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The 2025 evidence links inflammatory microglial activation, perivascular aquaporin-4 disorganization, and reduced CSF–interstitial fluid exchange to defective neuro-clearance, promoting protein aggregation and neuronal injury. 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The latest 2025 evidence reveals that inflammatory microglial activation, perivascular aquaporin-4 disorganization, and impaired cerebrospinal fluid-interstitial fluid exchange contribute to dysfunctional neuro-clearance, fostering protein aggregation and neuronal injury. Emerging data also highlight the potential for drug-mediated modulation of glial metabolism, vascular inflammation, and aquaporin-4 stability to support early neuro-barrier protection and glymphatic flow recovery.  \nKeywords: aquaporin-4, glial metabolism, glymphatic system, microglia, neuro-clearance, neuroinflammation, repurposed drugs  \nDear Editor,  \nThis correspondence discusses recent mechanistic and translational insights linking inflammation with impaired glymphatic neuro-clearance, emphasizing emerging opportunities for adjunct pharmacologic modulation. Neuroinflammation is no longer viewed as a bystander phenomenon in central nervous system (CNS) disorders but as a central driver of impaired glymphatic clearance, microvascular oxidative injury, and progressive neuronal damage[1] . Pathogen- or protein-load–centered models inadequately explain why some patients deteriorate rapidly while others do not. Data now confirm that activated microglia undergo glycolytic reprogramming, producing sustained interleukin-1 beta, interleukin-6, and tumor necrosis factor alpha, which disrupt perivascular cerebrospinal fluid (CSF) influx and impair lymphatic-like drainage in the brain[2].Recent 2025 molecular evidence shows that inflammatory injury destabilizes aquaporin-4 (AQP4) polarization along astrocytic end-feet, reducing CSF-interstitial  \naDepartment of Medicine, Azad Jammu and Kashmir Medical College, Muzaffrabad, Pakistan, bDepartment of Pharmacy, University of Swabi, Pakistan and cDepartment of Medicine, Gandaki Medical College Teaching Hospital and Research Center, Pokhara, Nepal  \nSponsorships or competing interests that may be relevant to content are disclosed at the end of this article.  \n*Corresponding author. Address: Department of Medicine, Gandaki Medical College Teaching Hospital and Research Center, Pokhara 33700, Nepal. Tel.: +[977-9745829807. E-mail:102raghabendrakumarmahato@gmail.com](977-9745829807. E-mail:102raghabendrakumarmahato@gmail.com)[ ](977-9745829807. E-mail:102raghabendrakumarmahato@gmail.com)(R.K. Mahato).  \nCopyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.  \nAnnals of Medicine & Surgery (2026) 88:1158–1159  \nReceived 2 December 2025; Accepted 4 December 2025  \nPublished online 15 December 2025  \n[http://dx.doi.org/10.1097/MS9.0000000000004598](http://dx.doi.org/10.1097/MS9.0000000000004598)  \nfluid exchange and slowing glymphatic flow[3]. This has strong implications for protein-accumulation prone diseases like Alzheimer’s and Parkinson’s, where impaired solute clearance precedes clinical decline. Therapeutic interest is shifting toward drugdriven modulation of the inflammatory microenvironment. A 2025 translational cohort revealed that atorvastatin exposure reduced perivascular inflammatory markers, improved endothelial stability, and was associated with enhanced glymphatic influx signals inneuroinflammation-dominant patient subsets[4] ","cbCaidacnqlEEf2v","https://ap.wps.com/l/cbCaidacnqlEEf2v","pdf",169599,"English","# Abstract\n# Letter to the Editor\n## Neuroinflammation and glymphatic clearance\n## Drug-based modulation and adjunct opportunities\n## Supporting sections (ethics, funding, contributions)","[{\"question\":\"Which drug-based strategies are discussed to modulate this pathway?\",\"answer\":\"Atorvastatin is described as reducing perivascular inflammatory markers and supporting glymphatic influx signals in specific inflammatory subsets. Metformin is also noted for calming inflammasome-driven glial redox injury via AMPK activation, indirectly supporting astrocytic homeostasis and reducing AQP4 disintegration.\"}]","Neuroinflammation-driven glymphatic dysfunction - implications for disease progression and drug-based modulation - Letter to the Editor | PDF",1790674106]