# Necroptosis of hippocampal neurons in paclitaxel chemotherapy-induced cognitive impairment mediates microglial activation via TLR4/MyD88 signaling pathway

## TL;DR

This study shows that paclitaxel chemotherapy causes brain cell death, which activates immune cells in the brain and worsens cognitive issues through a specific signaling pathway.

## Contribution

The study identifies the TLR4/MyD88 pathway as a novel mediator linking neuronal necroptosis and microglial activation in chemotherapy-induced cognitive impairment.

## Key findings

- PTX-induced neuronal necroptosis activates microglia and promotes M1 polarization.
- Inhibiting necroptosis with Nec-1 reduces M1 polarization and neuroinflammation.
- The TLR4/MyD88 pathway mediates microglial polarization in response to necroptotic neurons.

## Abstract

Paclitaxel (PTX) chemotherapy frequently induces cognitive impairment, which is closely associated with two key pathological processes: necroptosis of hippocampal neurons and microglial polarization. Necroptotic neurons release damage-associated molecular patterns, triggering inflammatory responses. As the primary immune cells in the central nervous system, microglia can exhibit either pro-inflammatory or anti-inflammatory activity depending on their polarization state. However, the relationship between PTX-induced neuronal necroptosis and microglial activation remains unclear.

In this study, both in vivo and in vitro experiments were conducted. In vivo, an adult male C57BL/6N mouse model of PTX-induced cognitive impairment was established and divided into three groups: Veh (vehicle control), PTX (paclitaxel only), and P + N (paclitaxel with Nec-1 treatment). Necrostatin-1 (Nec-1), a specific inhibitor of RIPK1, was used to inhibit necroptosis. In vitro, HT22 cells were used to prepare necroptosis-conditioned medium, and BV-2 cells were treated with this medium. TAK-242, a TLR4 inhibitor, was used to explore the role of the TLR4/MyD88 signaling pathway. Immunofluorescence staining, western blot, and ELISA were employed to detect relevant markers and cytokines.

The results demonstrated that PTX-induced necroptosis of hippocampal neurons activated microglia. Nec-1 effectively suppressed neuronal necroptosis and reduced M1 polarization of microglia. The TLR4/MyD88 signaling pathway was involved in microglial polarization induced by the necroptotic-conditioned medium of PTX-treated HT22 cells. TAK-242 significantly blocked the regulatory effect of PTX-induced neuronal necroptosis on BV-2 microglial polarization.

This study reveals that hippocampal neuron necroptosis activates microglia through the TLR4/MyD88 signaling pathway in PTX-induced cognitive impairment, promoting M1 polarization and neuroinflammation. Inhibiting necroptosis promotes M2 polarization and neuroprotection. These findings uncover a novel mechanism of PTX-induced cognitive impairment and suggest potential therapeutic targets.