# Pachymic Acid Targets PI3K/Akt Signaling Pathway to Attenuate tPA‐Induced Hemorrhagic Transformation After Ischemic Stroke

## TL;DR

Pachymic acid reduces brain bleeding after stroke by protecting the blood-brain barrier through the PI3K/Akt pathway.

## Contribution

Pachymic acid is shown to directly target PI3K and protect the BBB against tPA-induced hemorrhagic transformation.

## Key findings

- Pachymic acid dose-dependently reduces infarct and hemorrhagic volumes and improves neurological outcomes.
- Pachymic acid binds to PI3K and activates the PI3K/Akt pathway to protect the BBB.
- PI3K inhibition reverses the protective effects of pachymic acid, confirming its role in the pathway.

## Abstract

Tissue plasminogen activator (tPA)–induced cerebral hemorrhagic transformation (HT) after ischemic stroke limits its clinical use widely. Pachymic acid, a main active component of Poria cocos, mitigates brain ischemia/reperfusion injury, but its effect on tPA‐induced HT is unclear.

A focal middle cerebral artery occlusion/reperfusion model was established and administered with tPA and pachymic acid. Infarct volume and neurological function were assessed at 24 h after reperfusion. Blood–brain barrier (BBB) damage was evaluated using Evans blue leakage, immunofluorescence, and Western blot. Pachymic acid and PI3K protein interaction was identified using molecular docking, molecular dynamics (MD) simulation, and surface plasmon resonance (SPR).

Compared with the tPA group, pachymic acid dose‐dependently improves neurological and motor functions, reduces infarct volume and hemorrhagic volume, and alleviates permeability and tight junction protein degradation of BBB after ischemic stroke, with the strongest effects observed at the highest dose. Molecular docking, MD simulation, and SPR results indicate that pachymic acid can directly bind to PI3K protein. Further experiments showed that the PI3K inhibitor LY294002 reversed pachymic acid's protective effects.

This study demonstrated that pachymic acid protects the BBB by targeting PI3K to activate the PI3K/Akt signaling pathway, thereby alleviating tPA‐induced HT after ischemic stroke.

Pachymic acid protects blood–brain barrier (BBB) integrity by decreasing the degradation of tight junction proteins caused by tissue plasminogen activator (tPA). Pachymic acid activates the PI3K/Akt pathway via direct binding to PI3K protein, mitigating BBB damage and hemorrhagic transformation induced by tPA after ischemic stroke.