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Histopathological findings in the cerebellum among the groups. (A) Normal cerebellar architecture in control group, (B) Numerous degenerated Purkinje cells (arrows) in LPS group, (C) Decreased degenerated neurons (Purkinje cells) in PG treated group, HE, Bar = 50 μm.
Source publication
Backgrounds
The aim of this study was to investigate the oxidative damage and inflammatory effects in the hippocampus and cerebellum in lipopolysaccharide (LPS)-induced sepsis model and possible ameliorating effects of pregabalin (PG).
Methods
Twenty four female Wistar Albino rats (12 month old) were divided into 3 groups as follows: Group I (Cont...
Citations
... This shows that LPS stimulation altered the blood indices in the mice. Indeed, when LPS stimulates the organism, the leukocyte system is activated, and the number of WBCs increases [51]. Similarly, a significant GRAN is produced, leading to an exacerbated inflammatory response [52]. ...
In our previous study, two peptides with favorable anti-inflammatory effects, Asp-Gln-Thr-Phe (DQTF) and Gly-Tyr-Thr-Arg (GYTR), were screened from Ruditapes philippinarum using an in vitro–in silico strategy. The present study aims to investigate the ameliorative effect of Ruditapes philippinarum peptides (RPPs) on acute inflammation and clarify the potential mechanism through in vitro and in vivo experiments. The anti-inflammatory effects of DQTF and GYTR were verified with a lipopolysaccharide (LPS)-induced RAW264.7 cell acute inflammation model and the anti-inflammatory effect of the enzymatic hydrolysates of Ruditapes philippinarum was explored in vivo using an LPS-induced acute inflammatory injury model in mice. The results show that DQTF and GYTR improved the morphology of LPS-injured cells and decreased the concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in LPS-induced cells. Moreover, the antioxidant enzyme activity in cells was markedly increased with DQTF and GYTR. The enzymatic hydrolysates of Ruditapes philippinarum were obtained with hydrolysis using pepsin–chymotrypsin–trypsin (PeCTHC) and pepsin–trypsin (PeTHC), respectively. PeCTHC and PeTHC significantly reduced pro-inflammatory cytokines and nitric oxide (NO) in the serum. Additionally, the blood indices and levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), and malondialdehyde (MDA) in the livers of mice were markedly improved with RPPs administration. In conclusion, RPPs have preventive and protective effects on acute inflammation, with significant prospects for development in the field of functional foods.
... Leica RM 2155 rotary microtome was used to cut paraffin blocks into 5 lm sections (Leica Microsystem). Then examined under a light microscope after being stained with haematoxylin-eosin and a coverslip (Aslankoc et al., 2018). Microphotography was carried out using the Database Manual Cell Sens Life Science Imaging Software System (Olympus Co., Tokyo, Japan). ...
Water kefir (WK) is produced using WK grains containing beneficial bacteria and yeasts. It has antibacterial, anti‐inflammatory, anti‐diabetic, anti‐hyperlipidaemic, anti‐ulcerogenic, and antioxidant effects. The purpose of the research was to determine the effect of WK on irritable bowel syndrome (IBS). In this study, thirty‐two female Wistar‐Albino rats aged 3 months were randomly distributed to four groups: the control group (C), the WK group, the WK group with IBS (WK + IBS), and the IBS group. Results indicated that the IBS groups had higher white blood cell, lymphocyte, monocyte counts, and procalcitonin levels. The findings of WK + IBS group showed that WK improved against IBS. TNF‐α, NF‐kB expressions, and histopathological results significantly decreased after receiving WK treatment. In conclusion, ingestion of WK has prophylactic effects on IBS as exhibited through an in‐vivo murine model. The findings suggested that IBS may be prevented and treated with WK.
... Recently, it was documented that activated microglia can synthesize and release MPO in the brain tissue [29]. Aslankoc et al. (2018), when injecting a single dose of LPS (5 mg/kg ip) in 12-month-old Wistar rats, found increased neutrophil infiltration and augmented IL-6 and caspase-3 expression in the whole brain [30]. HOCl derived from MPO in brain tissue is associated with BBB impairment and eNOS activation [31]. ...
