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MDMX elevation by a novel Mdmx-p53 interaction inhibitor mitigates neuronal damage after ischemic stroke.

ABSTRACT: Mdmx and Mdm2 are two major suppressor factors for the tumor suppressor gene p53. In central nervous system, Mdmx suppresses the transcriptional activity of p53 and enhances the binding of Mdm2 to p53 for degradation. But Mdmx dynamics in cerebral infarction remained obscure. Here we investigated the role of Mdmx under ischemic conditions and evaluated the effects of our developed small-molecule Protein-Protein Interaction (PPI) inhibitors, K-181, on Mdmx-p53 interactions in vivo and in vitro. We found ischemic stroke decreased Mdmx expression with increased phosphorylation of Mdmx Serine 367, while Mdmx overexpression by AAV-Mdmx showed a neuroprotective effect on neurons. The PPI inhibitor, K-181 attenuated the neurological deficits by increasing Mdmx expression in post-stroke mice brain. Additionally, K-181 selectively inhibited HDAC6 activity and enhanced tubulin acetylation. Our findings clarified the dynamics of Mdmx in cerebral ischemia and provide a clue for the future pharmaceutic development of ischemic stroke.

SUBMITTER: Yan H

PROVIDER: S-EPMC9726886 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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MDMX elevation by a novel Mdmx-p53 interaction inhibitor mitigates neuronal damage after ischemic stroke.

Yan Haomin H Sasaki Tsutomu T Kanki Hideaki H Hirata Yoshiyuki Y Nishiyama Kumiko K Hisada Sunao S Matsumura Shigenobu S Nagaoka Yasuo Y Sumiyoshi Takaaki T Nagano Seiichi S Nakata Akiko A Yoshida Minoru M Uesato Shinichi S Mochizuki Hideki H

Scientific reports 20221206 1

Mdmx and Mdm2 are two major suppressor factors for the tumor suppressor gene p53. In central nervous system, Mdmx suppresses the transcriptional activity of p53 and enhances the binding of Mdm2 to p53 for degradation. But Mdmx dynamics in cerebral infarction remained obscure. Here we investigated the role of Mdmx under ischemic conditions and evaluated the effects of our developed small-molecule Protein-Protein Interaction (PPI) inhibitors, K-181, on Mdmx-p53 interactions in vivo and in vitro. W ...[more]

PMID: 36473920

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Project description:Background. Cardiac morbidities account for 20% of deaths after ischemic stroke and is the second commonest cause of death in acute stroke population. Elevation of cardiac troponin has been regarded as a prognostic biomarker of poor outcome in patients with acute stroke. Methods. This retrospective study enrolled 871 patients with acute ischemic stroke from August 2010 to March 2015. Data included vital signs, laboratory parameters collected in the emergency department, and clinical features during hospitalization. National Institutes of Health Stroke Scale (NIHSS), Barthel index, and modified Rankin Scale (mRS) were used to assess stroke severity and outcome. Results. Elevated troponin I (TnI) > 0.01 µg/L was observed in 146 (16.8%) patients. Comparing to patients with normal TnI, patients with elevated TnI were older (median age 77.6 years vs. 73.8 years), had higher median heart rates (80 bpm vs. 78 bpm), higher median white blood cells (8.40 vs. 7.50 1,000/m(3)) and creatinine levels (1.40 mg/dL vs. 1.10 mg/dL), lower median hemoglobin (13.0 g/dL vs. 13.7 g/dL) and hematocrit (39% vs. 40%) levels, higher median NIHSS scores on admission (11 vs. 4) and at discharge (8 vs. 3), higher median mRS scores (4 vs3) but lower Barthel index scores (20 vs. 75) at discharge (p < 0.001). Multivariate analysis revealed that age ≥ 76 years (OR 2.25, CI [1.59-3.18]), heart rate ≥ 82 bpm (OR 1.47, CI [1.05-2.05]), evidence of clinical deterioration (OR 9.45, CI [4.27-20.94]), NIHSS score ≥ 12 on admission (OR 19.52, CI [9.59-39.73]), and abnormal TnI (OR 1.98, CI [1.18-3.33]) were associated with poor outcome. Significant factors for in-hospital mortality included male gender (OR 3.69, CI [1.45-9.44]), evidence of clinical deterioration (OR 10.78, CI [4.59-25.33]), NIHSS score ≥ 12 on admission (OR 8.08, CI [3.04-21.48]), and elevated TnI level (OR 5.59, CI [2.36-13.27]). C-statistics revealed that abnormal TnI improved the predictive power of both poor outcome and in-hospital mortality. Addition of TnI > 0.01 ug/L or TnI > 0.1 ug/L to the model-fitting significantly improved c-statistics for in-hospital mortality from 0.887 to 0.926 (p = 0.019) and 0.927 (p = 0.028), respectively. Discussion. Elevation of TnI during acute stroke is a strong independent predictor for both poor outcome and in-hospital mortality. Careful investigation of possible concomitant cardiac disorders is warranted for patients with abnormal troponin levels.

Project description:The objectives of this study are to identify the mechanism of mitochondrial dysfunction during cerebral ischemic/reperfusion (I/R) injury and the therapeutic potential of tetrahydrocurcumin (THC) to mitigate mitochondrial dysfunction in experimental stroke model. In our study, 8-10 weeks old male C57BL/6 wild-type mice were subjected to middle cerebral artery occlusion (MCAO) for 40 min, followed by reperfusion for 72 h. THC (25mg/kg-BW/day) was injected intraperitoneally once daily for 3 days after 4 h of ischemia. The experimental groups were: (i) sham, (ii) I/R and (iii) I/R + THC. We noticed that THC treatment in ischemic mice significantly improved the functional capacity and motor co-ordination along with reduced neuroscore, infarct volume, brain edema and microvascular leakage in brain parenchyma. The study revealed that level of total homocysteine (tHcy), homocysteine metabolizing enzymes, mitochondrial oxidative stress were significantly altered in I/R mice compared to sham. We also observed alteration in mitochondrial transition pore, ATP production and O2 consumption in the ischemic brain as compared to sham. Further, elevated matrix metalloproteinases-9 (MMP-9) activity and reduced tight junction protein expressions intensified the brain vascular impairment in I/R mice compared to sham. Interestingly, we found that levels of mitophagy markers, fusion and fission proteins were significantly altered. However THC treatment in I/R mice almost normalized the above functional and molecular changes. Mechanistic study demonstrated that DNA Methyltransferase 1 (DNMT1) expression was higher and was associated with reduced mitochondrial tissue inhibitor of metalloproteinases 2 (TIMP-2) expression through hyper-methylation of CpG island of TIMP-2 promoter in I/R mice compared to sham. However, administration of epigenetic inhibitor, 5-Azacytidine (5-Aza) abrogated I/R induced hyper-methylation of TIMP-2 promoter and maintaining the extracellular matrix (ECM) integrity. In conclusion, this study suggests that THC epigenetically ameliorates mitochondrial dysfunction in brain vasculature during Ischemic Stroke.

Dataset Information

MDMX elevation by a novel Mdmx-p53 interaction inhibitor mitigates neuronal damage after ischemic stroke.

Publications

MDMX elevation by a novel Mdmx-p53 interaction inhibitor mitigates neuronal damage after ischemic stroke.

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