ReviewDruggable targets of the endocannabinoid system: Implications for the treatment of HIV-associated neurocognitive disorder
Introduction
Nearly half of all HIV-infected individuals experience cognitive and motor impairments (Heaton et al., 1995, Tozzi et al., 2005); these symptoms are collectively termed HIV-associated neurocognitive disorder (HAND). Combined antiretroviral therapy (cART) has reduced the number of patients that progress to AIDS (Heaton et al., 2010, McArthur, 1993), and increased the lifespan of infected individuals (ATCC, 2008, Dore et al., 2003). However, while cART suppresses viral load, it does not eradicate HIV from the brain (Valcour et al., 2011). Thus, the prevalence of HAND remains high (Cysique et al., 2004, Sacktor et al., 2001, Saylor et al., 2016), with no effective treatment available.
One promising area of therapeutic development is the endocannabinoid (eCB) system. This biological system is composed of endogenous lipid-based signaling molecules that bind to cannabinoid receptors, and the machinery that synthesizes and metabolizes them (Fig. 1). eCB signaling is dependent on neurons interacting with other neurons, astrocytes, and microglia (Ashton and Glass, 2007, Navarrete et al., 2014). The eCB system plays a role in many physiological processes. Here, we review its ability to provide on-demand protection against excitotoxicity and neuroinflammation (Marsicano et al., 2003, Walter and Stella, 2004), two hallmarks of many neurodegenerative disorders including HAND (Amor et al., 2010, Dong et al., 2009, Green et al., 2018).
Drugs can enhance the eCB system by mimicking or potentiating its neuroprotective function. Changes in the eCB system associated with some neurological disorders might impair the neuroprotection that the system affords, exacerbating excitotoxicity. Thus, strategies to prevent loss of eCB signaling may preserve its neuroprotective function, and drugs that mimic or enhance eCB signaling may compensate for its diminished capacity in neurotoxic or inflammatory conditions, such as HAND. Cannabimimetic drugs are relevant to HIV because they are used to treat wasting and nausea in AIDS patients (Plasse et al., 1991), cannabis use among HIV-positive individuals is high (Okafor et al., 2017), and recent efforts to legalize medicinal and recreational marijuana are increasing access (Cerda et al., 2017). Here, we examine the components and pharmacology of the eCB system and discuss evidence of its neuroprotective and anti-inflammatory properties. We then evaluate the therapeutic potential of drugs that modulate the eCB system and speculate that strategies that enhance eCB signaling might slow cognitive decline in HAND.
Section snippets
Cannabinoid receptors
CB1 and CB2 receptors have been studied extensively and are the best understood receptor components of the eCB system. However, eCBs also interact with ion channels and other G protein-coupled receptors (GPCRs). Anandamide activates the transient receptor potential vanilloid 1 (TRPV1) receptor, a calcium permeable, nonselective cation channel (Ross, 2003). Several orphan GPCRs, notably GPR55 and GPR18, have emerged as possible targets of eCBs (for review, see Cuevas-Olguin et al., 2017). While
Endogenous ligands, synthesis, and metabolism
Several putative endogenous cannabinoids have been discovered (Hanus et al., 1993, Hanus et al., 2001); here, we focus on the two best-characterized ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG) (Fig. 1). AEA functions relatively slowly and generates both retrograde and non-retrograde signaling (Ohno-Shosaku and Kano, 2014). 2-AG is best known for its role as a retrograde messenger in the CNS, playing an important role in spike timing-dependent plasticity and long-term depression (
Pathological impairment of the endocannabinoid system
One important determinant of clinical outcome is the degree to which the target biological system is functional. Studies in vitro and in vivo have shown that exposure to excitotoxic stimuli alters the eCB system (Chen et al., 2003, Feng et al., 2016, Li et al., 2012) with increased CB1R-mediated inhibition of GABA release changing the balance of network excitability. Currently, it is not known if eCB signaling is altered in the presence of HIV. In the context of another neurodegenerative
Conclusions and perspectives
The unique pathophysiology of HAND may be particularly amenable to modulation by the eCB system. The excitotoxic component of HAND is attenuated by activating presynaptic CB1Rs, either directly by agonists or indirectly through inhibition of eCB metabolism. The chronic neuroinflammation associated with HAND can be attenuated by activating CB2Rs on immune cells or inhibiting MGL-mediated AA production. Furthermore, expression of cannabinoid receptors is increased in HAND, potentially enhancing
Acknowledgements
This work was supported by National Institutes of Health Grants DA007304 and DA044809 to ST. MW was supported by NIH training grant T32 DA007097.
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