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  • TASIN-1 br Materials and methods br Results

    2022-05-20


    Materials and methods
    Results
    Discussion Chronic neuroinflammation underlies the pathogenesis of HAND (Saylor et al., 2016, Sodhi et al., 2004). Infected immune cells release viral proteins and inflammatory factors which act on microglia, astrocytes, and neurons to produce the synaptodendritic damage that correlates with cognitive decline in HIV infected patients (Ellis et al., 2007). Here we used a simplified in vitro model to study the interaction of the eCB system with the neuroinflammatory response evoked by the HIV envelope protein. HIV gp120 induced synapse loss, a hallmark of HAND, by activating microglia to release IL-1β that then potentiated NMDA receptor function (Kim et al., 2011, Viviani et al., 2006). Inhibiting the metabolism of the eCB, 2-AG, attenuated gp120-induced synapse loss via activation of CB2R and may have also protected synapses via reduced PG production. These pathways are summarized in Fig. 7. The suppression of gp120-induced synapse loss described here is the first report of a CB2R-mediated effect of JZL184 on neuroinflammation induced synaptic damage. 2-AG is one of the most abundant eCBs in the TASIN-1 and is a full agonist at both CB1R and CB2R (Gonsiorek et al., 2000). MGL is the primary enzyme responsible for 2-AG hydrolysis in brain, accounting for 85% of its metabolism (Blankman et al., 2007). Pharmacological and genetic inactivation of MGL has been shown to significantly increase brain 2-AG levels (Grabner et al., 2016, Long et al., 2009). Thus, the accumulation of 2-AG in the presence of JZL184 is expected. However, the relative contribution of increased 2-AG versus decreased AA following inhibition of MGL has varied in different models. In the mouse experimental autoimmune encephalitis model, inhibition of MGL reduced symptoms via a CB1R/CB2R mechanism (Brindisi et al., 2016). Blocking MGL suppresses LPS-induced neuroinflammation and loss of dopamine neurons in a model of Parkinson's disease by decreasing PG production with no evidence for enhanced eCB signaling (Nomura et al., 2011). Similarly, in transgenic mouse models of Alzheimer's disease JZL184 was neuroprotective but, without clear involvement of CB receptors (Chen et al., 2012, Piro et al., 2012). In mice, JZL184 increased brain 2-AG 8-fold and elicited an array of CB1R-mediated behavioral effects (Long et al., 2009). The principal conclusion from the studies described in this report is that CB2R activation following inhibition of MGL affords significant protection from synapse loss induced by gp120. There are several aspects of gp120-induced synapse loss that might render it particularly susceptible to CB2R activation. In a previous report, we showed that the CB1/2R agonist WIN55,212-2 blocked gp120-induced IL-1β production and synapse loss through activation of CB2Rs on microglia (Kim et al., 2011). Perhaps gp120 activation of the CXCR4 pathway to trigger IL-1β release from microglia is particularly sensitive to inhibition by CB2R activation. CB2R agonists have been shown to inhibit chemokine CXCL12-induced and CXCR4-mediated chemotaxis of T lymphocytes (Ghosh et al., 2006). The neuroprotective effects of JZL184 in transgenic models of Alzheimer's disease appear to result from activation of peroxisome proliferator-activated receptor-γ and decreased PG activation of NF-κB resulting in reduced expression of β-secretase and decreased Aβ production, a pathway not expected to be regulated by CB receptors (Piro et al., 2012, Zhang et al., 2014). Responses in microglia evoked by LPS activation of the toll-like receptor 4 pathway are inhibited by CB2R agonists (Ma et al., 2015, Malek et al., 2015, Merighi et al., 2012, Oh et al., 2010, Romero-Sandoval et al., 2009) although, there are reports of non-receptor mediated effects of CBs (Puffenbarger et al., 2000, Tham et al., 2007) and a lack of CB2R effects in some studies (Kouchi, 2015). The failure of CB2R to contribute to the anti-inflammatory effect of JZL184 in vivo may result from receptor desensitization following the prolonged treatment protocols used for in vivo studies (Nomura et al., 2011). Indeed, prolonged administration of JZL184 desensitizes CB1R (Schlosburg et al., 2010). However, desensitization of the CB2Rs that mediate the effect described here has not been explicitly shown, in part because the expression of CB2Rs is upregulated by inflammatory stimuli (Benito et al., 2008). In acute models of peripheral inflammatory pain, JZL184 produces analgesia via CB1 and CB2 receptors (Guindon et al., 2011). Thus, JZL184 may reduce neuroinflammation by PG and/or eCB mechanisms depending on the specific inflammatory stimulus and duration of treatment.