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K284-6111 prevents the amyloid beta-induced neuroinflammation and impairment of recognition memory through inhibition of NF-κB-mediated CHI3L1 expression.
J Neuroinflammation. 2018 Aug 11; 15(1):224.JN

Abstract

BACKGROUND

Alzheimer's disease, which is pathologically characterized by an excessive accumulation of amyloid beta (Aβ) fibrils, is a degenerative brain disease and the most common cause of dementia. In a previous study, it was reported that an increased level of CHI3L1 in plasma was found in AD patients. We investigated the inhibitory effect of 2-({3-[2-(1-cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111), an inhibitor of chitinase 3 like 1 (CHI3L1), on memory impairment in Aβ1-42-infused mice, and microglial BV-2 cells and astrocytes.

METHODS

We examined whether K284-6111 (3 mg/kg given orally for 4 weeks) prevents amyloidogenesis and memory loss in Aβ1-42-induced AD mice model. After intracerebroventrical (ICV) infusion of Aβ1-42 for 14 days, the cognitive function was assessed by the Morris water maze test and passive avoidance test. K284-6111 treatment was found to reduce Aβ1-42-induced memory loss.

RESULTS

A memory recovery effect was found to be associated with the reduction of Aβ1-42-induced expression of inflammatory proteins (iNOS, COX-2, GFAP, and Iba-1) and the suppression of CHI3L1 expression in the brain. Additionally, K284-6111 reduced Aβ1-42-induced β-secretase activity and Aβ generation. Lipopolysaccharide (LPS)-induced (1 μg/mL) expression of inflammatory (COX-2, iNOS, GFAP, Iba-1) and amyloidogenic proteins (APP, BACE1) were decreased in microglial BV-2 cells and cultured astrocytes by the K284-6111 treatment (0.5, 1, and 2 μM). Moreover, K284-6111 treatment suppressed p50 and p65 translocation into the nucleus, and phosphorylation of IκB in vivo and in vitro.

CONCLUSION

These results suggest that CHI3L1 inhibitor could be an applicable intervention drug in amyloidogenesis and neuroinflammation, thereby preventing memory dysfunction via inhibition of NF-κB.

Authors+Show Affiliations

College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31 Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk, 28160, Republic of Korea.College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31 Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk, 28160, Republic of Korea.College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31 Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk, 28160, Republic of Korea.College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31 Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk, 28160, Republic of Korea.College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31 Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk, 28160, Republic of Korea.College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31 Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk, 28160, Republic of Korea.College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31 Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk, 28160, Republic of Korea. jinthong@chungbuk.ac.kr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30098604

Citation

Choi, Ji Yeon, et al. "K284-6111 Prevents the Amyloid Beta-induced Neuroinflammation and Impairment of Recognition Memory Through Inhibition of NF-κB-mediated CHI3L1 Expression." Journal of Neuroinflammation, vol. 15, no. 1, 2018, p. 224.
Choi JY, Yeo IJ, Kim KC, et al. K284-6111 prevents the amyloid beta-induced neuroinflammation and impairment of recognition memory through inhibition of NF-κB-mediated CHI3L1 expression. J Neuroinflammation. 2018;15(1):224.
Choi, J. Y., Yeo, I. J., Kim, K. C., Choi, W. R., Jung, J. K., Han, S. B., & Hong, J. T. (2018). K284-6111 prevents the amyloid beta-induced neuroinflammation and impairment of recognition memory through inhibition of NF-κB-mediated CHI3L1 expression. Journal of Neuroinflammation, 15(1), 224. https://doi.org/10.1186/s12974-018-1269-3
Choi JY, et al. K284-6111 Prevents the Amyloid Beta-induced Neuroinflammation and Impairment of Recognition Memory Through Inhibition of NF-κB-mediated CHI3L1 Expression. J Neuroinflammation. 2018 Aug 11;15(1):224. PubMed PMID: 30098604.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - K284-6111 prevents the amyloid beta-induced neuroinflammation and impairment of recognition memory through inhibition of NF-κB-mediated CHI3L1 expression. AU - Choi,Ji Yeon, AU - Yeo,In Jun, AU - Kim,Ki Cheon, AU - Choi,Won Rack, AU - Jung,Jae-Kyung, AU - Han,Sang-Bae, AU - Hong,Jin Tae, Y1 - 2018/08/11/ PY - 2018/03/09/received PY - 2018/08/02/accepted PY - 2018/8/13/entrez PY - 2018/8/14/pubmed PY - 2019/5/21/medline KW - Alzheimer’s disease KW - Amyloidogenesis KW - CHI3L1 KW - NF-κB KW - Neuroinflammation SP - 224 EP - 224 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 15 IS - 1 N2 - BACKGROUND: Alzheimer's disease, which is pathologically characterized by an excessive accumulation of amyloid beta (Aβ) fibrils, is a degenerative brain disease and the most common cause of dementia. In a previous study, it was reported that an increased level of CHI3L1 in plasma was found in AD patients. We investigated the inhibitory effect of 2-({3-[2-(1-cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111), an inhibitor of chitinase 3 like 1 (CHI3L1), on memory impairment in Aβ1-42-infused mice, and microglial BV-2 cells and astrocytes. METHODS: We examined whether K284-6111 (3 mg/kg given orally for 4 weeks) prevents amyloidogenesis and memory loss in Aβ1-42-induced AD mice model. After intracerebroventrical (ICV) infusion of Aβ1-42 for 14 days, the cognitive function was assessed by the Morris water maze test and passive avoidance test. K284-6111 treatment was found to reduce Aβ1-42-induced memory loss. RESULTS: A memory recovery effect was found to be associated with the reduction of Aβ1-42-induced expression of inflammatory proteins (iNOS, COX-2, GFAP, and Iba-1) and the suppression of CHI3L1 expression in the brain. Additionally, K284-6111 reduced Aβ1-42-induced β-secretase activity and Aβ generation. Lipopolysaccharide (LPS)-induced (1 μg/mL) expression of inflammatory (COX-2, iNOS, GFAP, Iba-1) and amyloidogenic proteins (APP, BACE1) were decreased in microglial BV-2 cells and cultured astrocytes by the K284-6111 treatment (0.5, 1, and 2 μM). Moreover, K284-6111 treatment suppressed p50 and p65 translocation into the nucleus, and phosphorylation of IκB in vivo and in vitro. CONCLUSION: These results suggest that CHI3L1 inhibitor could be an applicable intervention drug in amyloidogenesis and neuroinflammation, thereby preventing memory dysfunction via inhibition of NF-κB. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/30098604/K284_6111_prevents_the_amyloid_beta_induced_neuroinflammation_and_impairment_of_recognition_memory_through_inhibition_of_NF_κB_mediated_CHI3L1_expression_ L2 - https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-018-1269-3 DB - PRIME DP - Unbound Medicine ER -