Ruta graveolens water extract (RGWE) ameliorates ischemic damage and improves neurological deficits in a rat model of transient focal brain ischemia

Campanile, Marta; Cuomo, Ornella; Brancaccio, Paola; Vinciguerra, Antonio; Casamassa, Antonella; Pastorino, Olga; Volpicelli, Floriana; Gentile, Maria Teresa; Amoroso, Salvatore; Annunziato, Lucio; Colucci-D’Amato, Luca; Pignataro, Giuseppe

doi:10.1016/j.biopha.2022.113587

Cited by 5 publications

(3 citation statements)

References 38 publications

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“…This was described by the study of Du et al, since microglia activation and prominent neuroinflammation following global cerebral ischemia in animal models contribute to demyelination (Du et al 2020 ). Our study is congruent with several studies evidencing that enormous ROS production, increased GFAP expression, and apoptosis signaling are the main cornerstones in cerebral I/R-induced brain injury (Yuan et al 2020 ; Campanile et al 2022 ; Du et al 2023 ; Hu et al 2023 ) because they have a direct influence on halting autophagy, which has a significant role in neuroprotection (Carloni and Balduini 2020 ). Different studies have reported the impact of autophagy on regulating Notch1 signaling.…”

Section: Discussionsupporting

confidence: 92%

Sesamol defends neuronal damage following cerebral ischemia/reperfusion: a crosstalk of autophagy and Notch1/NLRP3 inflammasome signaling

El-Sayyad,

El-Ella,

Hafez

et al. 2023

Inflammopharmacol

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Objective Sesamol (SES) is a phenolic compound found in sesame seed oil. Several studies have revealed its anti-inflammatory and antioxidant properties. However, its complete underlying mechanistic perspective about cerebral ischemia/reperfusion (I/R) lesions has not yet been disclosed. Consequently, we aimed to scrutinize its neuroprotective mechanism against cerebral injury during a global cerebral I/R in a rat model, considering its impact on autophagy and Notch1/NLRP3 inflammasome signaling regulation. Methods To affirm our purpose, adult Wistar rats were allotted into five groups: sham and the other four groups in which transient global cerebral ischemia was induced by bilateral common ligation (2VO) for 1 h, then reperfusion for either 24 h or 5 days: I/R (1/24), I/R (1/5), SES + I/R (1/24), and SES + I/R (1/5). In treated groups, SES (100 mg/kg, p.o., for 21 days) was administered before cerebral I/R induction. The assessment of histopathological changes in brain tissues, immunohistochemistry, biochemical assays, ELISA, and qRT-PCR were utilized to investigate our hypothesis. Results Advantageously, SES halted the structural neuronal damage with lessened demyelination induced by cerebral I/R injury. Restoring oxidant/antioxidant balance was evident by boosting the total antioxidant capacity and waning lipid peroxidation. Furthermore, SES reduced inflammatory and apoptosis markers. Additionally, SES recovered GFAP, Cx43, and autophagy signaling, which in turn switched off the Notch-1/NLRP3 inflammasome trajectory. Conclusions Our results revealed the neuroprotective effect of SES against cerebral I/R injury through alleviating injurious events and boosting autophagy, consequently abolishing Notch1/NLRP3 inflammasome signaling.

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Section: Discussionsupporting

confidence: 92%

Sesamol defends neuronal damage following cerebral ischemia/reperfusion: a crosstalk of autophagy and Notch1/NLRP3 inflammasome signaling

El-Sayyad,

El-Ella,

Hafez

et al. 2023

Inflammopharmacol

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“…Higher dosages of PIM have demonstrated a strong antiepileptic impact against ICES (26) as well as substantial nootropic effects on the MES model (7). Another well-known flavonoid is rutin, which has nootropic properties (19)(20)(21)(22)(23)(24)(25).Therefore, the goal of this investigation was to convince the effect. Thus in this study it was intended to persuade the effect of co administration of PIM and Rutin with a clinically established AED in antiepileptic therapy.…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Rutin on Cognition Impairment Caused by Levetiracetam.

