Neuroprotective Effects of a 3-Amino Quinazoline Derivative via Keap1-Nrf2 Pathway Activation in an ICV-STZ-Induced Rat Model of Sporadic Alzheimer's Disease

The Keap1-Nrf2 pathway has emerged as a promising target for Alzheimer's disease (AD). This study employed in silico modeling to identify Nrf2 activators through Keap1 inhibition. The most promising quinazoline derivative, LMDP10, was then evaluated in a rat model of sporadic AD induced by Intracerebroventricular (ICV) streptozotocin (STZ). ICV STZ-induced rats were treated with LMDP10 (5-50 mg/kg, orally). Behavioral changes were assessed using the Morris water maze (MWM) and novel object recognition (NOR) tests. Additionally, neurochemical marker (oxidant/antioxidant), proinflammatory cytokine (TNF-α) levels, Nrf2 levels, and histopathological alterations were analyzed in both the hippocampus and cortex. An oral toxicity study of LMDP10 was performed according to the OECD Guideline 425. LMDP10 treatment (50 mg/kg/day) significantly improved memory performance (increased percentage time spent in target quadrant in the MWM test and increased discrimination index in the NOR test; P < 0.001 for both). Notably, this dose also significantly increased Nrf2, SOD, and GSH levels while attenuating elevated MDA and TNF-α levels in both brain regions compared to those in vehicle-treated STZ rats. LMDP10 emerged as a potential therapeutic candidate for AD. LMDP10 improved memory function and increased Nrf2 signaling and antioxidant defenses while reducing neuroinflammation. These findings suggest that the neuroprotective effects of LMDP10 may involve Keap1-Nrf2 pathway activation, warranting further investigation of its therapeutic potential in AD.

Alzheimer’s disease; Keap1-Nrf2 pathway; dementia; intracerebroventricular-streptozotocin; oxidative stress; quinazoline derivatives.