PMID- 33396372 OWN - NLM STAT- MEDLINE DCOM- 20210325 LR - 20210325 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 22 IP - 1 DP - 2020 Dec 31 TI - Vanillic Acid, a Bioactive Phenolic Compound, Counteracts LPS-Induced Neurotoxicity by Regulating c-Jun N-Terminal Kinase in Mouse Brain. LID - 10.3390/ijms22010361 [doi] LID - 361 AB - The receptor for advanced glycation end products (RAGE), a pattern recognition receptor signaling event, has been associated with several human illnesses, including neurodegenerative diseases, particularly in Alzheimer's disease (AD). Vanillic acid (V.A), a flavoring agent, is a benzoic acid derivative having a broad range of biological activities, including antioxidant, anti-inflammatory, and neuroprotective effects. However, the underlying molecular mechanisms of V.A in exerting neuroprotection are not well investigated. The present study aims to explore the neuroprotective effects of V.A against lipopolysaccharides (LPS)-induced neuroinflammation, amyloidogenesis, synaptic/memory dysfunction, and neurodegeneration in mice brain. Behavioral tests and biochemical and immunofluorescence assays were applied. Our results indicated increased expression of RAGE and its downstream phospho-c-Jun n-terminal kinase (p-JNK) in the LPS-alone treated group, which was significantly reduced in the V.A + LPS co-treated group. We also found that systemic administration of LPS-injection induced glial cells (microglia and astrocytes) activation and significantly increased expression level of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB) and secretion of proinflammatory cytokines including tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL1-beta), and cyclooxygenase (COX-2). However, V.A + LPS co-treatment significantly inhibited the LPS-induced activation of glial cells and neuroinflammatory mediators. Moreover, we also noted that V.A treatment significantly attenuated LPS-induced increases in the expression of AD markers, such as beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) and amyloid-beta (Abeta). Furthermore, V.A treatment significantly reversed LPS-induced synaptic loss via enhancing the expression level of pre- and post-synaptic markers (PSD-95 and SYP), and improved memory performance in LPS-alone treated group. Taken together; we suggest that neuroprotective effects of V.A against LPS-induced neurotoxicity might be via inhibition of LPS/RAGE mediated JNK signaling pathway; and encourage future studies that V.A would be a potential neuroprotective and neurotherapeutic candidate in various neurological disorders. FAU - Ullah, Rahat AU - Ullah R AD - Division of Life Sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea. FAU - Ikram, Muhammad AU - Ikram M AUID- ORCID: 0000-0001-5226-4081 AD - Division of Life Sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea. FAU - Park, Tae Ju AU - Park TJ AD - Haemato-Oncology/Systems Medicine Group, Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences (MVLS), University of Glasgow, Glasgow G12OZD, UK. FAU - Ahmad, Riaz AU - Ahmad R AUID- ORCID: 0000-0001-7411-9483 AD - Division of Life Sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea. FAU - Saeed, Kamran AU - Saeed K AD - Division of Life Sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea. FAU - Alam, Sayed Ibrar AU - Alam SI AD - Division of Life Sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea. FAU - Rehman, Inayat Ur AU - Rehman IU AD - Division of Life Sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea. FAU - Khan, Amjad AU - Khan A AD - Division of Life Sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea. FAU - Khan, Ibrahim AU - Khan I AD - Division of Life Sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea. FAU - Jo, Min Gi AU - Jo MG AUID- ORCID: 0000-0002-2863-6989 AD - Division of Life Sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea. FAU - Kim, Myeong Ok AU - Kim MO AD - Division of Life Sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea. LA - eng PT - Journal Article DEP - 20201231 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Lipopolysaccharides) RN - 0 (Neuroprotective Agents) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) RN - GM8Q3JM2Y8 (Vanillic Acid) SB - IM MH - Animals MH - Brain/*drug effects/metabolism/pathology MH - Gene Expression Regulation, Enzymologic/*drug effects MH - Gliosis/chemically induced/*drug therapy/metabolism/pathology MH - JNK Mitogen-Activated Protein Kinases/genetics/*metabolism MH - Lipopolysaccharides/*toxicity MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Neuroprotective Agents/*pharmacology MH - Vanillic Acid/*pharmacology PMC - PMC7795830 OTO - NOTNLM OT - amyloidogenesis OT - c-Jun N-terminal kinases OT - lipopolysaccharide OT - neurodegenerative diseases OT - neuroinflammation OT - synaptic and memory impairment OT - vanillic acid COIS- The authors declare no conflict of interest. EDAT- 2021/01/06 06:00 MHDA- 2021/03/26 06:00 PMCR- 2020/12/31 CRDT- 2021/01/05 01:12 PHST- 2020/12/09 00:00 [received] PHST- 2020/12/24 00:00 [revised] PHST- 2020/12/24 00:00 [accepted] PHST- 2021/01/05 01:12 [entrez] PHST- 2021/01/06 06:00 [pubmed] PHST- 2021/03/26 06:00 [medline] PHST- 2020/12/31 00:00 [pmc-release] AID - ijms22010361 [pii] AID - ijms-22-00361 [pii] AID - 10.3390/ijms22010361 [doi] PST - epublish SO - Int J Mol Sci. 2020 Dec 31;22(1):361. doi: 10.3390/ijms22010361.