Malignant gliomas (MGs) are among the most aggressive types of cancers in the human brain. Frequent tumor recurrence caused by a lack of effective therapeutic approaches results in a poor prognosis. Signal transducer and activator of transcription 3 (STAT3), an oncogenic protein, is constitutively activated in MGs and predicts a poor clinical outcome. STAT3 therefore is considered to be a promising target for the treatment of MGs. Cryptotanshinone (CTS), the main bioactive compound from the root of Salvia miltiorrhiza Bunge, has been reported to have various pharmacological effects. However, little is known about its function in MG cells. In this study, we evaluated the effect of CTS on the proliferation of human glioma cell lines (T98G and U87). Our results revealed that CTS significantly suppresses glioma cell proliferation. The phosphorylation of STAT3 Tyr705, but not Ser727, was inhibited by CTS, and STAT3 nuclear translocation was attenuated. Overexpression of constitutively active mutant STAT3C reversed the inhibitory effect of CTS, while knockdown STAT3 showed a similar inhibitory effect as CTS treatment. Following the downregulation of STAT3-regulated proteins cyclinD1 and survivin, cell cycle progression significantly arrested in G1/G0 phase. These results indicate that CTS may be a potential antiproliferation agent for the treatment of MGs and that its mechanism may be related to the inhibition of STAT3 signaling.

Monoacylglycerol lipase (MGL) hydrolyzes 2-arachidonoylglycerol to arachidonic acid and glycerol. Inhibition of MGL may attenuate neuroinflammation by enhancing endocannabinoid signaling and decreasing prostaglandin (PG) production. Almost half of HIV infected individuals are afflicted with HIV-associated neurocognitive disorder (HAND), a neuroinflammatory disease in which cognitive decline correlates with synapse loss. HIV infected cells shed the envelope protein gp120 which is a potent neurotoxin that induces synapse loss. Here, we tested whether inhibition of MGL, using the selective inhibitor JZL184, would prevent synapse loss induced by gp120. The number of synapses between rat hippocampal neurons in culture was quantified by imaging clusters of a GFP-tagged antibody-like protein that selectively binds to the postsynaptic scaffolding protein, PSD95. JZL184 completely blocked gp120-induced synapse loss. Inhibition of MGL decreased gp120-induced interleukin-1β (IL-1β) production and subsequent potentiation of NMDA receptor-mediated calcium influx. JZL184-mediated protection of synapses was reversed by a selective cannabinoid type 2 receptor (CBR) inverse agonist/antagonist. JZL184 also reduced gp120-induced prostaglandin E2 (PGE) production; PG signaling was required for gp120-induced IL-1β expression and synapse loss. Inhibition of MGL prevented gp120-induced synapse loss by activating CBR resulting in decreased production of the inflammatory cytokine IL-1β. Because PG signaling was required for gp120-induced synapse loss, JZL184-induced decreases in PGE levels may also protect synapses. MGL presents a promising target for preventing synapse loss in neuroinflammatory conditions such as HAND.

No abstract

A defining feature of HIV-associated neurocognitive disorder (HAND) is the loss of excitatory synaptic connections. Synaptic changes that occur during exposure to HIV appear to result, in part, from a homeostatic scaling response. Here we discuss the mechanisms of these changes from the perspective that they might be part of a coping mechanism that reduces synapses to prevent excitotoxicity. In transgenic animals expressing the HIV proteins Tat or gp120, the loss of synaptic markers precedes changes in neuronal number. In vitro studies have shown that HIV-induced synapse loss and cell death are mediated by distinct mechanisms. Both in vitro and animal studies suggest that HIV-induced synaptic scaling engages new mechanisms that suppress network connectivity and that these processes might be amenable to therapeutic intervention. Indeed, pharmacological reversal of synapse loss induced by HIV Tat restores cognitive function. In summary, studies indicate that there are temporal, mechanistic and pharmacological features of HIV-induced synapse loss that are consistent with homeostatic plasticity. The increasingly well delineated signaling mechanisms that regulate synaptic scaling may reveal pharmacological targets suitable for normalizing synaptic function in chronic neuroinflammatory states such as HAND.

HIV-associated neurocognitive disorder affects about half of HIV-infected patients. HIV impairs neuronal function through indirect mechanisms mainly mediated by inflammatory cytokines and neurotoxic viral proteins, such as the envelope protein gp120. HIV gp120 elicits a neuroinflammatory response that potentiates NMDA receptor function and induces the loss of excitatory synapses. How gp120 influences neuronal inhibition remains unknown. In this study, we expressed a green fluorescent protein (GFP)-tagged recombinant antibody-like protein that binds to the post-synaptic scaffolding protein gephyrin to label inhibitory synapses in living neurons. Treatment with 600 pM gp120 for 24 h increased the number of labeled inhibitory synapses. HIV gp120 evoked the release of interleukin-1b (IL-1b) from microglia to activate IL-1 receptors on neurons. Subsequent activation of the tyrosine kinase Src and GluN2A-containing NMDA receptors increased the number of inhibitory synapses via a process that required protein synthesis. In na€ ıve cultures, inhibition of neuronal p38 mitogen-activated protein kinase (p38 MAPK) increased the number of inhibitory synapses suggesting that p38 MAPK produces a basal suppression of inhibitory synapses that is overcome in the presence of gp120. Direct activation of a mutant form of p38 MAPK expressed in neurons mimicked basal suppression of inhibitory synapses. This study shows for the first time that gp120-induced neuroinflammation increases the number of inhibitory synapses and that this increase overcomes a basal suppression of synaptic inhibition. Increased inhibition may be an adaptive mechanism enabling neurons to counteract excess excitatory input in order to maintain network homeostasis.