Geraniol attenuates oxidative stress and neuroinflammation-mediated cognitive impairment in D galactose-induced mouse aging model.

D-galactose (D-gal) administration was proven to induce cognitive impairment and aging in rodents' models. Geraniol (GNL) belongs to the acyclic isoprenoid monoterpenes. GNL reduces inflammation by changing important signaling pathways and cytokines, and thus it is plausible to be used as a medicine for treating disorders linked to inflammation. Herein, we examined the therapeutic effects of GNL on D-gal-induced oxidative stress and neuroinflammation-mediated memory loss in mice. The study was conducted using six groups of mice (6 mice per group). The first group received normal saline, then D-gal (150 mg/wt) dissolved in normal saline solution (0.9%, w/v) was given orally for 9 weeks to the second group. In the III group, from the second week until the 10th week, mice were treated orally (without anesthesia) with D-gal (150 mg/kg body wt) and GNL weekly twice (40 mg/kg body wt) four hours later. Mice in Group IV were treated with GNL from the second week up until the end of the experiment. For comparison of young versus elderly mice, 4 month old (Group V) and 16-month-old (Group VI) control mice were used. We evaluated the changes in antioxidant levels, PI3K/Akt levels, and Nrf2 levels. We also examined how D-gal and GNL treated pathological aging changes. Administration of GNL induced a significant increase in spatial learning and memory with spontaneously altered behavior. Enhancing anti-oxidant and anti-inflammatory effects and activating PI3K/Akt were the mechanisms that mediated this effect. Further, GNL treatment upregulated Nrf2 and HO-1 to reduce oxidative stress and apoptosis. This was confirmed using 99mTc-HMPAO brain flow gamma bioassays. Thus, our data suggested GNL as a promising agent for treating neuroinflammation-induced cognitive impairment.

The Inhibitory Effect of Geraniol on CCL4-induced Hepatorenal Toxicity in Pregnant Mice through the PI3K/AKT Signaling Pathway.

Background: Hepatotoxicity caused by CCL4 is well known. Geraniol (GNL) has high antioxidant effect that can induces liver regeneration. However, the protective effect of GNL effect on CCL4-induced hepatorenal toxicity in pregnant mice has not yet been studied. Objective: To investigate whether GNL could protect against oxidative stress induced by CCL4 via the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, which is regulated by phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), and has been found to have protective effects on renal and hepatic tissues. Materials and Methods: Forty-eight female albino mice weighing 25-30 g were randomly allocated to 4 groups: Group I served as a control; Group II received a toxicity-inducing single dose of 15 µL of CCL4 on the 4th day after mating; Group III received 40 mg/kg GNL + CCL4 (with GNL from the 1st day of assimilation to delivery); and Group IV received GNL alone from the 1st day of assimilation to the end of the delivery period. GNL was evaluated for its protective effects on hepatotoxicity in CCL4-treated pregnant mice. Litter size, weight, survival rate, and resorption were recorded. In addition, H & E staining was done for liver and kidney pathology as well as biochemical markers and oxidative markers malondialdehyde, superoxide dismutase, and catalase were analyzed. Results: CCL4 significantly reduced survival rate and increased resorption after exposure. Alanine transaminase and aspartate aminotransferase concentrations in the serum, tissue MDA, blood urea nitrogen, and creatinine were increased after CCL4 exposure. GNL improved enzyme and antioxidant levels and prevented CCL4-induced hepatic injury in mice. Caspase-3 cleavage was decreased by GNL, which increased PI3K, phosphorylated AKT, Nrf2, and B-cell lymphoma 2. Conclusion: GNL demonstrates a protective effect against CCl4-induced hepatorenal toxicity, mediated through the activation of the PI3K/AKT signaling pathway and the upregulation of Nrf2. These findings highlight the potential therapeutic implications of GNL in mitigating oxidative stress and inflammation in liver and kidney tissues.

Isoimperatorin therapeutic effect against aluminum induced neurotoxicity in albino mice.

