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. 2022 Nov 3:14:930016.
doi: 10.3389/fnagi.2022.930016. eCollection 2022.

Molar loss further exacerbates 2-VO-induced cognitive impairment associated with the activation of p38MAPK/NFκB pathway

Yunping Lu  1 , Qian Pang  1 , Qianqian Wu  2 , Bin Luo  1 , Xiaofei Tang  3 , Qingsong Jiang  1
Affiliations

Molar loss further exacerbates 2-VO-induced cognitive impairment associated with the activation of p38MAPK/NFκB pathway

Yunping Lu et al. Front Aging Neurosci. .

Erratum in

Abstract

Background: Vascular dementia is characterized by reduced cognitive function due to chronic cerebral hypoperfusion and has become a significant public health challenge as the global population ages. Recent studies suggested that molar loss, a common problem among the elderly, may trigger the development of cognitive decline. Our previous study found that the molar loss affected cognitive dysfunction, and the astrocytes in the hippocampus of chronic cerebral ischemia rats were affected, but the underlying mechanism is unclear.

Methods: In this study, we established the animal model of molar loss with 2-VO rats and the Morris water maze was used to test the cognitive ability of rats in each group. The damage to neurons was observed via Nissl staining, and neuronal apoptosis was analyzed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay in the hippocampus of the rats. Quantitative Real-Time PCR and immunohistochemistry and histology (IHC) were used to detect the expression of p38MAPK, NFκB, caspase 3, and iNOS in the hippocampus. The astrocytes were detected by IHC and Immunofluorescence analysis for GFAP. After 2-VO MO surgery, rats were administered DMSO or p38MAPK inhibitor (SB203580) by intrathecal injection.

Results: The Morris water maze test showed that the molar loss aggravated spatial memory learning ability with chronic cerebral ischemia decreased in the rats. The neuronal damage and more apoptotic cells were observed in the hippocampus of 2-VO rats. After the molar loss, the mRNA and protein expression of iNOS, p38MAPK, NFκB, and caspase 3 were further upregulated in 2-VO rats. Molar loss upregulated GFAP expression, and the p38MAPK-positive cells were labeled with the astrocyte marker GFAP. SB203580 reduced cognitive impairment and apoptosis of hippocampal neurons in 2-VO rats following the molar loss.

Conclusion: Molar loss can aggravate cognitive impairment in 2-VO rats to a certain extent. The mechanism of molar loss exacerbating the cognitive decline in 2-VO rats may be associated with the activation of the p38MAPK-NFκB-caspase 3 signaling pathway, which induces neuronal apoptosis.

Keywords: apoptosis; cognitive impairment; molar loss; p38MAPK; vascular dementia.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic of the experimental protocol.
FIGURE 2
FIGURE 2
Evaluation of memory and learning function via Morris water maze test. (A) Changes of escape latency in learning trial. (B) Representative traces of the probe test in the water maze test; (C) the time of first passing the platform (TFPP). (D) The frequency of passing the platform (FPP) in each group. (E) Time spent in the target quadrant of four groups in the probe trial. (F) Body weight changes in groups (All values are expressed as mean ± SD, n = 10, *p < 0.05).
FIGURE 3
FIGURE 3
Effects of molar loss on the CA1 and CA3 neurons morphology in 2-VO rats’ hippocampus (Nissl’s staining, ×200, n = 4).
FIGURE 4
FIGURE 4
TUNEL staining of CA1 region of rat hippocampus. (A) Cell nuclei (blue), the red spots represent TUNEL-positive cells. (B) The TUNEL-positive rate in CA1 quantification (×200, the positive rate is expressed as mean ± SD, n = 4, *p < 0.05, **p < 0.01).
FIGURE 5
FIGURE 5
Effects of molar loss on the mRNA expression of p38MAPK (A), NFκB (B), caspase3 (C), and iNOS (D) in the rat hippocampus. All values are expressed as mean ± SD, *p < 0.05, n = 6).
FIGURE 6
FIGURE 6
Effects of molar loss on the protein expression of p38MAPK, NFκB and caspase3 in the CA1 region of rat hippocampus. (A) Representative IHC images of p38MAPK, NFκB, and caspase 3 (IHC, ×200). (B–D) The MOD values are expressed as mean ± SD, n = 4, *p < 0.05, **p < 0.01.
FIGURE 7
FIGURE 7
Effects of molar loss on GFAP in the rat hippocampus. (A,B) IHC staining showed the expression of GFAP (IHC, ×200, n = 4, MOD values are expressed as mean ± SD, *p < 0.05, **p < 0.01). (C) Double immunofluorescent staining revealed colocalization of GFAP (green) and p38MAPK (red) proteins in the rat hippocampus, and the nuclei were in blue (magnification ×400).
FIGURE 8
FIGURE 8
Effects of SB203580 on cognitive impairment and apoptosis of hippocampal neurons in 2-VO rats following molar loss. (A) Changes in escape latency in learning trial (*p < 0.05). (B) The frequency of passing the platform (FPP) in each group (*p < 0.05). (C,D) TUNEL staining of CA1 region of rat hippocampus cell nuclei (blue), the red spots represent TUNEL-positive cells (×200, the positive rate is expressed as mean ± SD, n = 6, **p < 0.01). IHC staining showed the expression of p38MAPK, caspase3, and NFκB (IHC, × 200, n = 6, MOD values are expressed as mean ± SD, **p < 0.01).
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References

    1. Ashabi G., Alamdary S. Z., Ramin M., Khodagholi F. (2013). Reduction of hippocampal apoptosis by intracerebroventricular administration of extracellular signal-regulated protein kinase and/or p38 inhibitors in amyloid beta rat model of Alzheimer’s disease: involvement of nuclear-related factor-2 and nuclear factor-κB. Basic Clin. Pharmacol. Toxicol. 112 145–155. 10.1111/bcpt.12000 - DOI - PubMed
    1. Bird C. W., Taylor D. H., Pinkowski N. J., Chavez G. J., Valenzuela C. F. (2018). Long-term reductions in the population of GABAergic Interneurons in the Mouse Hippocampus following Developmental Ethanol Exposure. Neuroscience 383 60–73. 10.1016/j.neuroscience.2018.05.003 - DOI - PMC - PubMed
    1. Cao Y., Li K., Fu K. Y., Xie Q. F., Chiang C. Y., Sessle B. J. (2013). Central sensitization and MAPKs are involved in occlusal interference-induced facial pain in rats. J. Pain 14 793–807. 10.1016/j.jpain.2013.02.005 - DOI - PMC - PubMed
    1. Cerutti-Kopplin D., Feine J., Padilha D. M., de Souza R. F., Ahmadi M., Rompre P., et al. (2016). Tooth loss increases the risk of diminished cognitive function: a systematic review and meta-analysis. JDR Clin. Trans. Res. 1 10–19. 10.1177/2380084416633102 - DOI - PubMed
    1. Chang Y. C., Huang C. C. (2006). Perinatal brain injury and regulation of transcription. Curr. Opin. Neurol. 19 141–147. 10.1097/01.wco.0000218229.73678.a8 - DOI - PubMed