Dendritic damage and loss of synaptic connections
Dendritic damage and loss of synaptic connections correlate with cognitive decline in HAND patients. Synapse loss induced by HIV proteins occurs early and via a different signaling pathway from that leading to neuronal death (Kim et al., 2008), suggesting that synapse loss might be a mechanism to reduce excitotoxicity (Hargus and Thayer, 2013). Indeed, synapse loss is reversible (Shin et al., 2012) and rescue of synapses lost following exposure to the neuroinflammatory HIV protein Tat restored cognitive function (Raybuck et al., 2017). Chronic inhibition of MGL in amyloid precursor protein transgenic mice induced recovery of synaptic spines and improvement of spatial learning and memory function (Chen et al., 2012). Perhaps the synapse loss induced by the neuroinflammatory component of neurodegenerative diseases is readily reversible. It will be interesting to determine whether, in addition to protecting synapses from loss induced by HIV proteins, MGL inhibition by drugs such as JZL184 can rescue synapses when given after loss has already occurred.
This report shows for the first time that pharmacological inhibition of MGL can afford neuroprotection via activation of CB2 receptors on Alexidine dihydrochloride synthesis microglia. This mechanism differs from other reports in which the reduced neuroinflammation produced by JZL184 was primarily mediated via reduced PG signaling. The mechanism of protection afforded by MGL inhibitors may depend on the specific cell types involved in the neuroinflammatory response, the concentration and duration of drug treatment and the unique signaling pathways recruited in response to various inflammatory stimuli. This is the first report showing inhibition of MGL affords neuroprotection in a model of HAND, suggesting that the chronic neuroinflammation that underlies this disorder may be particularly susceptible to modulation of the eCB system.
Conflict of interest
Acknowledgements This work was supported by the U.S. National Institutes of Health (National Institute on Drug Abuse Grant DA07304 to S.A.T.).
Introduction Human immunodeficiency virus (HIV)-associated dementia (HAD), also known as AIDS-dementia complex (ADC), is associated with cognitive impairments, movement disorders, and mental and behavioral abnormalities (Lucas and Nelson, 2015, Peluso and Spudich, 2014). Learning and memory dysfunction is one of the core symptoms of HAD, and the neuroinflammatory response induced by HIV-1 is probably a major contributor to HAD-related cognitive and behavioral changes (Fitting et al., 2013, Hong and Banks, 2015). In the brain, the multiplication of HIV in infected macrophages/microglia releases HIV proteins such as gp120 and Tat; the activation of microglia may then result in increased HIV replication, as well as increased production of inflammatory mediators such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), which play an important role in neuronal injury and death caused by HAD (Brabers and Nottet, 2006, Purohit et al., 2011). P2X7 receptor has been implicated in the release of cytokines and in the induction of cell death. It was originally identified in macrophages, microglia, and certain lymphocytes, and its activation is known to have dramatic cytotoxic properties. Due to its ability to regulate the release of proinflammatory cytokines, P2X7 receptor can affect neuronal cell death and may be involved in the pathophysiology of neurodegeneration (Skaper et al., 2010). P2X7 receptor activation on the microglia appears to be necessary for the microglial-mediated injury of neurons, and further, P2X7 receptor activation is able to initiate the ATP-induced chemotaxis of microglial cells (Monif et al., 2009). To this effect, targeting P2X7 receptors may be a helpful approach to the treatment of acute and chronic neurodegenerative disorders (Skaper et al., 2006). Naringin (4′,5,7-trihydroxyflavanone-7-rhamnoglucoside), a flavonoid naturally existing in grapefruit and other citrus fruits, has been shown to possess numerous biological benefits such as antioxidant, anti-inflammatory, and anti-apoptotic properties. Preclinical evidence has demonstrated that naringin exerts favorable effects on atherosclerosis, cardiovascular disorders, diabetes mellitus, neurodegenerative disorders, osteoporosis, and rheumatological disorders (Bharti et al., 2014). Naringin has been shown to protect against neurodegeneration induced by 3-nitropropionic acid via modulating oxidative stress and inflammatory responses, as well (Gopinath et al., 2011, Gopinath and Sudhandiran, 2012). Protection against HIV-associated neurodegeneration by naringin has not yet been reported, however. In this study, we investigated the ameliorative effect of naringin on HIV-1 envelope glycoprotein gp120-induced learning and memory deficits in addition to P2X7 receptor expression in the hippocampus to explore the underlying mechanisms of naringin.