Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), 400056, Mumbai, India.
Neurotox Res. 2021 Jun;39(3):949-965. doi: 10.1007/s12640-021-00343-z. Epub 2021 Mar 9.
Drug discovery and development for Alzheimer's disease (AD) are complex and challenging due to the higher failure rate in the drug development process. The overproduction and deposition of Aβ senile plaque and intracellular neurofibrillary tangle (NFT) formation are well-recognized diagnostic hallmarks of AD. Numerous transgenic models of Alzheimer's disease have restrictions on cost-effectiveness and time in the preclinical setup. Zebrafish has emerged as an excellent complementary model for neurodegenerative research due to simpler organisms with robust, clearly visible behavior forms. Glutaminergic and cholinergic pathways responsible for learning and memory are present in zebrafish and actively participate in the transmission process. Therefore, it is imperative to study neurotoxic agents' mechanisms that induce dysfunction of memory, learning, and neurons in the zebrafish. This review illustrates the in-depth molecular mechanism of several neurotoxic agents such as okadaic acid, cigarette smoke extract, and metals to produce cognitive deficits or neurodegeneration similar to mammals. These updates would determine an ideal and effective neurotoxic agent for producing AD pathophysiology in the zebrafish brain for preclinical screening.
由于药物开发过程中的高失败率，阿尔茨海默病（AD）的药物发现和开发是复杂且具有挑战性的。β淀粉样蛋白（Aβ）老年斑的过度产生和沉积以及细胞内神经原纤维缠结（NFT）的形成是公认的 AD 诊断标志物。许多阿尔茨海默病的转基因模型在临床前设置中受到成本效益和时间的限制。由于斑马鱼具有简单的生物体和强大、清晰可见的行为形式，因此它已成为神经退行性研究的优秀互补模型。负责学习和记忆的谷氨酸能和胆碱能途径存在于斑马鱼中，并积极参与传递过程。因此，研究神经毒性剂诱导记忆、学习和神经元功能障碍的机制至关重要。本综述说明了几种神经毒性剂（如岗田酸、香烟烟雾提取物和金属）的深入分子机制，这些神经毒性剂可产生类似于哺乳动物的认知缺陷或神经退行性变。这些更新将确定一种理想且有效的神经毒性剂，用于在斑马鱼大脑中产生 AD 病理生理学，以进行临床前筛选。
