LX2343 alleviates cognitive impairments in AD model rats by inhibiting oxidative stress-induced neuronal apoptosis and tauopathy

Alzheimer’s disease (AD) is a progressive neurodegenerative disease leading to the irreversible loss of brain neurons and cognitive abilities, and the vicious interplay between oxidative stress (OS) and tauopathy is believed to be one of the major players in AD development. Here, we demonstrated the capability of the small molecule N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2- methoxy(phenylsulfonyl)anilino]acetamide (LX2343) to ameliorate the cognitive dysfunction of AD model rats by inhibiting OS-induced neuronal apoptosis and tauopathy. Streptozotocin (STZ) was used to induce OS in neuronal cells in vitro and in AD model rats that were made by intracerebroventricular injection of STZ (3 mg/kg, bilaterally), and Morris water maze test was used to evaluate the cognitive dysfunction in ICV-STZ rats. Treatment with LX2343 (5–20 μmol/L) significantly attenuated STZ-induced apoptosis in SH-SY5Y cells and mouse primary cortical neurons by alleviating OS and inhibiting the JNK/p38 and pro-apoptotic pathways. LX2343 was able to restore the integrity of mitochondrial function and morphology, increase ATP biosynthesis, and reduce ROS accumulation in the neuronal cells. In addition, LX2343 was found to be a non-ATP competitive GSK-3β inhibitor with IC₅₀ of 1.84±0.07 μmol/L, and it potently inhibited tau hyperphosphorylation in the neuronal cells. In ICV-STZ rats, administration of LX2343 (7, 21 mg·kg^-1·d^-1, ip, for 5 weeks) efficiently improved their cognitive deficits. LX2343 ameliorates the cognitive dysfunction in the AD model rats by suppressing OS-induced neuronal apoptosis and tauopathy, thus highlighting the potential of LX2343 for the treatment of AD.