Bisdemethoxycurcumin mitigates traumatic brain injury in rats by modulating autophagy and oxidative stress via heat shock protein 90 alpha family class A member 1-mediated nuclear translocation of transcription factor EB.

BACKGROUND

Bisdemethoxycurcumin (BDMC), the primary active compound found in turmeric, exhibits diverse pharmacological properties. The study aimed to investigate the mechanisms underlying the protective effects of BDMC in traumatic brain injury (TBI).

METHODS

A rat TBI model was established using the Feeney's freefall epidural impact method, followed by BDMC treatment. Rat cortical neuron cells were exposed to hydrogen peroxide (HO) to induce oxidative stress and then treated with BDMC. The cells were also pretreated with autophagy inhibitor 3-MA and heat shock protein 90 alpha family class A member 1 (HSP90AA1) inhibitor 17-AAG. Additionally, the experiments also involved treating HO-exposed cortical neurons with 17-AAG and silencing HSP90AA1 expression. Co-immunoprecipitation was utilized to verify interactions between HSP90AA1 and transcription factor EB (TFEB), TFEB and nuclear factor erythroid 2 related factor 2 (Nrf2), and the localization of these complexes in the cytoplasm and nucleus.

RESULTS

BDMC treatment significantly reduced modified neurological severity scores, brain water content, inflammatory infiltration, oxidative stress, and apoptosis in the cerebral cortex of TBI rats. Additionally, BDMC treatment elevated the expression of Beclin 1 and light chain 3 (LC3) II/LC3 I ratio while decreasing p62 expression. It also promoted TFEB nuclear translocation and increased HSP90AA1 levels in both the cytoplasm and nucleus, along with elevated nuclear Nrf2 expressions in TBI models. In vitro experiments showed decreased malondialdehyde levels, elevated glutathione peroxidase and superoxide dismutase levels upon BDMC treatment, along with repressed cortical neurons apoptosis, elevated Beclin 1 and LC3 II/LC3 I expressions, decreased p62 expressions, reduced cytoplasmic TFEB expression, increased nuclear TFEB and Nrf2 expression, and elevated HSP90AA1 expression in the cytoplasm and nucleus. Mechanistically, BDMC mediated autophagy and oxidative stress by activating HSP90AA1/TFEB/Nrf2 axis. Finally, HSP90AA1 was shown to regulate Nrf2 expression by binding to TFEB in the cellular model.

CONCLUSIONS

BDMC alleviated TBI in rats by regulating autophagy and oxidative stress through HSP90AA1-mediated nuclear translocation of TFEB.