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<p>Aluminum (Al), a pervasive environmental neurotoxicant, has been strongly implicated in the onset and progression of Alzheimer’s disease (AD)-like pathology. Chronic and sub-chronic exposure to aluminum chloride (AlCl<sub>3</sub>) induces cognitive deficits, oxidative stress, cholinergic dysfunction, neuroinflammation, and neuronal damage, making it a widely used agent for modeling AD in preclinical research. This study aimed to evaluate the neuroprotective efficacy of TKM01, a novel 4-anilinoquinazoline derivative, in an AlCl<sub>3</sub>-induced AD-like zebrafish model. Adult zebrafish were exposed to AlCl<sub>3</sub> (11&#xa0;mg/L for 15 days) and pre-treated with TKM01 at two concentrations (240 and 480&#xa0;µg/mL). Behavioral assessments, including the T-maze, novel object recognition (NOR), and open field test (OFT), demonstrated significant improvements in spatial learning, recognition memory, and reduced anxiety-like behavior in TKM01-treated groups. Biochemical analyses revealed decreased acetylcholinesterase (AChE) activity and lipid peroxidation (LPO), alongside elevated antioxidant enzyme activities, including superoxide dismutase (SOD) and catalase (CAT). ELISA showed a reduction in pro-inflammatory cytokines (TNF-α and IL-1β), and RT-PCR analysis confirmed downregulation of NLRP3, ASC, and caspase A gene expression. Furthermore, histopathological examination revealed that TKM01 mitigated AlCl<sub>3</sub>-induced neuronal degeneration, edema, and cellular disorganization in brain telencephalon. Additionally, molecular docking and 200 ns molecular dynamics simulations supported stable and favorable binding interactions between TKM01 and IL-1β/ASC. Collectively, these findings suggest that TKM01 attenuates AlCl<sub>3</sub>-induced neurotoxicity via antioxidant, anti-inflammatory, anticholinesterase, and neuroprotective mechanisms. TKM01 emerges as a promising multifunctional therapeutic candidate for AD, warranting further investigation in mammalian models.</p>

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Exploring the Therapeutic Potential of N-(3,4-dimethoxy phenyl)-6,7-dimethoxyquinazoline-4-amine (TKM01) in Aluminium-Induced Alzheimer’s Disease-Like Model of Zebrafish

  • 期刊论文

  • 发表日期：

    2026年1月21日

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  • Mohd Kashif,
  • Karthikeyan Chandrabose,
  • Ashok Kumar Pandurangan

摘要

Aluminum (Al), a pervasive environmental neurotoxicant, has been strongly implicated in the onset and progression of Alzheimer’s disease (AD)-like pathology. Chronic and sub-chronic exposure to aluminum chloride (AlCl3) induces cognitive deficits, oxidative stress, cholinergic dysfunction, neuroinflammation, and neuronal damage, making it a widely used agent for modeling AD in preclinical research. This study aimed to evaluate the neuroprotective efficacy of TKM01, a novel 4-anilinoquinazoline derivative, in an AlCl3-induced AD-like zebrafish model. Adult zebrafish were exposed to AlCl3 (11 mg/L for 15 days) and pre-treated with TKM01 at two concentrations (240 and 480 µg/mL). Behavioral assessments, including the T-maze, novel object recognition (NOR), and open field test (OFT), demonstrated significant improvements in spatial learning, recognition memory, and reduced anxiety-like behavior in TKM01-treated groups. Biochemical analyses revealed decreased acetylcholinesterase (AChE) activity and lipid peroxidation (LPO), alongside elevated antioxidant enzyme activities, including superoxide dismutase (SOD) and catalase (CAT). ELISA showed a reduction in pro-inflammatory cytokines (TNF-α and IL-1β), and RT-PCR analysis confirmed downregulation of NLRP3, ASC, and caspase A gene expression. Furthermore, histopathological examination revealed that TKM01 mitigated AlCl3-induced neuronal degeneration, edema, and cellular disorganization in brain telencephalon. Additionally, molecular docking and 200 ns molecular dynamics simulations supported stable and favorable binding interactions between TKM01 and IL-1β/ASC. Collectively, these findings suggest that TKM01 attenuates AlCl3-induced neurotoxicity via antioxidant, anti-inflammatory, anticholinesterase, and neuroprotective mechanisms. TKM01 emerges as a promising multifunctional therapeutic candidate for AD, warranting further investigation in mammalian models.