Aconitine induces brain tissue damage by increasing the permeability of the cerebral blood-brain barrier and over-activating endoplasmic reticulum stress

Objective: This study aimed to explore the neurotoxicity of aconitine and its underlying mechanism. Methods: The rats were administered with the aconitine solution intragastrically at different dosages (0.5 mg/kg, 1.5 mg/kg, and 2.5 mg/kg). Evans blue (EB) extravasation and evaluation of tight junction protein expression were performed to determine the permeability of the blood-brain barrier. Cellular damage, apoptosis, and levels of endoplasmic reticulum (ER) stress markers were determined using H&E staining, Tunnel assay, and western blotting. The effects of aconitine on cell viability, apoptosis, and activation of the ER stress signaling in PC12 cells were assessed in vitro using the MTT assay, flow cytometry, western blot, and immunofluorescence analysis. Results: Aconitine was observed to significantly increase the murine blood-brain barrier penetrability in a dose-dependent manner. The in vivo experimental results revealed that aconitine could stimulate the pathway for endoplasmic reticulum stress. The increase in the endoplasmic reticulum stress in the brain tissue promoted apoptosis, leading to brain damage. Moreover, PC12 cell proliferation was inhibited upon treatment with aconitine in a dose-dependent manner. In addition, cell apoptosis was increased upon treatment with aconitine also in a dose-dependent manner. These findings indicated that aconitine caused damage to PC12 cells via endoplasmic reticulum stress. Conclusion: Aconitine induces brain tissue damage by increasing the penetrability of the blood-brain barrier in the cerebral region and over-activating the endoplasmic reticulum stress.