Monoacylglycerol Lipase Inhibitor JZL184 Prevents HIV-1 gp120-induced Synapse Loss by Altering Endocannabinoid Signaling

Neuropharmacology. 2018 Jan;128:269-281. doi: 10.1016/j.neuropharm.2017.10.023. Epub 2017 Oct 20.

Abstract

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 (CB2R) inverse agonist/antagonist. JZL184 also reduced gp120-induced prostaglandin E2 (PGE2) production; PG signaling was required for gp120-induced IL-1β expression and synapse loss. Inhibition of MGL prevented gp120-induced synapse loss by activating CB2R resulting in decreased production of the inflammatory cytokine IL-1β. Because PG signaling was required for gp120-induced synapse loss, JZL184-induced decreases in PGE2 levels may also protect synapses. MGL presents a promising target for preventing synapse loss in neuroinflammatory conditions such as HAND.

Keywords: Cannabinoid receptor; HIV gp120; JZL184; JZL184, 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (PubChem CID: 25021165); Monoacylglycerol lipase; Prostaglandin E2; Synapse loss.

MeSH terms

  • Amidohydrolases / metabolism
  • Animals
  • Benzodioxoles / pharmacology*
  • Cells, Cultured
  • Disks Large Homolog 4 Protein / genetics
  • Disks Large Homolog 4 Protein / metabolism
  • Embryo, Mammalian
  • Endocannabinoids / metabolism*
  • Enzyme Inhibitors / therapeutic use*
  • Excitatory Amino Acid Agonists / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • HIV Envelope Protein gp120 / toxicity*
  • Hippocampus / cytology
  • Interleukin 1 Receptor Antagonist Protein / pharmacology
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Monoacylglycerol Lipases / metabolism
  • N-Methylaspartate / pharmacology
  • Neurons / drug effects*
  • Piperidines / pharmacology*
  • Prostaglandin Antagonists / pharmacology
  • Rats
  • Signal Transduction / drug effects*
  • Synapses / drug effects*
  • Xanthones / pharmacology

Substances

  • Benzodioxoles
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • Endocannabinoids
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • HIV Envelope Protein gp120
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta
  • JZL 184
  • Piperidines
  • Prostaglandin Antagonists
  • Xanthones
  • gp120 protein, Human immunodeficiency virus 1
  • 6-isopropoxy-9-oxoxanthene-2-carboxylic acid
  • N-Methylaspartate
  • Monoacylglycerol Lipases
  • Amidohydrolases
  • fatty-acid amide hydrolase