... Recently, it was documented that activated microglia can synthesize and release MPO in the brain tissue [29]. Aslankoc et al. (2018), when injecting a single dose of LPS (5 mg/kg ip) in 12-month-old Wistar rats, found increased neutrophil infiltration and augmented IL-6 and caspase-3 expression in the whole brain [30]. HOCl derived from MPO in brain tissue is associated with BBB impairment and eNOS activation [31]. ...
Methylmercury (MeHg) is highly toxic to the human brain. Although much is known about MeHg neurotoxic effects, less is known about how chronic MeHg affects hippocampal amino acids and other neurochemical markers in adult mice. In this study, we evaluated the MeHg effects on systemic lipids and inflammation, hippocampal oxidative stress, amino acid levels, neuroinflammation, and behavior in adult male mice. Challenged mice received MeHg in drinking water (2 mg/L) for 30 days. We assessed weight gain, total plasma cholesterol (TC), triglycerides (TG), endotoxin, and TNF levels. Hippocampal myeloperoxidase (MPO), malondialdehyde (MDA), acetylcholinesterase (AChE), amino acid levels, and cytokine transcripts were evaluated. Mice underwent open field, object recognition, Y, and Barnes maze tests. MeHg-intoxicated mice had higher weight gain and increased the TG and TC plasma levels. Elevated circulating TNF and LPS confirmed systemic inflammation. Higher levels of MPO and MDA and a reduction in IL-4 transcripts were found in the hippocampus. MeHg-intoxication led to increased GABA and glycine, reduced hippocampal taurine levels, delayed acquisition in the Barnes maze, and poor locomotor activity. No significant changes were found in AChE activity and object recognition. Altogether, our findings highlight chronic MeHg-induced effects that may have long-term mental health consequences in prolonged exposed human populations.
... LPS administration induces damage in the brain [24,25], lungs [26], heart [15], liver [27], pancreas [28], kidneys [29,30], and intestines [31]. Thus, oxidative stress and inflammation may play important roles in the development of LPS-induced damage. ...
Typical indications for radon therapy include autoimmune diseases such as rheumatoid arthritis (RA). We had previously reported that radon inhalation inhibits Th17 immune responses in RA mice by activating Th1 and Th2 immune responses. However, there are no reports on how radon inhalation affects the activated Th1 and Th17 immune responses, and these findings may be useful for identifying new indications for radon therapy. Therefore, in this study, we investigated the effect of radon inhalation on the lipopolysaccharide (LPS)-induced inflammatory response, focusing on the expression of related cytokines and antioxidant function. Male BALB/c mice were exposed to 2000 Bq/m3 radon for one day. Immediately after radon inhalation, LPS was administered intraperitoneally at 1.0 mg/kg body weight for 4 h. LPS administration increased the levels of Th1- and Th17-prone cytokines, such as interleukin-2, tumor necrosis factor-α, and granulocyte-macrophage colony-stimulating factor, compared to no treatment control (sham). However, these effects were suppressed by radon inhalation. IL-10 levels were significantly increased by LPS administration, with or without radon inhalation, compared to sham. However, radon inhalation did not inhibit oxidative stress induced by LPS administration. These findings suggest that radon inhalation has immunomodulatory but not antioxidative functions in LPS-induced injury.
... [46] More so, it has been reported that TOS and OSI levels increased and TAS levels decreased in the hippocampus and cerebellum tissues of rats with LPS-induced sepsis. [47,48] On the other hand, treatment with The redox status of cells is kept well-balanced by low-molecular nonenzymatic antioxidants (i.e., GSH, urate, and ascorbate), as well as the complex antioxidative enzyme system including CAT, SOD, GPx, GR, and GST. All of which are responsible for the protection of cells against the detrimental effects of free radicals. ...