2024

Journal of Chemical Health Risks

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Objective: To investigate how levetiracetam and rutin, as opposed to levetiracetam and piracetam, affects mice's ability to control their seizures and their cognitive and motor abilities. Materials and Methods: Utilizing the increasing current electroshock seizure (ICES) test, levetiracetam and piracetam's combined effect on convulsions was assessed. While motor capabilities were screened utilizing a rolling roller equipment and counting the number of arm entries on a plus maze, cognitive functions in mice were evaluated by means of spontaneous alternation in behavior on a plus maze. The Ellman et al. method was used to quantify the activity of brain acetylcholinesterase (AChE). Results: The research demonstrated that rutin, when given in addition to levetiracetam, dramatically reversed the drug's lowering of spontaneous alternation without affecting levetiracetam's effectiveness against In both short-term and long-term research, ICES. Moreover, it undid the rise in AChE activity brought on by levetiracetam. Conclusion: In summary, rutin mitigated the cognitive deficit brought on by levetiracetam while maintaining its antiepileptic effectiveness.

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“…The fluorescence of proteins HDAC9, HIF1, TfR1, SP1, GPX4 has been quantified in terms of pixel intensity on tissue sections at the level of the cortex by using Image J software, as previously described 41 , 42 . Images from the same areas of brain cortex were compared.…”

Section: Methodsmentioning

confidence: 99%

Stroke by inducing HDAC9-dependent deacetylation of HIF-1 and Sp1, promotes TfR1 transcription and GPX4 reduction, thus determining ferroptotic neuronal death

Sanguigno,

Guida,

Anzilotti

et al. 2023

Int. J. Biol. Sci.

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Background: The inhibition of histone deacetylase 9 (HDAC9) represents a promising druggable target for stroke intervention. Indeed, HDAC9 is overexpressed in neurons after brain ischemia where exerts a neurodetrimental role. However, mechanisms of HDAC9-dependent neuronal cell death are not yet well established. Methods: Brain ischemia was obtained in vitro by primary cortical neurons exposed to glucose deprivation plus reoxygenation (OGD/Rx) and in vivo by transient middle cerebral artery occlusion. Western blot and quantitative real-time polymerase chain reaction were used to evaluate transcript and protein levels. Chromatin immunoprecipitation was used to evaluate the binding of transcription factors to the promoter of target genes. Cell viability was measured by MTT and LDH assays. Ferroptosis was evaluated by iron overload and 4-hydroxynonenal (4-HNE) release. Results: Our results showed that HDAC9 binds to hypoxia-inducible factor 1 (HIF-1) and specificity protein 1 (Sp1), two transcription activators of transferrin 1 receptor (TfR1) and glutathione peroxidase 4 (GPX4) genes, respectively, in neuronal cells exposed to OGD/Rx. Consequently, HDAC9 induced: (1) an increase in protein level of HIF-1 by deacetylation and deubiquitination, thus promoting the transcription of the pro-ferroptotic TfR1 gene; and (2) a reduction in Sp1 protein levels by deacetylation and ubiquitination, thus resulting in a down-regulation of the anti-ferroptotic GPX4 gene. Supporting these results, the silencing of HDAC9 partially prevented either HIF-1 increase and Sp1 reduction after OGD/Rx. Interestingly, silencing of the neurodetrimental factors, HDAC9, HIF-1, or TfR1 or the overexpression of the prosurvival factors Sp1 or GPX4 significantly reduced a well-known marker of ferroptosis 4-HNE after OGD/Rx. More important, in vivo , intracerebroventricular injection of siHDAC9 reduced 4-HNE levels after stroke by preventing: (1) HIF-1 and TfR1 increase and thus the augmented intracellular iron overload; and (2) a reduction of Sp1 and its target gene GPX4. Conclusions: Collectively, results obtained suggest that HDAC9 mediates post-traslational modifications of HIF-1 and Sp1 that, in turn, increases TfR1 and decreases GPX4 expression, thus promoting neuronal ferroptosis in in vitro and in vivo models of stroke.

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Ruta graveolens water extract (RGWE) ameliorates ischemic damage and improves neurological deficits in a rat model of transient focal brain ischemia

Cited by 5 publications

References 38 publications

Sesamol defends neuronal damage following cerebral ischemia/reperfusion: a crosstalk of autophagy and Notch1/NLRP3 inflammasome signaling

Sesamol defends neuronal damage following cerebral ischemia/reperfusion: a crosstalk of autophagy and Notch1/NLRP3 inflammasome signaling

Protective Effect of Rutin on Cognition Impairment Caused by Levetiracetam.

Stroke by inducing HDAC9-dependent deacetylation of HIF-1 and Sp1, promotes TfR1 transcription and GPX4 reduction, thus determining ferroptotic neuronal death

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