Inhibitors of NF-κB and P2X7/NLRP3/Caspase 1 pathway in microglia: Novel therapeutic opportunities in neuroinflammation induced early-stage Alzheimer’s disease

• Published in: Journal of neuroimmunology 2019-01, Vol.326, p.62-74
• Main Authors: Thawkar, Baban S., Kaur, Ginpreet
• Format: Article
• Language: English
• Subjects: Brain penetrant P2X7 antagonist; Caspase 1; IL-1β; Inflammasome; Microglia; Neuroinflammation; NF-kB; NLRP3; Purinoceptors; Radiotracer
• ISSN: 0165-5728; 1872-8421
• DOI: 10.1016/j.jneuroim.2018.11.010

Microglial activation is a distinguished attribute in many neurodegenerative diseases of aging. Compelling evidence suggests that neuroinflammation stimulated by microglia, the resident macrophage-like immune cells in the brain, play a contributing role in the pathogenesis of Alzheimer's disease (AD). Postmortem brain tissue of individuals with AD has credibly demonstrated that neuroinflammation is likely to be a key driver of the disease. Recently, It has been found that manipulating β-amyloid directly is an impracticable approach for therapeutic intervention due to the failure of β-amyloid-lowering drugs in clinical trials. Further, Current treatments relieve only symptoms and modestly improve disease condition but do not reverse or prevent disease. Therefore, Inhibition of microglia activation is effective strategies against the multifactorial and complex AD. More recently there has been a center of attention on converting microglia from this classic state to an alternate state in which the noxious effects are reduced and their phagocytic action toward Aβ improved. The nuclear factor-kappa B (NF- kB) and NLRP3 inflammasome activation by P2X7/NLRP3/caspase 1 pathways are closely linked to Alzheimer’s disease (AD) via neuroinflammation, therefore it could be a rational strategy to target these proteins to counteract the AD pathology. These strategies could work effectively if therapeutic intervention started at an early stage. This review highlights the potentials of drugs acting on the P2X7 receptor and its downstream protein targets for inhibition of neuroinflammation. Thus it might act as a futuristic strategy to treat Alzheimer’s disease. [Display omitted] •Activation of microglia is one of the early events of the AD.•Modulation of microglia activation in the early stage is the best therapeutic approached to reverse AD progression.•Suppressing neuroinflammation by inhibiting activation of NF-kB signalling and P2X7/NLRP 3 pathways.•Purinoreceptor (P2X7) antagonist could be an important therapeutic target, especially in a neuroinflammation induced AD in the early stage.