Enhanced drug delivery by a prodrug approach effectively relieves neuroinflammation in mice
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14740%2F22%3A00128511" target="_blank" >RIV/00216224:14740/22:00128511 - isvavai.cz</a>
Result on the web
<a href="https://www.sciencedirect.com/science/article/pii/S0024320522007883?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0024320522007883?via%3Dihub</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.lfs.2022.121088" target="_blank" >10.1016/j.lfs.2022.121088</a>
Alternative languages
Result language
angličtina
Original language name
Enhanced drug delivery by a prodrug approach effectively relieves neuroinflammation in mice
Original language 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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30104 - Pharmacology and pharmacy
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2022
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Life Sciences
ISSN
0024-3205
e-ISSN
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Volume of the periodical
310
Issue of the periodical within the volume
DEC
Country of publishing house
GB - UNITED KINGDOM
Number of pages
12
Pages from-to
121088
UT code for WoS article
000880317300008
EID of the result in the Scopus database
2-s2.0-85140372202