The objective of this study was to examine the protective effects of S‐methyl methionine sulfonium chloride (MMSC) against galactosamine (GalN)‐induced brain and cerebellum injury in rats. A total of 22 female Sprague–Dawley rats were randomly divided into four groups as follows: Group I (n = 5), intact animals; Group II (n = 6), animals received 50 mg/kg/day of MMSC by gavage technique for 3 consecutive days; Group III (n = 5), animals injected with a single dose of 500 mg/kg of GalN intraperitoneally (ip); and Group IV (n = 6), animals injected with the same dose of GalN 1 h after MMSC treatment. After 6 h of the last GalN treatment (at the end of the experiments), all animals were killed under anesthesia, brain and cerebellum tissues were dissected out. Reduced glutathione, total antioxidant status levels, and antioxidant enzymes (catalase, superoxide dismutase, and glutathione‐related enzymes), aryl esterase, and carbonic anhydrase activities remarkably declined whereas advanced oxidized protein products, reactive oxygen species, total oxidant status, oxidative stress index levels, and myeloperoxidase, acetylcholinesterase, lactate dehydrogenase, and xanthine oxidase activities were significantly elevated in the GalN group compared with intact rats. In contrast, the administration of MMSC to GalN groups reversed these alterations. In conclusion, we may suggest that MMSC has protective effects against GalN‐induced brain and cerebellar toxicity in rats.
... It is important to note that PGB crosses the blood-brain barrier (BBB) and preferentially binds to the α2-δ1 auxiliary subunit, which is present in higher density amounts in brain regions involved in cortical processing, learning and memory, defensive behavior, neuroendocrine secretion, defensive behavior, general arousal (Takahashi et al. 2018;Cole et al. 2005). Additionally, studies have demonstrated that PGB induces neuroprotective effects by reducing oxidative stress and disrupting inflammatory processes in different pathological situations like sepsis, neuropathy, and retinopathy associated with diabetes (Sałat et al. 2016;Aslankoc et al. 2018;Cruz-Álvarez et al. 2018;Ali et al. 2019;Demir et al. 2021). ...
... Thus, we can speculate that the antioxidant action of PGB may not be the only mechanism responsible for the beneficial action of PGB on fear memory and anxiety-like response in these induced-T1DM animals. In this regard, it is not surprising that PGB induces neuroprotective effects through other mechanisms, including an anti-inflammatory action by disrupting the expression of several inflammatory markers (Sałat et al. 2016;Aslankoc et al. 2018;Cruz-Álvarez et al. 2018;Ali et al. 2019). Curiously, in 2014 we had already observed in this animal model of T1DM that a prolonged treatment with insulin, vitamin E or imipramine induced antidepressant-like effect that was related to the improvement on oxidative stress parameters in the PFC and HIP (de Morais et al. 2014). ...
Anxiety Disorders and Posttraumatic Stress Disorders (PTSD) associated with type-1 diabetes mellitus (T1DM) are increasingly common comorbidities and the treatment is quite challenging. In that sense, evidence indicates that the anticonvulsant pregabalin is highly effective in treating severe cases of anxiety, as well as PTSD and diabetic neuropathic pain which is also very prevalent in T1DM. Herein, the short- and long-term effects of a single injection of pregabalin on the acquisition of a fear extinction memory and parameters of anxiety in induced-T1DM animals were investigated. For that, we used the contextual fear conditioning (CFC) and elevated plus maze paradigms, respectively. A putative antioxidant activity was also evaluated. Our findings demonstrated that induced-T1DM animals presented greater expression of fear memory, difficulty in extinguishing this fear memory, associated with a more pronounced anxiety-like response. Pregabalin was able to induce a short and long-lasting effect by facilitating the acquisition of the fear extinction memory and inducing a later anxiolytic-like effect. Also, the increased lipid peroxidation levels in the hippocampus and prefrontal cortex of induced-T1DM rats were reduced after pregabalin injection, while the decreased levels of reduced glutathione were increased in the hippocampus. Despite the need for more studies to understand the mechanism of action of pregabalin under these conditions, our data demonstrate for the first time that a single injection of pregabalin in a specific time window was able to improve behavioral parameters in addition to inducing neuroprotective effect. Thus, pregabalin has potential worth exploring for the treatment of PTSD and/or Anxiety associated with T1DM.
... Reportedly, LPS acts as a neurotoxin that binds to toll-like receptor-4 and induced neuroinflammatory mediators like cytokines and chemokine expressions in the brain (Lee et al., 2019). An early report highlighted that LPS-induced acute inflammation results in oxidative stress, blood-brain barrier disruption, and neuronal loss in the hippocampus and cerebellum in adult as well as aged rats (Aslankoc et al., 2018;Garcia et al., 2018). Furthermore, it was reported that intraperitoneal (i.p.) injection of LPS elevated the MDA level, i.e. oxidative stress, and reduced glutathione peroxidase (GPx) activity and GSH levels in the cerebellum (Garcia et al., 2018). ...
