RESUMEN
Vanillic acid (VA) exhibited antioxidant and neuroprotective properties in some neurodegenerative disorders. So, the current study examined the neuroprotective potential of VA as an antiepileptic agent in pentylenetetrazole (PTZ)-induced epileptic rats and the prospective role of Insulin like growth factor-1 (IGF-1) and nuclear factor-2 erythroid-related factor-2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in this respect. Thirty male albino rats were equally subdivided into 3 groups; (1) normal control (NC) group, (2) PTZ-group: received PTZ (50 mg/Kg, i.p. every other day) for 14 days, and (3) PTZ + VA group: received PTZ and VA (50 mg/Kg daily for 2 weeks). The seizure score and latency were evaluated after PTZ injection. Also, the markers of oxidative stress (malondialdehyde (MDA), catalase, and reduced glutathione (GSH)), histopathological examination, the expression of glial fibrillary acidic protein (GFAP) (a marker of astrocytes) IGF-1, Nrf2, and HO-1 were assessed in the brain tissues by the end of the experiment. PTZ caused significant decrease in seizure latency and significant increase in seizure score by the end of the experiment (p < 0.01). This was associated with significant increase in MDA and GFAP with significant decrease in GSH, total antioxidant capacity (TAC) and IGF-1 in brain tissues compared to normal group (p < 0.01). On the other hand, treatment with VA caused significant attenuation in PTZ-induced seizures which was associated with significant improvement in oxidative stress markers and downregulation in GFAP and upregulation of Nrf2, HO-1 and IGF-1 in CA3 hippocampal region (p < 0.01). VA showed neuroprotective and anti-epileptic effects against PTZ-induced epilepsy which probably might be due to its antioxidant properties and upregulation of Nrf2/HO-1 pathway and IGF-1.
Asunto(s)
Anticonvulsivantes/farmacología , Antioxidantes/farmacología , Epilepsia/tratamiento farmacológico , Epilepsia/metabolismo , Hemo Oxigenasa (Desciclizante)/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/efectos de los fármacos , Factor 2 Relacionado con NF-E2/efectos de los fármacos , Ácido Vanílico/farmacología , Animales , Anticonvulsivantes/administración & dosificación , Antioxidantes/administración & dosificación , Convulsivantes/farmacología , Modelos Animales de Enfermedad , Epilepsia/inducido químicamente , Masculino , Pentilenotetrazol/farmacología , Ratas , Transducción de Señal/efectos de los fármacos , Ácido Vanílico/administración & dosificaciónRESUMEN
The current study investigated the effects of stevia extracts on a PTZ-induced epileptic rat model and its potential mechanism. Thirty male Sprague-Dawley rats were equally subdivided into 3 groups; (1) normal control (NC) group, (2) PTZ-group: received PTZ (50 mg/kg, i.p. every other day) for 2 weeks, and (3) PTZ+ Stevia group: received PTZ and stevia (200 mg/kg orally daily) for 4 weeks (2 weeks before the start of PTZ treatment and 2 weeks with PTZ administration). The first jerk latency and the seizure score were assessed in rats. Also, brain tissue samples were collected by the end of the experiment, and oxidative stress markers (catalase, MDA, and total antioxidant capacity (TAC)) were measured by biochemical analysis in hippocampal brain homogenates. Also, in the hippocampus, the expression of IL6 and Bcl-2 at the mRNA level and expression of Sirt-1, P53, caspase-3, GFAP, and NF-kB in CA3 hippocampal region by immunohistochemistry was investigated. PTZ substantially increased the seizure score and decreased the seizure latency. Also, PTZ significantly increased MDA, GFAP, IL-6, NF-kB, caspase-3, and p53 and significantly reduced Sirt-1, TAC, and Bcl-2 in hippocampal tissues compared to the control group (p < 0.01). However, Stevia Rebaudiana Bertoni (Stevia R.) significantly attenuated the PTZ-induced seizures, improved oxidative stress markers, downregulated GFAP, IL-6, NF-kB, caspase-3, and p53, and upregulated Sirt-1 and Bcl-2 in the CA3 hippocampal region (p < 0.01). In conclusion, Stevia R. exhibits neuroprotective and antiepileptic actions in PTZ-induced epilepsy due to its antioxidant, anti-apoptotic, and anti-inflammatory effects. Additionally, the Sirt-1 pathway might be involved in the antiepileptic and neuroprotective effects of stevia in PTZ-kindled epileptic rat model.
