Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Aug 12;23(16):8997.
doi: 10.3390/ijms23168997.

12/15-Lipoxygenase Regulation of Diabetic Cognitive Dysfunction Is Determined by Interfering with Inflammation and Cell Apoptosis

Qi Chen  1   2 , Qixue Zheng  1 , Yang Yang  3 , Ying Luo  1 , Hong Wang  1 , Huan Li  1 , Lu Yang  1 , Congli Hu  1 , Jiahua Zhang  1 , Yuke Li  1 , Hui Xia  1 , Zhihao Chen  1 , Jie Ma  1 , Xiaoyan Tian  1 , Junqing Yang  1
Affiliations

12/15-Lipoxygenase Regulation of Diabetic Cognitive Dysfunction Is Determined by Interfering with Inflammation and Cell Apoptosis

Qi Chen et al. Int J Mol Sci. .

Abstract

This study aimed to discuss the role of 12/15-lipoxygenase (12/15-LOX) regulation involved in diabetes cognitive dysfunction. First, Mini Mental State Examination (MMSE) test was used to evaluate cognitive ability in diabetic patients and normal controls. The plasma test showed that the plasma level of 12/15-LOX in patients with MMSE scores below 27 was significantly increased compared with that of the normal group. Second, 12/15-LOX inhibitor was administered to diabetic rats. Behavioral tests, biochemistry, enzyme-linked immunosorbent assays, and Western blotting were used in this study. We found that the levels of fasting and random blood glucose increased rapidly in diabetic rats, the levels of triglycerides and total cholesterol in the diabetic group increased, and insulin levels decreased significantly. In the Morris water maze test, the escape latency was prolonged, and the crossing times decreased in the diabetic group. Under the microscope, the apoptosis of hippocampal neurons in diabetic rats increased significantly. The levels of TNF-α, IL-6 and 12-hydroxyindoleic acid (12(S)-HETE) significantly increased, and the protein expression of 12/15-LOX, p38 MAPK, Aβ1-42, caspase-3, caspase-9 and cPLA2 increased, while that of Bcl-2 decreased. However, the use of 12/15-LOX inhibitor reversed these results. Third, 12/15-LOX shRNA and p38MAPK inhibitor were administered to HT22 cells in high-glucose medium. The results of the cell experiment were consistent with those of the animal experiment. Our results indicated that the 12/15-LOX pathway participates in diabetic brain damage by activating p38MAPK to promote inflammation and neuronal apoptosis, and intervention 12/15-LOX can improve diabetic cognitive dysfunction.

Keywords: 12/15-lipoxygenase; cell apoptosis; diabetic cognitive dysfunction; inflammation; regulation.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
12/15-LOX is related to cognitive dysfunction in diabetes patients. The level of 12/15-LOX in the plasma of the diabetic patients with cognitive dysfunction.
Figure 2
Figure 2
The establishment of diabetes model. Fasting blood glucose level (A). Random blood glucose level (B). Insulin level (C). TG level (D). T−CHO level (E). LDH level (F). ** p < 0.01 compared with normal group.
Figure 3
Figure 3
The effect and mechanism of 12/15-LOX in hippocampal injury in diabetic rats. Morris water maze test (A). The change in 12(S)-HETE in diabetic rats hippocampal (B). The change in inflammatory factor in diabetic rats hippocampal (C). Changes in hippocampal pathology diabetic rats (D). Changes in hippocampus-related proteins in diabetic rats (E). MDA level (F). * p < 0.05, ** p < 0.05 and **** p < 0.0001 compared with normal group; # p < 0.05, ## p < 0.01 compared with model group.
Figure 4
Figure 4
The effect and mechanism of 12/15-LOX in HT22 cells damaged by high glucose. The effect of Baicalein in HT22 cells damaged by high glucose (A). Changes in 12/15-LOX and p38MAPK mRNA in HT22 cells damaged by high glucose (B). Changes in proteins in HT22 cells damaged by high glucose (C). * p < 0.05, ** p < 0.05 compared with normal group; # p < 0.05, ## p < 0.01 compared with model group.
Figure 5
Figure 5
The effect and mechanism of lentiviral knockdown 12/15-LOX in HT22 cells damaged by high glucose. The effect of knockdown 12/15-LOX in HT22 cells damaged by high glucose (A). Changes in proteins in knockdown 12/15-LOX HT22 cells damaged by high glucose (B). The effect of knockdown 12/15-LOX with p38MAPK inhibitor in HT22 cells damaged by high glucose (C). Changes in proteins in knockdown 12/15-LOX with p38MAPK inhibitor in HT22 cells damaged by high glucose (D). * p < 0.05, ** p < 0.01 compared with normal group; # p < 0.05, ## p < 0.01 compared with model group. ^ p < 0.05 and ^^ p < 0.05. ∆ p < 0.05 and ∆∆ p < 0.05.
Figure 6
Figure 6
Activation of 12/15-LOX leads to diabetic cognitive dysfunction by increasing the inflammatory response in the hippocampus. 12/15-LOX regulates p38 MAPK to mediate the inflammatory response and apoptosis which aggravate diabetic cognitive dysfunction.
See this image and copyright information in PMC

References

    1. International Diabetes Federation . IDF Diabetes Atlas. 9th ed. International Diabetes Federation; Brussels, Belgium: 2019.
    1. Reagan L.P. Diabetes as a chronic metabolic stressor: Causes, consequences and clinical complications. Exp. Neurol. 2012;233:68–78. doi: 10.1016/j.expneurol.2011.02.004. - DOI - PMC - PubMed
    1. Surkova E.V. Diabetes mellitus and the central nervous system. Ter. Arkh. 2016;88:82–86. doi: 10.17116/terarkh201688682-86. - DOI - PubMed
    1. Meyer J.S., Rauch G., Rauch R.A., Haque A. Risk factors for cerebral hypoperfusion, mild cognitive dysfunction, and dementia. Neurobiol. Aging. 2000;21:161–169. doi: 10.1016/S0197-4580(00)00136-6. - DOI - PubMed
    1. Akaishi T., Homma S. Baroreceptor control of vasopressin-producing cells in streptozotocin diabetic rats. Brain Res. Bull. 1993;31:719–722. doi: 10.1016/0361-9230(93)90147-4. - DOI - PubMed

MeSH terms

Substances