NeuroAllergy Research Laboratory (NARL), School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia.
Centre for Sustainable Bioproducts, School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia.
Int J Mol Sci. 2024 Oct 30;25(21):11638. doi: 10.3390/ijms252111638.
Neuroinflammation, characterised by the activation of immune cells in the central nervous system (CNS), plays a dual role in both protecting against and contributing to the progression of neurodegenerative diseases, such as Alzheimer's disease (AD) and multiple sclerosis (MS). This review explores the role of phosphoinositide 3-kinase (PI3K), a key enzyme involved in cellular survival, proliferation, and inflammatory responses, within the context of neuroinflammation. Two PI3K isoforms of interest, PI3Kγ and PI3Kδ, are specific to the regulation of CNS cells, such as microglia, astrocytes, neurons, and oligodendrocytes, influencing pathways, such as Akt, mTOR, and NF-κB, that control cytokine production, immune cell activation, and neuroprotection. The dysregulation of PI3K signalling is implicated in chronic neuroinflammation, contributing to the exacerbation of neurodegenerative diseases. Preclinical studies show promise in targeting neuronal disorders using PI3K inhibitors, such as AS605240 (PI3Kγ) and idelalisib (PI3Kδ), which have reduced inflammation, microglial activation, and neuronal death in in vivo models of AD. However, the clinical translation of these inhibitors faces challenges, including blood-brain barrier (BBB) permeability, isoform specificity, and long-term safety concerns. This review highlights the therapeutic potential of PI3K modulation in neuroinflammatory diseases, identifying key gaps in the current research, particularly in the need for brain-penetrating and isoform-specific inhibitors. These findings underscore the importance of future research to develop targeted therapies that can effectively modulate PI3K activity and provide neuroprotection in chronic neurodegenerative disorders.
神经炎症表现为中枢神经系统（CNS）中免疫细胞的激活，在阿尔茨海默病（AD）和多发性硬化症（MS）等神经退行性疾病的进展中既具有保护作用，也具有促进作用。本综述探讨了磷脂酰肌醇 3-激酶（PI3K）在神经炎症背景下的作用，PI3K 是一种参与细胞存活、增殖和炎症反应的关键酶。两种有意义的 PI3K 同工型，PI3Kγ和 PI3Kδ，特异性调节 CNS 细胞，如小胶质细胞、星形胶质细胞、神经元和少突胶质细胞，影响 Akt、mTOR 和 NF-κB 等通路，控制细胞因子产生、免疫细胞激活和神经保护。PI3K 信号转导的失调与慢性神经炎症有关，导致神经退行性疾病恶化。临床前研究表明，使用 PI3K 抑制剂靶向神经元疾病具有潜力，如 AS605240（PI3Kγ）和idelalisib（PI3Kδ），它们在 AD 的体内模型中减少了炎症、小胶质细胞激活和神经元死亡。然而，这些抑制剂的临床转化面临挑战，包括血脑屏障（BBB）通透性、同工型特异性和长期安全性问题。本综述强调了 PI3K 调节在神经炎症性疾病中的治疗潜力，确定了当前研究中的关键空白，特别是需要穿透大脑的和同工型特异性的抑制剂。这些发现强调了未来研究的重要性，以开发靶向治疗方法，有效地调节 PI3K 活性，并为慢性神经退行性疾病提供神经保护。