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Anticonvulsivantes/farmacología , Antioxidantes/farmacología , Epilepsia/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Extractos Vegetales/farmacología , Stevia , Animales , Anticonvulsivantes/administración & dosificación , Antioxidantes/administración & dosificación , Apoptosis , Convulsivantes/farmacología , Modelos Animales de Enfermedad , Epilepsia/inducido químicamente , Epilepsia/inmunología , Epilepsia/metabolismo , Hipocampo/inmunología , Hipocampo/metabolismo , Masculino , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/metabolismo , Pentilenotetrazol/farmacología , Extractos Vegetales/administración & dosificación , Ratas , Ratas Sprague-Dawley , Sirtuina 1/efectos de los fármacos , Sirtuina 1/metabolismoRESUMEN
The unprecedented pandemic of COVID-19 swept millions of lives in a short period, yet its menace continues among its survivors in the form of post-COVID syndrome. An exponentially growing number of COVID-19 survivors suffer from cognitive impairment, with compelling evidence of a trajectory of accelerated aging and neurodegeneration. The novel and enigmatic nature of this yet-to-unfold pathology demands extensive research seeking answers for both the molecular underpinnings and potential therapeutic targets. Ferroptosis, an iron-dependent cell death, is a strongly proposed underlying mechanism in post-COVID-19 aging and neurodegeneration discourse. COVID-19 incites neuroinflammation, iron dysregulation, reactive oxygen species (ROS) accumulation, antioxidant system repression, renin-angiotensin system (RAS) disruption, and clock gene alteration. These events pave the way for ferroptosis, which shows its signature in COVID-19, premature aging, and neurodegenerative disorders. In the search for a treatment, melatonin shines as a promising ferroptosis inhibitor with its repeatedly reported safety and tolerability. According to various studies, melatonin has proven efficacy in attenuating the severity of certain COVID-19 manifestations, validating its reputation as an anti-viral compound. Melatonin has well-documented anti-aging properties and combating neurodegenerative-related pathologies. Melatonin can block the leading events of ferroptosis since it is an efficient anti-inflammatory, iron chelator, antioxidant, angiotensin II antagonist, and clock gene regulator. Therefore, we propose ferroptosis as the culprit behind the post-COVID-19 trajectory of aging and neurodegeneration and melatonin, a well-fitting ferroptosis inhibitor, as a potential treatment.
Asunto(s)
COVID-19 , Ferroptosis , Melatonina , Humanos , Melatonina/farmacología , Melatonina/uso terapéutico , Melatonina/metabolismo , Antioxidantes/metabolismo , Encéfalo/metabolismo , Envejecimiento , Hierro/metabolismoRESUMEN
Introduction: Despite a well-established direct toxic effect of alcohol on renal cells, there is a salutary dose-dependent effect of alcohol consumption on common laboratory parameters related to kidney performance. Alcohol also impacts thyroid hormones, while thyroid status modulates kidney function. The modulation of kidney parameters with thyrotropin (TSH) and thyroid status indicates a possible interaction between alcohol, kidney, and thyroid functions. This retrospective study was conducted to test the hypothesis that the positive effect of alcohol use on the estimated glomerular filtration rate (eGFR) is mediated by alcohol's effect on thyroid hormones. Methods: We reviewed the electronic medical records of 767 hospitalized adult patients free of thyroid disorders who received medical care in the Mayo Clinic Health System from June 2019 through June 2022 and had blood alcohol concentration (BAC), serum TSH, and serum creatinine measured during the hospitalization. We calculated the eGFR using both the re-expressed Modification of Diet in Renal Disease (MDRD II) study equation and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine equation. Results: We found a significant relationship of BAC with eGFR (CKD-EPI) and TSH in males only. BAC had a positive association with eGFR (b = 0.24, p = 0.0001) and negative with TSH (b=-0.17, p = 0.006). The covariance between the two outcomes (eGFR and TSH) was negative (b = -0.12, p = 0.049). The path analyses using the eGFR MDRD II equation were not significant in males, whereas females had no significant path analyses with either of the eGFR equations. Discussion: We observed that BAC influences both eGFR and TSH, whereas eGFR and TSH influence each other. After considering important covariates (e.g., age, body mass index, diabetes mellitus, cardiovascular disease, chronic kidney disease, and chronic liver disease) and the negative bidirectional effect of TSH and eGFR, a positive impact of BAC on eGFR was observed in males.
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Introduction: The sex difference in alcohol use disorder (AUD) is ingrained in distinctive neurobiological responses between men and women, which necessitates further investigation for a more tailored management. Methods: Minding the findings of iron dysregulation in AUD and the sex difference in iron homeostasis in multiple physiological and pathological settings, we examined the sex difference in the association between serum ferritin and blood alcohol concentration (BAC) in intoxicated males (n = 125) and females (n = 59). We included patients with both serum ferritin tested of any value and a BAC above the level of detection during the same hospital admission period. We investigated sex difference in the relationship between BAC, serum ferritin and liver enzymes in intoxicated critically ill and noncritically ill patients. Results: We found a negative association between serum ferritin and BAC in critically ill, intoxicated females [R2 = 0.44, F(1,14) = 11.02, p = 0.005], with much attenuated serum ferritin in females compared to their male counterparts (194.5 ± 280.4 vs. 806.3 ± 3405.7 ng/L, p = 0.002). We found a positive association between serum ferritin and liver enzymes [alanine transaminase (ALT) and aspartate transferase (AST)] in critically ill intoxicated females [ALT: R2 = 0.48, F(1,10) = 9.1, p = 0.013; AST: R2 = 0.68, F(1,10) = 21.2, p = 0.001] and in noncritically ill intoxicated males [ALT: R2 = 0.1, F(1,83) = 9.4, p = 0.003; AST: R2 = 0.1, F(1,78) = 10.5, p = 0.002]. The effect of BAC on serum ferritin was not mediated by ALT [indirect effect: (B = 0.13, p = 0.1)]. We also found a significant effect of sex, anemia, intensive care unit (ICU) admission and mortality on serum ferritin. Discussion: Our results suggest that high BAC in intoxicated female patients is associated with attenuated serum ferritin levels, questioning the role of low serum ferritin in female vulnerability to alcohol.