Background: Although aluminum (Al) is not biologically crucial to the human body, classical studies have demonstrated that excessive human exposure to Al can induce oxidative damage, neuroinflammatory conditions and neurotoxic manifestations implicated in Alzheimer's disease (AD). Exposure to Al was reported to be associated with oxidative damage, neuroinflammation, and to enhance progressive multiregional neurodegeneration in animal models. Several plant-derived natural biomolecules have been recently used to reduce the toxic effects of Al through decreasing the oxidative stress and the associated diseases. A good candidate still to be tested is an active natural furanocoumarin, the isoimperatorin (IMP) that can be extracted from Lemon and lime oils and other plants. Here, we examined the neuroprotective effects of IMP on aluminum chloride (AlCl3)-induced neurotoxicity in albino mice. Methods: Twenty-four male albino mice were used in this study. Mice were randomly devided into 5 groups. The first group was given distilled water as a control, the second group was given AlCl3 orally (10 mg/wt/day) starting from the 2nd week to the end of the 6th week, the third group received AlCl3 orally and IMP interperitoneally, i. p. (30 mg/wt/day) starting from week 2 till week 6 where IMP was supplement 1st and then 4 h later AlCl3 was given to mice. The fourth group received the control (IMP 30 mg/wt, i. p.) from the 2nd week till the end of the experiment. Rodent models of central nervous system (CNS) disorders were assessed using object location memory and Y-maze tests in 6th week began. Essential anti-inflammatory and oxidative stress indicators were evaluated, including interleukin-1 ß (IL-1ß), tumor necrosis factor α (TNF-α), malondialdehyde (MDA), total antioxidant capacity (TAC), and catalase activity (CAT). In addition, serum levels of brain neurotransmitters such as corticosterone, acetylcholine (ACh), dopamine and serotonin in brain homogenates were measured calorimetrically. Results: The study results revealed that the daily treatment of AlCl3 upregulated the TNF-α and IL-1ß levels, increased MDA accumulation, and decreased TAC and CAT activity. In addition, aluminum induced a reduction in concentrations of ACh, serotonin and dopamine in the brain. However, IMP significantly ameliorates the effect of AlCl3 through modulating the antioxidant and regulating the inflammatory response through targeting Nrf2 (NF-E2-related factor 2) and mitogen-activated protein kinase (MAPK). Conclusion: Thus, IMP might be a promising treatment option for neurotoxicity and neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, which are associated with neuro-inflammation and oxidative stress.

Kaempferol Inhibits Zearalenone-Induced Oxidative Stress and Apoptosis via the PI3K/Akt-Mediated Nrf2 Signaling Pathway: In Vitro and In Vivo Studies.

In this study, kaempferol (KFL) shows hepatoprotective activity against zearalenone (ZEA)-induced oxidative stress and its underlying mechanisms in in vitro and in vivo models were investigated. Oxidative stress plays a critical role in the pathophysiology of various hepatic ailments and is normally regulated by reactive oxygen species (ROS). ZEA is a mycotoxin known to exert toxicity via inflammation and ROS accumulation. This study aims to explore the protective role of KFL against ZEA-triggered hepatic injury via the PI3K/Akt-regulated Nrf2 pathway. KFL augmented the phosphorylation of PI3K and Akt, which may stimulate antioxidative and antiapoptotic signaling in hepatic cells. KFL upregulated Nrf2 phosphorylation and the expression of antioxidant genes HO-1 and NQO-1 in a dose-dependent manner under ZEA-induced oxidative stress. Nrf2 knockdown via small-interfering RNA (siRNA) inhibited the KFL-mediated defence against ZEA-induced hepatotoxicity. In vivo studies showed that KFL decreased inflammation and lipid peroxidation and increased H2O2 scavenging and biochemical marker enzyme expression. KFL was able to normalize the expression of liver antioxidant enzymes SOD, CAT and GSH and showed a protective effect against ZEA-induced pathophysiology in the livers of mice. These outcomes demonstrate that KFL possesses notable hepatoprotective roles against ZEA-induced damage in vivo and in vitro. These protective properties of KFL may occur through the stimulation of Nrf2/HO-1 cascades and PI3K/Akt signaling.