Aminooxyacetic acid ameliorates alcohol-induced learning and memory deficits through BDNF-TrkB pathway and calcium homeostasis

Chronic alcohol-related brain damage (ARBD) is mainly manifested as learning and memory impairment and cognitive decline in the long term. Ca²⁺ plays a key role in learning and memory impairment. The increase of intracellular Ca²⁺ concentration can directly cause mitochondrial dysfunction, destroy normal physiological signal transduction, and accelerate the process of learning and memory decline. Aminooxyacetic acid (AOAA), a selective inhibitor of Cystathionineβ-synthase (CBS), has a good effect on a variety of diseases, including improving stroke and reducing the incidence of convulsions. However, its potential in maintaining learning and memory functions by regulating Ca²⁺ and mitochondrial functional status remains uncertain. In this study, chronic alcoholism rats and human neuroblastoma cells (SHSY-5Y) were used as the research objects to establish a chronic alcohol-related brain damage model. We aimed to elucidate the specific mechanisms by which AOAA protects learning and memory functions in alcohol-induced learning and memory impairment. Through Morris water maze test, LTP test, Western blot (WB), immunohistochemistry (IHC), mitochondrial observation under electron microscope, calcium ion concentration measurement and mitochondrial membrane potential measurement, it was found that AOAA could not only regulate the level of endoplasmic reticulum stress (ERS) caused by H₂S elevation, but also maintain the role of valve of Sec61 channel on Ca²⁺ by restoring the level of BIP, a key indicator of ERS, significantly alleviate mitochondrial dysfunction caused by Ca²⁺ overload, and optimize learning and memory function. The mechanism may be closely related to the BDNF-TrkB pathway.