Medical records documentation of constipation preceding Parkinson disease

TLDR

HIV‑1 associated neurocognitive disorder (HAND) is common in HIV‑infected patients, and neuronal toxicity from viral Tat protein is exacerbated by drug abuse. The study aimed to identify therapeutic targets for HAND by employing the literature mining system MOLIERE. The authors used MOLIERE to uncover potential anti‑HAND targets. Validation of DDX3 as a target showed that the selective inhibitor RK‑33 blocked Tat‑ and cocaine‑induced neurotoxicity, microglial activation, and proinflammatory cytokine production in rodent cortical cultures, indicating DDX3 inhibition as a promising therapy for HAND and possibly other neurodegenerative diseases.

Abstract

<h3>Abstract</h3> HIV-1 Associated Neurocognitive Disorder (HAND) is commonly seen in HIV-infected patients. Viral proteins including Tat cause neuronal toxicity and is worsened by drugs of abuse. To uncover potential targets for anti-HAND therapy, we employed a literature mining system, MOLIERE. Here, we validated Dead Box RNA Helicase 3 (DDX3) as a target to treat HAND via a selective DDX3 inhibitor, RK-33. The combined neurotoxicity of Tat protein and cocaine was blocked by RK-33 in rat and mouse cortical cultures. Transcriptome analysis showed that Tat-activated transcripts include makers and regulators of microglial activation, and RK-33 blocked Tat-induced activation of these mRNAs. Elevated production of proinflammatory cytokines was also inhibited by RK-33. These findings show that DDX3 contributes to microglial activation triggered by Tat and cocaine, and DDX3 inhibition shows promise as a therapy for HAND. Moreover, DDX3 may contribute to the pathology of other neurodegenerative diseases with pathological activation of microglia.