PMID- 33969676 OWN - NLM STAT- MEDLINE DCOM- 20211125 LR - 20211125 IS - 1509-572X (Electronic) IS - 1509-572X (Linking) VI - 59 IP - 1 DP - 2021 TI - Fasudil ameliorates cognitive deficits, oxidative stress and neuronal apoptosis via inhibiting ROCK/MAPK and activating Nrf2 signalling pathways in APP/PS1 mice. PG - 32-49 LID - 43762 [pii] LID - 10.5114/fn.2021.105130 [doi] AB - Alzheimer's disease (AD) is a severe neurodegenerative disorder of the central nervous system (CNS) characterized by neuron loss and dementia. Previous abundant evidence demonstrates that the first critical step in the course of AD is the state of oxidative stress and the neuronal loss is closely related to the interaction of several signalling pathways. The neuroprotective efficacy of Rho-associated protein kinase (ROCK) inhibitor in the treatment of AD has been reported, but its exact mechanism has not been well elucidated. The purpose of this study is to investigate the therapeutic effects of Fasudil on amyloid precursor protein/presenilin-1 (APP/PS1) mice and to discover the potential underlying mechanism. Sixteen 8-month-old APP/PS1 mice were divided into model and Fasudil treatment groups and 8 wild-type mice were used as a normal control group. After the behavioural test, all mice were sacrificed for immunofluorescence and other biochemical tests. The results showed that the administration of Fasudil improved learning and memory ability, elevated the concentration of antioxidative substances and decreased lipid peroxides, as well as inhibited neuronal apoptosis by increasing the expression of B-cell lymphoma-2 (Bcl-2) (p < 0.05), reducing Bcl-2 Associated X (Bax) (p < 0.05) and cleaved caspase-3 (p < 0.05) of APP/PS1 mice. Moreover, Fasudil treatment also ameliorated the phosphorylation of p38 (p < 0.01), c-Jun N-terminal kinase (JNK) (p < 0.001) and extracellular regulated protein kinases (ERK) (p < 0.001), and accelerated the nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) (p < 0.01) expression and its antioxidative downstream molecules (p < 0.05, p < 0.05, and p < 0.05, respectively). Data from the present study demonstrate that Fasudil significantly restored cognitive function, restrained oxidative stress and reduced neuronal apoptosis in the hippocampus, probably by inhibiting ROCK/MAPK and activating Nrf2 signalling pathways in APP/PS1 mice. FAU - Wei, Wenyue AU - Wei W AD - Department of Neurology, First Affiliated Hospital, Shanxi Medical University, Taiyuan, P.R. China. AD - 2Research Center of Neurobiology, The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine, Shanxi University of Chinese Medicine, Jinzhong 030619, P.R. China. AD - Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Shanxi Datong University, Datong, P.R. China. FAU - Wang, Yuyin AU - Wang Y AD - 2Research Center of Neurobiology, The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine, Shanxi University of Chinese Medicine, Jinzhong 030619, P.R. China. AD - Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Shanxi Datong University, Datong, P.R. China. FAU - Zhang, Jing AU - Zhang J AD - 2Research Center of Neurobiology, The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine, Shanxi University of Chinese Medicine, Jinzhong 030619, P.R. China. AD - Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Shanxi Datong University, Datong, P.R. China. FAU - Gu, Qingfang AU - Gu Q AD - Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Shanxi Datong University, Datong, P.R. China. FAU - Liu, Xiaoqin AU - Liu X AD - Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Shanxi Datong University, Datong, P.R. China. FAU - Song, Lijuan AU - Song L AD - Department of Neurology, First Affiliated Hospital, Shanxi Medical University, Taiyuan, P.R. China. AD - 2Research Center of Neurobiology, The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine, Shanxi University of Chinese Medicine, Jinzhong 030619, P.R. China. FAU - Chai, Zhi AU - Chai Z AD - Department of Neurology, First Affiliated Hospital, Shanxi Medical University, Taiyuan, P.R. China. AD - 2Research Center of Neurobiology, The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine, Shanxi University of Chinese Medicine, Jinzhong 030619, P.R. China. AD - Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Shanxi Datong University, Datong, P.R. China. FAU - Guo, Minfang AU - Guo M AD - Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Shanxi Datong University, Datong, P.R. China. FAU - Yu, Jiezhong AU - Yu J AD - Department of Neurology, First Affiliated Hospital, Shanxi Medical University, Taiyuan, P.R. China. AD - Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Shanxi Datong University, Datong, P.R. China. AD - Department of Neurology, Datong Fourth People's Hospital, Datong, P.R. China. FAU - Ma, Cungen AU - Ma C AD - Department of Neurology, First Affiliated Hospital, Shanxi Medical University, Taiyuan, P.R. China. AD - 2Research Center of Neurobiology, The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine, Shanxi University of Chinese Medicine, Jinzhong 030619, P.R. China. AD - Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Shanxi Datong University, Datong, P.R. China. LA - eng PT - Journal Article PL - Poland TA - Folia Neuropathol JT - Folia neuropathologica JID - 9437431 RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (NF-E2 Transcription Factor, p45 Subunit) RN - 0 (Presenilin-1) RN - 84477-87-2 (1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine) RN - EC 2.7.11.1 (Rock2 protein, mouse) RN - EC 2.7.11.1 (rho-Associated Kinases) RN - Q0CH43PGXS (fasudil) SB - IM MH - 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/*analogs & derivatives/pharmacology/therapeutic use MH - Alzheimer Disease/drug therapy MH - Amyloid beta-Protein Precursor MH - Animals MH - Apoptosis/*drug effects MH - Cognition/*drug effects MH - Disease Models, Animal MH - Hippocampus/metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - NF-E2 Transcription Factor, p45 Subunit/*metabolism MH - Oxidative Stress/*drug effects MH - Presenilin-1 MH - Signal Transduction/*drug effects MH - rho-Associated Kinases/*metabolism OTO - NOTNLM OT - MAPK OT - Nrf2. OT - ROCK OT - apoptosis OT - oxidative stress OT - Alzheimer's disease EDAT- 2021/05/11 06:00 MHDA- 2021/11/26 06:00 CRDT- 2021/05/10 07:40 PHST- 2021/05/10 07:40 [entrez] PHST- 2021/05/11 06:00 [pubmed] PHST- 2021/11/26 06:00 [medline] AID - 43762 [pii] AID - 10.5114/fn.2021.105130 [doi] PST - ppublish SO - Folia Neuropathol. 2021;59(1):32-49. doi: 10.5114/fn.2021.105130.