Neurodegeneration is the gradual atrophy of the structure and functionality of the neurons, which culminates in the death of the neurons. This pathological process is central to numerous neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. The global prevalence of neurodegenerative diseases is increasing rapidly, posing a significant public health burden. The various interconnected molecular pathways are disrupted in the pathogenesis of neurodegenerative diseases. Among them, TLR/MyD88/NF-κB and MAPK/NF-κB signaling cascades are critical ones that activate neuroinflammation. Whereas, NLRP3 inflammasome-mediated pyroptosis contributes to inflammatory cell death. Moreover, the BDNF/Trk-B-mediated PI3K/Akt/mTOR pathway controls the synaptic plasticity that is necessary in the learning and memory processes. In addition, caspase and AIF-mediated apoptotic signaling pathways are disrupted in neurodegenerative diseases. Till now, various natural phenolic compounds have shown high potential in combating different neurodegenerative diseases. Paeonol is a 2’-hydroxy-4’-methoxyacetophenone, commonly found in the root bark of Paeonia suffruticosa and other Paeonia species. It possesses diverse pharmacological actions, including neuroprotection, anti-inflammatory, antioxidant and cardioprotective. Various cell lines and preclinical reports have documented that paeonol confers neuroprotection through modulation of various mediators, including TLR4, MAPK, PI3K, mTOR, BDNF, NF-κB, ROS, AMPK, NLRP3, apoptotic proteins and inflammatory mediators, among others. Given that paeonol can modulate these mediators, the current study was designed to investigate the mechanistic interactions that underlie its neuroprotective effects. Examining these interrelated pathways will give future researchers the fundamental knowledge to fill the existing gaps and better understand the potential of in neurodegenerative diseases.
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