodegenerative disorders that combine inflammatory responses, as Alzheimer’s Disease (AD), Multiple Sclerosis (MS), Huntington and Parkinson Diseases [78]. Hyperactive microglia, a common feature of these neurodegenerative diseases, secrete a number of pro- and anti-inflammatory cytokines, chemokines, glutamate, prostanoids, neurotrophic factors, and a range of free radicals that provide a milieu for oxidative stress. In this context, cannabidiol (CBD) has emerged as a promising strategy to treat inflammation that results from microglial hyperactivation [78], with no psychotropic side effects. Moreover, CBD has been shown to attenuate oxidative and nitrosative stress in several human disease models [78-81]. Other cannabinoid compounds that have been used in preclinical studies are exemplified in Table 1.

Alzheimer’s disease (AD) is characterized by the presence of beta-amyloid (Aβ) plaques and neurofibrillary tangles in the brain, as well as cognitive decline and memory deficits. The abnormal processing of a 42-amino acid peptide (Aβ peptide) that precipitates in the extra-cellular space may be the cause of Aβ plaques accumulation, which leads to neuronal death. Activated microglia are found surrounding Aβ plaques, even before neuronal death [97]. In AD patients, increased microglial CB₁ and CB₂ receptor expression is found especially in plaque-bearing areas [84], suggesting a role of cannabinoids in AD pathophysiology. Eubanks et al. [82] found that THC competitively inhibits the enzyme acetylcholinesterase (AChE) by binding to the peripheral anionic site of AChE, the critical region involved in amyloidogenesis. Other studies have been conducted to support the participation of cannabinoids in AD (see Table 1).

Parkinson’s disease (PD) is a degenerative condition affecting dopaminergic neurotransmission in the basal ganglia resulting in hypokinesia [98]. Some of the neurodegenerative features of this disease include intracellular accumulation of misfolded proteins and Lewy bodies, oxidative stress, excitotoxicity, and neuroinflammation. The endocannabinoid system may be a therapeutic target because of its marked activity in the basal ganglia where it regulates neuro-transmitter release and motor activity [5, 99]. It has been demonstrated that in PD patients, endocannabinoid levels in the cerebrospinal fluid are increased [100]. As mentioned before, the use of cannabinoid drugs that activate CB₁ receptors may induce motor impairment; therefore, CB₁ antagonists are more suitable candidates as therapeutic agents in PD. Indeed, results drawn from preclinical studies have proposed that SR141716A may reduce the hypokinesia in an animal model of PD, at a low dose [95].

Another neurodegenerative disease involving the basal ganglia is Huntington’s disease (HD). HD has a delayed onset, defined by selective neuronal vulnerability and widespread expression of disease-related proteins during the whole lifetime. A genetic defect causes abnormal protein processing and aggregation; and cellular toxic effects involve defective autophagy-lysosomal function, transcriptional dysregulation, oxidative stress, apoptosis, mitochondrial and metabolic dysfunction [101]. HD patients develop progressive psychiatric manifestations, cognitive decline and choreiform movements [102]. In HD, there is a reduction in CB₁ expression in the basal ganglia [87, 103], where the most prominent cell loss occurs. The downregulation of CB₁ receptors has been thought to be a key pathogenic event in HD. Lastres-Becker and colleagues [104] found that in a rat model of HD, AEA and 2-AG levels were decreased in the striatum, while there was an increase in AEA level in the substantia nigra. These changes in endocannabinoid levels are similar to those found in the brain of HD patients. However, further studies are still necessary to clarify how cannabinoids may participate in this disorder, since many preclinical results are controversial.