Pidazone

Tat, a regulatory protein of human immunodeficiency virus (HIV)-1, is a potent viral neurotoxin which can activate the NLRP3 inflammasome in microglia and contribute to neurotoxicity. Here, we found that HIV Tat induces mitochondrial dysfunction in microglia and promotes mtDNA leakage into the cytoplasm to activate the NLRP3 inflammasome. Degrading mtDNA with DNase I significantly blocks the activation of NLRP3 inflammasome and IL-1β secretion. Interestingly, we found that HIV Tat promotes the translocation of TDP-43 from nucleus to mitochondria. Furthermore, we found that ROS accumulation mediated by HIV Tat could activate NF-κB signaling pathway to facilitate the transcription of IL-1β precursor. Scavenging intracellular ROS significantly inhibits the activation of the NF-κB signaling pathway, thereby reducing the transcription and secretion of IL-1β. Conditioned medium from microglia treated with Tat significantly induces SH-SY5Y and primary neuronal cell apoptosis, which can be alleviated by GIBH-130. In conclusion, our results suggest that HIV-1 Tat promotes TDP-43 abnormal localization to mitochondria and mitochondrial dysfunction, inducing cytosolic mtDNA stress and ROS accumulation. These events respectively activate the NLRP3 inflammasome and NF-κB signaling pathway, thereby promoting IL-1β secretion and neuronal damage. This study reveals a new underlying mechanism for neuroinflammation mediated by HIV infection.

Neuroinflammation mediated by microglia is widely recognized as a key pathophysiological mechanism in neurodegenerative diseases. Lappaconitine (LA) is a natural C₁₈-diterpenoid alkaloid isolated from Aconitum sinomontanum Nakai, and previous study showed that LA and its derivatives inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells. However, the anti-neuroinflammatory effects of LA and its derivatives on microglia are still not clear. Here, LA analogues were designed and synthesized, and the anti-neuroinflammatory activity of the synthesized compounds was screened using LPS-induced overexpression of NO in BV-2 microglia. The screening results showed that compound 10 displayed the highest ability to inhibit NO production (IC₅₀ = 9.98 ± 1.6 µM). Mechanistic investigations revealed that compound 10 attenuated LPS-activated neuroinflammation through suppression of TLR4/MyD88/NF-κB pathway in BV-2 microglia. Acute toxicity assays showed that compound 10 (LD₅₀ = 508.1 mg/kg) was safer relative to LA (LD₅₀ = 30.6 mg/kg). Collectively, our findings show that compound 10 could have potential as anti-neuroinflammatory agents.