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Coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), is associated with the persistence of pre-existing or the emergence of new neurological and psychiatric manifestations as a part of a multi-system affection known collectively as "post-COVID syndrome." Cognitive decline is the most prominent feature among these manifestations. The underlying neurobiological mechanisms remain under intense investigation. Ferroptosis is a form of cell death that results from the excessive accumulation of intracellular reactive iron, which mediates lipid peroxidation. The accumulation of lipid-based reactive oxygen species (ROS) and the impairment of glutathione peroxidase 4 (GPX4) activity trigger ferroptosis. The COVID-19-associated cytokine storm enhances the levels of circulating pro-inflammatory cytokines and causes immune-cell hyper-activation that is tightly linked to iron dysregulation. Severe COVID-19 presents with iron overload as one of the main features of its pathogenesis. Iron overload promotes a state of inflammation and immune dysfunction. This is well demonstrated by the strong association between COVID-19 severity and high levels of ferritin, which is a well-known inflammatory and iron overload biomarker. The dysregulation of iron, the high levels of lipid peroxidation biomarkers, and the inactivation of GPX4 in COVID-19 patients make a strong case for ferroptosis as a potential mechanism behind post-COVID neuropsychiatric deficits. Therefore, here we review the characteristics of iron and the attenuation of ferroptosis as a potential therapeutic target for neuropsychiatric post-COVID syndrome.
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Background: To examine the impact of aging on the response of rats to pentylenetetrazole (PTZ)-induction of epilepsy and the possible role of oxidative stress and nuclear factor erythroid 2-related factor 2 (Nrf2)/ heme oxygenase (HO)-1 pathway in this response. Methods: Forty male albino rats were equally allocated into 4 groups; 1) Young control (YC) group, aged 8-12 weeks, 2) Old control (OC) group, aged 24 months, 3) PTZ-Young group: young rats received PTZ (50 mg/Kg, i.p. every other day) for 2 weeks and 4) PTZ-Old group: as group 3 but rats were old. The seizure score stage and latency to the first jerk were recorded in rats. Redox state markers in brain tissues including malondialdehyde (MDA), catalase and total antioxidant capacity (TAC) were evaluated. Also, the expression of Nrf2 and HO-1 genes were measured in the brain tissues. Results: Old rats showed an early and a significant rise in the seizure score with PTZ administration and a significant drop in the seizure latency compared to young rats (P <0.01). Also, old rats showed a significantly higher MDA concentration and a significantly lower TAC and catalase activity than young rats (P <0.01). Moreover, the expression of Nrf2 and HO-1 was significantly lowered in old rats compared to young rats with PTZ administration (P < 0.01). Conclusion: Aging increases the vulnerability of rats to PTZ-induced epilepsy. An effect might come down to the up-regulation of oxidative stress and the down regulation of antioxidant pathways including Nrf2 and HO-1.
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We examined the effects of psychiatric comorbidity, sex, and ICU admission on serum ferritin concentration in 628 elderly patients (79.7 ± 8.5 years) with positive SARS-CoV-2 PCR test. Hospitalization was required in 96% of patients and 17% required ICU admission. Patients with COVID-19 and psychiatric comorbidities (n = 212) compared to patients without psychiatric comorbidities (n = 416) had significantly lower ferritin concentration (570.4 ± 900.1 vs. 744.1 ± 965, P = 0.029), a greater incidence of delirium (22.6 vs. 14.4%, P = 0.013) and higher mortality (35.3 vs. 27.6%, P = 0.015). Furthermore, we found significant effects for sex (P = 0.002) and ICU admission (P = 0.007). Among patients without comorbid psychiatric conditions, males had significantly higher ferritin compared to females (1,098.3 ± 78.4 vs. 651.5 ± 94.4, P < 0.001). ICU patients without comorbid psychiatric conditions had significantly higher serum ferritin compared to ICU patients with comorbid psychiatric conditions: (1,126.6 ± 110.7 vs. 668.6 ± 156.5, P < 0.001). Our results suggest that the presence of comorbid psychiatric conditions in elderly patients with COVID-19 is associated with higher rates of delirium and mortality and lower ferritin levels during severe illness. Whether high serum ferritin is protective during severe infection requires further investigation.