1. Academic Validation
  2. Morinda officinalis oligosaccharides mitigate depression-like behaviors in hypertension rats by regulating Mfn2-mediated mitophagy

Morinda officinalis oligosaccharides mitigate depression-like behaviors in hypertension rats by regulating Mfn2-mediated mitophagy

  • J Neuroinflammation. 2023 Feb 10;20(1):31. doi: 10.1186/s12974-023-02715-y.
Lixuan Yang 1 Yutian Ao 1 Yannan Li 1 Baoan Dai 1 Jingchun Li 1 Wenzhe Duan 1 Wei Gao 2 Zhonghui Zhao 1 3 Zhenyun Han 4 Rongjuan Guo 5
Affiliations

Affiliations

  • 1 Second Clinical Medical College, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China.
  • 2 Department of Clinical Psychology, Yuquan Hospital of Tsinghua University, Beijing, 100049, People's Republic of China.
  • 3 Department of Traditional Chinese Medicice, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, People's Republic of China.
  • 4 Department of Neurology, Shenzhen Hospital of Beijing University of Chinese Medicine, Shenzhen, 518110, Guangdong, People's Republic of China.
  • 5 Department of Neurology, Dongfang Hospital, Beijing University of Chinese Medicine, No.6, Fangxingyuan 1st Block, Fengtai District, Beijing, 100078, People's Republic of China. dfguorongjuan@163.com.
Abstract

Objective: Patients with hypertension have a risk of depression. Morinda officinalis oligosaccharides (MOOs) have anti-depressant properties. In this study, we aimed to determine whether MOOs can improve the symptoms of depression in individuals with hypertension.

Methods: Dahl salt-sensitive rats fed with a high-salt diet were stimulated by chronic unpredictable mild stress to mimic hypertension with depression. Primary astrocytes and neurons were isolated from these rats. Astrocytes underwent LPS stimulation to simulate the inflammatory astrocytes during depression. MOOs were administrated at 0.1 mg/g/day in vivo and 1.25, 2.5, and 5 mg/mL in vitro. Mitophagy was inhibited using 5 mM 3-methyladenine (3-MA). Astrocyte-mediated neurotoxicity was detected by co-culturing astrocytes and neurons.

Results: MOOs decreased systolic pressure, diastolic pressure, and mean arterial pressure, thereby improving depression-like behavior, including behavioral despair, lack of enthusiasm, and loss of pleasure during hypertension with depression. Furthermore, MOOs inhibited inflammation, astrocytic dysfunction, and mitochondrial damage in the brain. Then, MOOs promoted autophagosome and lysosome enriched in mitochondria in LPS-stimulated astrocytes. MOOs suppressed mitochondrial damage and the release of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β in astrocytes undergoing LPS stimulation. Importantly, MOOs rescued the impaired neurons co-cultured with astrocytes. The effects of MOOs on LPS-stimulated astrocytes were reversed by 3-MA. Finally, MOOs upregulated LPS-downregulated Mfn2 expression in astrocytes. Mfn2 inhibition partly reversed the effects of MOOs on hypertension with depression. Intriguingly, Mfn2 suppression activated PI3K/Akt/mTOR pathway during MOOs treatment.

Conclusions: Astrocytes develop neuroinflammation in response to mitochondrial damage during hypertension with depression. MOOs upregulated Mfn2 expression to activate the PI3K/Akt/mTOR pathway-mediated Mitophagy, thereby removing impaired mitochondria in astrocytes.

Highlights: 1. MOOs have anti-hypertensive and anti-depressive properties. 2. MOOs inhibit inflammation and injury in astrocytes during hypertension with depression. 3. MOOs induce Mitophagy activation in inflammatory astrocytes with mitochondrial damage. 4. MOOs upregulate Mfn2 expression in astrocytes. 5. Mfn2 activates Mitophagy to resist mitochondrial damage in astrocytes.

Keywords

Astrocytes; Depression; Hypertension; Mitochondrial damage; Morinda officinalis oligosaccharides.

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