Abstract Therapeutically, piracetam has been used for decades as a cognitive enhancer for memory- related neuronal disorders. The present study aimed to investigate the neuroprotective potential of piracetam on lipopolysaccharides (LPS)-induced neuronal deficit using both in-vitro and in-vivo experimental models. For the in-vitro analysis, EOC-20 murine microglial cells were induced with a neuronal toxicity of 100 µg/ml of LPS, and the formation of intracellular reactive oxygen species (ROS) and nitric oxide (NO) productions were determined. For in-vivo neuroprotective analysis, groups of mice were treated orally with two doses of piracetam (200 and 400 mg/kg) for 30 days. Neuronal toxicity was induced by four intraperitoneal injections of LPS (250 µg/kg/day). The malondialdehyde (MDA) level was measured for oxidative stress, and catalase reduced glutathione (GSH), glutathione reductase (GRD), and superoxide dismutase (SOD) levels were determined as the antioxidant parameters. The result of the cell viability study was that pre-treatment with piracetam significantly protected the LPS-induced cell loss, and attenuated the ROS generation and NO production in LPS-induced EOC-20 cells. Moreover, the treatment of piracetam significantly reduced the MDA levels and improved catalase, GSH, GRD, and SOD activities in LPS-induced mice brains. The overall results from this study supported the neuroprotective effects of piracetam against LPS-induced neuronal toxicity.
... Although the pathomechanism of sepsis-associated encephalopathy is not fully understood, it is recognized that the CNS responds to peripheral cytokine release through an increase in blood-brain barrier (BBB) permeability (4). BBB leakage associated with edematous cerebral cortex lesions (5)(6)(7) and injury of hippocampal-cerebellar structures have already been identified at the early phase (~6-8h) of various models of sepsis (8). In parallel with damage to BBB integrity, infiltration of activated polymorphonuclear leukocytes into brain tissues also occurs (9). ...
... Infiltration of immune cells into the CNS following BBB injury causes myelin degradation and axonal damage (4), thus underlining the importance of modulating BBB permeability during systemic inflammation. In our model, S100B served not only as a marker of astrocyte-derived brain injury but also as an indicator of early BBB damage during sepsis (8). In this model, a diffuse BBB dysfunction can be presumed because EB accumulation (a good indicator of macromolecular passage through the BBB), occurred in both the hippocampal and cerebellar regions. ...
Background and Aims
The systemic host response in sepsis is frequently accompanied by central nervous system (CNS) dysfunction. Evidence suggests that excessive formation of neutrophil extracellular traps (NETs) can increase the permeability of the blood–brain barrier (BBB) and that the evolving mitochondrial damage may contribute to the pathogenesis of sepsis-associated encephalopathy. Kynurenic acid (KYNA), a metabolite of tryptophan catabolism, exerts pleiotropic cell-protective effects under pro-inflammatory conditions. Our aim was to investigate whether exogenous KYNA or its synthetic analogues SZR-72 and SZR-104 affect BBB permeability secondary to NET formation and influence cerebral mitochondrial disturbances in a clinically relevant rodent model of intraabdominal sepsis.
Methods
Sprague–Dawley rats were subjected to fecal peritonitis (0.6 g kg⁻¹ ip) or a sham operation. Septic animals were treated with saline or KYNA, SZR-72 or SZR-104 (160 µmol kg⁻¹ each ip) 16h and 22h after induction. Invasive monitoring was performed on anesthetized animals to evaluate respiratory, cardiovascular, renal, hepatic and metabolic parameters to calculate rat organ failure assessment (ROFA) scores. NET components (citrullinated histone H3 (CitH3); myeloperoxidase (MPO)) and the NET inducer IL-1β, as well as IL-6 and a brain injury marker (S100B) were detected from plasma samples. After 24h, leukocyte infiltration (tissue MPO) and mitochondrial complex I- and II-linked (CI–CII) oxidative phosphorylation (OXPHOS) were evaluated. In a separate series, Evans Blue extravasation and the edema index were used to assess BBB permeability in the same regions.
