Central Administration of Biologicals, Innovative Products, and Clinical Studies, Egyptian Drug Authority, EDA, Giza, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Faculty of Pharmacy, King Salman International University (KSIU), South Sinai 46612, Egypt.
Brain Res. 2024 Jul 1;1834:148893. doi: 10.1016/j.brainres.2024.148893. Epub 2024 Mar 28.
Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. The dopamine D3 receptor (D3R) plays a significant role in the pathogenesis and treatment of PD. Activation of receptor tyrosine kinases (RTKs) inhibits signaling mediated by G protein-coupled receptor (GPCR). Epidermal growth factor receptors (EGFRs) and dopamine D3 receptors in the brain are directly associated with PD, both in terms of its development and potential treatment. Therefore, we investigated the impact of modulating the EGFR, a member of the RTKs family, and the dopamine D3R, a member of the GPCR family. In the present study, 100 mg/kg of lapatinib (LAP) was administered to rotenone-intoxicated rats for three weeks. Our findings indicate that LAP effectively alleviated motor impairment, improved histopathological abnormalities, and restored dopaminergic neurons in the substantia nigra. This restoration was achieved through the upregulation of dopamine D3R and increase of tyrosine hydroxylase (TH) expression, as well as boosting dopamine levels. Furthermore, LAP inhibited the activity of p-EGFR, GRK2, and SCR. Additionally, LAP exhibited antioxidant properties by inhibiting the 4-hydroxynonenal (4-HNE) and PLCγ/PKCβII pathway, while enhancing the antioxidant defense mechanism by increasing GSH-GPX4 pathway. The current study offers insights into the potential repositioning of LAP as a disease-modifying drug for PD. This could be achieved by modulating the dopaminergic system and curbing oxidative stress.
帕金森病（PD）的特征是黑质中多巴胺能神经元的进行性丧失。多巴胺 D3 受体（D3R）在 PD 的发病机制和治疗中起着重要作用。受体酪氨酸激酶（RTKs）的激活抑制 G 蛋白偶联受体（GPCR）介导的信号转导。大脑中的表皮生长因子受体（EGFRs）和多巴胺 D3 受体与 PD 的发展和潜在治疗都直接相关。因此，我们研究了调节 EGFR（RTKs 家族的一员）和多巴胺 D3R（GPCR 家族的一员）的影响。在本研究中，向鱼藤酮中毒大鼠给予 100mg/kg 的拉帕替尼（LAP），持续三周。我们的研究结果表明，LAP 有效缓解了运动障碍，改善了组织病理学异常，并恢复了黑质中的多巴胺能神经元。这种恢复是通过上调多巴胺 D3R 和增加酪氨酸羟化酶（TH）表达以及提高多巴胺水平来实现的。此外，LAP 抑制了 p-EGFR、GRK2 和 SCR 的活性。此外，LAP 通过抑制 4-羟壬烯醛（4-HNE）和 PLCγ/PKCβII 途径表现出抗氧化特性，同时通过增加 GSH-GPX4 途径增强抗氧化防御机制。本研究为 LAP 作为 PD 的疾病修饰药物的潜在重新定位提供了思路。这可以通过调节多巴胺能系统和抑制氧化应激来实现。
