Enhanced drug delivery by a prodrug approach effectively relieves neuroinflammation in mice

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Authors	MONTASER Ahmed B KUIRI Janita NATUNEN Teemu HRUSKA Pavel POTĚŠIL David AURIOLA Seppo HILTUNEN Mikko TERASAKI Tetsuya LEHTONEN Marko JALKANEN Aaro HUTTUNEN Kristiina M
Year of publication	2022
Type	Article in Periodical
Magazine / Source	Life Sciences
MU Faculty or unit	Central European Institute of Technology
Citation
Web	https://www.sciencedirect.com/science/article/pii/S0024320522007883?via%3Dihub
Doi	http://dx.doi.org/10.1016/j.lfs.2022.121088
Keywords	Grid -hanging test; LAT1; LPS-induced neuroinflammation; Mouse brain proteome; Mouse membrane transporters; Rotarod
Description	Aims: Neuroinflammation is a prominent hallmark in several neurodegenerative diseases (NDs). Halting neu-roinflammation can slow down the progression of NDs. Improving the efficacy of clinically available non -steroidal anti-inflammatory drugs (NSAIDs) is a promising approach that may lead to fast-track and effective disease-modifying therapies for NDs. Here, we aimed to utilize the L-type amino acid transporter 1 (LAT1) to improve the efficacy of salicylic acid as an example of an NSAID prodrug, for which brain uptake and intra-cellular localization have been reported earlier.Main methods: Firstly, we confirmed the improved LAT1 utilization of the salicylic acid prodrug (SA-AA) in freshly isolated primary mouse microglial cells. Secondly, we performed behavioural rotarod, open field, and four-limb hanging tests in mice, and a whole-brain proteome analysis.Key findings: The SA-AA prodrug alleviated the lipopolysaccharide (LPS)-induced inflammation in the rotarod and hanging tests. The proteome analysis indicated decreased neuroinflammation at the molecular level. We identified 399 proteins linked to neuroinflammation out of 7416 proteins detected in the mouse brain. Among them, Gps2, Vamp8, Slc6a3, Slc18a2, Slc5a7, Rgs9, Lrrc1, Ppp1r1b, Gnal, and Adcy5/6 were associated with the drug's effects. The SA-AA prodrug attenuated the LPS-induced neuroinflammation through the regulation of critical pathways of neuroinflammation such as the cellular response to stress and transmission across chemical synapses.Significance: The efficacy of NSAIDs can be improved via the utilization of LAT1 and repurposed for the treatment of neuroinflammation. This improved brain delivery and microglia localisation can be applied to other inflam-matory modulators to achieve effective and targeted CNS therapies.
Related projects:	e-Infrastruktura CZ