Results
Sepsis was characterized by significantly elevated ROFA scores, while the increased BBB permeability and plasma S100B levels demonstrated brain damage. Plasma levels of CitH3, MPO and IL-1β were elevated in sepsis but were ameliorated by KYNA and its synthetic analogues. The sepsis-induced deterioration in tissue CI–CII-linked OXPHOS and BBB parameters as well as the increase in tissue MPO content were positively affected by KYNA/KYNA analogues.
Conclusion
This study is the first to report that KYNA and KYNA analogues are potential neuroprotective agents in experimental sepsis. The proposed mechanistic steps involve reduced peripheral NET formation, lowered BBB permeability changes and alleviation of mitochondrial dysfunction in the CNS.
... Pretreatment with STV-Na restored these parameters (Supplemental Fig. 1). Our results further affirmed that LPS causes alterations in the hematological parameters [36], and we are the first to report the potential role of STV-Na in protecting the blood circulatory system. Histopathological data showed that LPS caused severe injury in the heart, liver, lung, spleen and kidney, while STV-Na alleviated this injury (Fig. 3), suggesting that STV-Na exerted a protective effect on LPS-induced tissue injury by inhibiting macrophages. ...
Sepsis is a severe inflammatory disorder that can lead to multiple organ injury. Isosteviol sodium (STV-Na) is a terpenoid derived from stevioside that exerts anti-inflammatory, antioxidant and antiapoptotic activities. However, the influence of STV-Na on sepsis remains unknown. Here, we assessed the potential effects of STV-Na on sepsis and multiple organ injury induced by lipopolysaccharide (LPS). We found that STV-Na increased the survival rate of mice treat with LPS, significantly improved the functions of the heart, lung, liver, and kidney, reduced the production of inflammatory cytokines and decreased macrophage infiltration. Moreover, Multiorgan metabolomics analysis demonstrated that glutathione metabolism, purine metabolism, glycerophospholipid metabolism and pantothenate and CoA biosynthesis, were significantly altered by STV-Na. This study provides novel insights into the metabolite changes of multiple organ injury in septic mice, which may help characterize the underlying mechanism and provide an improved understanding of the therapeutic effects of STV-Na on sepsis.
... Septic brain injury can lead to the activation of endothelial cells in the brain, which produce inflammatory mediators, including TNF-α, IL-1β, and IL-6 (Aly et al., 2006). The concentrations of TNF-α and IL-6 increased in the sera and fresh hippocampal tissues of rats with brain injuries induced by sepsis (Aslankoc et al., 2018). The results of this study showed that the pathogenesis of sepsis-associated brain injury induced the expression of TNF-α, IL-1β, and IL-6. ...
Our preliminary study found that the long noncoding RNA (LncRNA)-5657 can reduce the expression of inflammatory factors during inflammatory reactions in rat glial cells. However, the role played by LncRNA-5657 during septic brain injury remains unclear. In the present study, rat models of septic encephalopathy were established by cecal ligation and puncture, and then the rats were treated with a hippocampal injection small hairpin RNA (shRNA) against LncRNA-5657 (sh-LnCRNA-5657). The sh-LncRNA-5657 treatment reduced the level of neuronal degeneration and necrosis in the rat hippocampus, reduced the immunoreactivities of aquaporin 4, heparanase, and metallopeptidase-9, and lowered the level of tumor necrosis factor-alpha. Glial cells were pre-treated with sh-LncRNA-5657 and then treated with 1 µg/mL lipopolysaccharide. Sh-LncRNA-5657 transfection decreased the expression of LncRNA-5657 in lipopolysaccharide-treated glial cells and decreased the mRNA and protein levels of tumor necrosis factor-alpha, interleukin-1β, and interleukin-6. These findings suggested that LncRNA-5657 expression can significantly reduce the inflammatory reaction during septic encephalopathy and induce protective effects against this disease. This study was approved by the Institutional Ethics Committee at the First Affiliated Hospital of Nanchang University of China (approval No. 2017-004) in 2017.
