Betulin ameliorates neuronal apoptosis and oxidative injury via DJ-1/Akt/Nrf2 signaling pathway after subarachnoid hemorrhage.

Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101473265 Publication Model: Print Cited Medium: Internet ISSN: 1755-5949 (Electronic) Linking ISSN: 17555930 NLM ISO Abbreviation: CNS Neurosci Ther Subsets: MEDLINE

Original Publication: Oxford, UK : Wiley-Blackwell, c2008-

Subarachnoid Hemorrhage*/metabolism ; Subarachnoid Hemorrhage*/drug therapy ; Subarachnoid Hemorrhage*/pathology ; Protein Deglycase DJ-1*/metabolism ; NF-E2-Related Factor 2*/metabolism ; Signal Transduction*/drug effects ; Signal Transduction*/physiology ; Apoptosis*/drug effects ; Rats, Sprague-Dawley* ; Triterpenes*/pharmacology ; Neurons*/drug effects ; Neurons*/metabolism ; Neurons*/pathology ; Oxidative Stress*/drug effects ; Oxidative Stress*/physiology ; Proto-Oncogene Proteins c-akt*/metabolism; Animals ; Rats ; Male ; Neuroprotective Agents/pharmacology ; Reactive Oxygen Species/metabolism ; Betulinic Acid

Aims: We aimed to resolve the uncertainty as to whether betulin exerted neuroprotection on early brain injury (EBI) caused by subarachnoid hemorrhage (SAH), and to investigate the related molecular mechanisms.
Methods: Bioinformatic analysis was performed to pre-study the differently expressed genes (DEGs) and the possible signaling pathways. Rat and cellular model of SAH were introduced in this study, and betulin, an activator of DJ-1 protein, was administered to reveal the effect. Gross assessment regarding mortality, neurofunctions, SAH grade, brain water content (BWC) along with multiple cellular and molecular studies in vivo or/and in vitro such as immunofluorescence (IF) staining, western blot (WB), reactive oxygen species (ROS) assay, and flow cytometry (FCM) were all conducted after SAH induction to verify the protective effect and the relevant mechanisms of DJ-1 in diverse levels. In addition, MK2206 (selective inhibitor of Akt) and iRNADj-1 (interfering RNA to Dj-1) were utilized to confirm the mechanisms of the effect.
Results: The data from our study showed that DJ-1 protein was moderately expressed in neurons, microglia, and astrocytes; its level in brain tissue elevated and peaked at 24-72 h after SAH induction. Betulin could efficaciously induce the expression of DJ-1 which in turn activated Akt and Bcl-2, and anti-oxidative enzymes SOD2 and HO-1, functioning to reduce the activation of cleaved caspase-3 (c-Casp-3) and reactive oxygen species (ROS). The induced DJ-1 could upregulate the expression of Nrf2. However, Akt seemed no direct effect on elevating the expression of Nrf2. DJ-1 alone could as well activate Akt-independent antiapoptotic pathway via suppressing the activation of caspase-8 (Casp-8).
Conclusions: Betulin which was a potent agonist of DJ-1 had the ability to induce its expression in brain tissue. DJ-1 had neuroprotective effect on EBI through comprehensive mechanisms, including facilitating intrinsic and extrinsic antiapoptotic pathway, and reducing oxidative injury by upregulating the expression of redox proteins. Betulin as an inexpensive drug showed the potential for SAH treatment.
(© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

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KUST-KH2023005Z Joint Projects of Yunnan Provincial Science and Technology Department and Kunming University of Science and Technology; 202101AY070001-252 Joint Projects of Yunnan Provincial Science and Technology Department and Kunming Medical University for Applied Basic Research; Z-2016-20-2101 Innovation Research Projects on Cerebrovascular Diseases for Young Doctors, China International Medical Foundation; 82001278 National Natural Science Foundation of China; 202401CF070007 Yunnan Fundamental Research Projects; KHBS-2022-018 The Fund for Young Doctors with the First People's Hospital of Yunnan Province

Keywords: DJ‐1; betulin; early brain injury; neuronal apoptosis; oxidative injury; subarachnoid hemorrhage

EC 3.1.2.- (Protein Deglycase DJ-1)
0 (NF-E2-Related Factor 2)
0 (Triterpenes)
6W70HN7X7O (betulin)
EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
0 (Nfe2l2 protein, rat)
EC 3.1.2.- (PARK7 protein, rat)
0 (Neuroprotective Agents)
0 (Reactive Oxygen Species)
4G6A18707N (Betulinic Acid)

Date Created: 20240906 Date Completed: 20240906 Latest Revision: 20240913

20250114

PMC11377304

10.1111/cns.70019

39238115