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© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Background: Despite the important clinical issue of cognitive impairment after moderate traumatic brain injury (TBI), there is currently no suitable treatment. Here, we used in vitro and in vivo models to investigate the effect of Donepezil—an acetylcholinesterase (AChE) inhibitor—on cognitive impairment in the acute period following injury, while focusing on neuroinflammation and autophagy- and mitophagy-related markers. Methods: The purpose of the in vitro study was to investigate potential neuroprotective effects in TBI-induced cells after donepezil treatment, and the in vivo study, the purpose was to investigate therapeutic effects on cognitive impairment in the acute period after injury by analyzing neuroinflammation and autophagy- and mitophagy-related markers. The in vitro TBI model involved injuring SH-SY5Y cells using a cell-injury controller and then investigating the effect of donepezil at a concentration of 80 μM. The in vivo TBI model was made using a stereotaxic impactor for male C57BL/6J mice. Immuno-histochemical markers and cognitive functions were compared after 7 days of donepezil treatment (1 mg/kg/day). Mice were divided into four groups: sham operation with saline treatment, sham operation with donepezil treatment, TBI with saline treatment, and TBI with donepezil treatment (18 mice in each group). Donepezil treatment was administered within 4 h post-TBI. Results: In vitro, donepezil was found to lead to increased cell viability and 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimi-dazolylcarbocyanine iodide (JC-1), along with decreased reactive oxygen species (ROS), lactate-dehydrogenase (LDH), 2′-7′-dichlorodihydrofluorescein diacetate (DCFH-DA)-positive cells, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells. The mRNA and protein expressions of neuroinflammation (Cyclooxygenase-2, COX-2; NOD-like receptor protein 3, NLRP3; Caspase-1; and Interleukin-1 beta, IL-1β), as well as autophagy- and mitophagy-related markers (death-associated protein kinase 1, DAPK1; PTEN-induced kinase 1, PINK1; BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like, BNIP3L; Beclin-1, BECN1; BCL2-associated X protein, BAX; microtubule-associated protein 1A/1B-light chain 3B (LC3B); Sequestosome-1; and p62) were all found to decrease after donepezil treatment. The in vivo study also showed that donepezil treatment resulted in decreased levels of cortical tissue losses and brain swelling in TBI compared to the TBI group without donepezil treatment. Donepezil treatment was also shown to decrease the mRNA and Western blotting expressions of all markers, and especially COX-2 and BNIP3L, which showed the most significant decreases. Moreover, TBI mice showed an decreased escape latency, increased alteration rate, and improved preference index, altogether pointing to better cognitive performance after donepezil treatment. Conclusions: Donepezil treatment may be beneficial in improving cognitive impairment in the early phase of moderate traumatic brain injury by ameliorating neuroinflammation, as well as autophagy and mitophagy.

Details

Title
Therapeutic Effect of Donepezil on Neuroinflammation and Cognitive Impairment after Moderate Traumatic Brain Injury
Author
Youn, Dong Hyuk 1 ; Lee, Younghyurk 1   VIAFID ORCID Logo  ; Sung Woo Han 1 ; Jong-Tae, Kim 1   VIAFID ORCID Logo  ; Jung, Harry 1 ; Han, Gui Seung 2 ; Jung In Yoon 3 ; Lee, Jae Jun 4 ; Jeon, Jin Pyeong 5   VIAFID ORCID Logo 

 Institute of New Frontier Research Team, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea; [email protected] (D.H.Y.); [email protected] (Y.L.); [email protected] (S.W.H.); [email protected] (J.-T.K.); [email protected] (H.J.) 
 Life Genomics Co., Ltd., Research & Development Center, Suwon 16417, Republic of Korea; [email protected] 
 Department of Biological Sciences and Bioengineering, Inha University, Incheon 22212, Republic of Korea; [email protected] 
 Institute of New Frontier Research Team, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea; [email protected] (D.H.Y.); [email protected] (Y.L.); [email protected] (S.W.H.); [email protected] (J.-T.K.); [email protected] (H.J.); Department of Anesthesiology and Pain Medicine, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea 
 Institute of New Frontier Research Team, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea; [email protected] (D.H.Y.); [email protected] (Y.L.); [email protected] (S.W.H.); [email protected] (J.-T.K.); [email protected] (H.J.); Department of Neurosurgery, Hallym University College of Medicine, Chuncheon 24253, Republic of Korea 
First page
839
Publication year
2024
Publication date
2024
Publisher
MDPI AG
e-ISSN
20751729
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3084930431
Copyright
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.