Encephalopathy In Rats Research Articles

Securidaca inappendiculata Polyphenol Rich Extract Counteracts Cognitive Deficits, Neuropathy, Neuroinflammation and Oxidative Stress in Diabetic Encephalopathic Rats via p38 MAPK/Nrf2/HO-1 Pathways.

Diabetic encephalopathy is one of the serious emerging complication of diabetes. Securidaca inappendiculata is an important medicinal plant with excellent antioxidant and anti-inflammatory properties. This study investigated the neuroprotective effects of S. inappendiculata polyphenol rich extract (SiPE) against diabetic encephalopathy in rats and elucidated the potential mechanisms of action. Type 2 diabetes mellitus (T2DM) was induced using high fructose solution/intraperitoneal injection of streptozotocin and the diabetic rats were treated with SiPE (50, 100 and 200 mg/kg) for 8 weeks. Learning and memory functions were assessed using the Morris water and Y maze tests, depressive behaviour was evaluated using forced swimming and open field tests, while neuropathic pain assessment was assessed using hot plate, tail immersion and formalin tests. After the experiments, acetylcholinesterase (AChE), oxidative stress biomarkers and proinflammatory cytokines, caspase-3 and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) were determined by ELISA kits. In addition, the expression levels of p38, phospho-p38 (p-p38), nuclear factor erythroid 2–related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were determined by western blot analyses. The results indicated that SiPE administration significantly lowered blood glucose level, attenuated body weight loss, thermal/chemical hyperalgesia, improved behavioural deficit in the Morris water maze, Y maze test and reduced depressive-like behaviours. Furthermore, SiPE reduced AChE, caspase-3, NF-κB, malonaldehyde malondialdehyde levels and simultaneously increased antioxidant enzymes activity in the brain tissues of diabetic rats. SiPE administration also significantly suppressed p38 MAPK pathway and upregulated the Nrf2 pathway. The findings suggested that SiPE exerted antidiabetic encephalopathy effects via modulation of oxidative stress and inflammation.

Thymoquinone improves cognitive and hippocampal long-term potentiation deficits due to hepatic encephalopathy in rats.

Objective(s):Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that causes brain disturbances. Thymoquinone (TQ) has a wide spectrum of activities such as antioxidant, anti-inflammatory, and anticancer. This study aimed to evaluate the effects of TQ on spatial memory and hippocampal long-term potentiation (LTP) in rats with thioacetamide (TAA)-induced liver injury and hepatic encephalopathy. Materials and Methods:Adult male Wistar rats were divided into six groups randomly: 1) Control; 2) HE, received TAA (200 mg/kg); 3-5) Treated groups (HE+TQ5, HE+TQ10, and HE+TQ20). TQ (5, 10, and 20 mg/kg) was injected intraperitoneally (IP) for 12 consecutive days from day 18 to 29. Subsequently, spatial memory performance was evaluated by the Morris water maze paradigm and hippocampal LTP was recorded from the dentate gyrus (DG) region. Activity levels of Malondialdehyde (MDA) and superoxide dismutase (SOD) were measured in the hippocampal tissue.Results:Data showed that the hippocampal content of MDA was increased while SOD activities were decreased in TAA-induced HE. TQ treatment significantly improved spatial memory and LTP. Moreover, TQ restored the levels of MDA and SOD activities in the hippocampal tissue in HE rats. Conclusion:Our data confirm that TQ could attenuate cognitive impairment and improve LTP deficit by modulating the oxidative stress parameters in this model of HE, which leads to impairment of spatial cognition and LTP deficit. Thus, these results suggest that TQ may be a promising agent with positive therapeutic effects against liver failure and HE defects.

Neural precursor cells are decreased in the hippocampus of the delayed carbon monoxide encephalopathy rat model

The pathophysiology of delayed carbon monoxide (CO) encephalopathy remains unclear. In this study, the effects of CO exposure on the dentate gyrus (DG) were investigated in a Wistar rat model by histochemical and molecular methods. Model rats showed significant cognitive impairment in the passive-avoidance test beginning 7 days after CO exposure. Immunohistochemistry showed that compared to the control, the cell number of SRY (sex-determining region Y)-box 2 (SOX2)+/brain lipid binding protein (BLBP)+/glial fibrillary acidic protein (GFAP)+ cells in the DG was significantly less, but the number of SOX2+/GFAP− cells was not, reflecting a decreased number of type 1 and type 2a neural precursor cells. Compared to the control, the numbers of CD11b+ cells and neuron glial antigen 2+ cells were significantly less, but the number of SOX2−/GFAP+ cells was not. Flow cytometry showed that the percent of live microglial cells isolated from the hippocampus in this CO rat model was significantly lower than in controls. Furthermore, mRNA expression of fibroblast growth factor 2 and glial cell-derived neurotrophic factor, which are neurogenic factors, was significantly decreased in that area. We conclude that, in this rat model, there is an association between delayed cognitive impairment with dysregulated adult hippocampal neurogenesis and glial changes in delayed CO encephalopathy.

Sirtuin-3 activation by honokiol restores mitochondrial dysfunction in the hippocampus of the hepatic encephalopathy rat model of ammonia neurotoxicity.

The neurotoxic level of ammonia in the brain during liver cirrhosis causes a nervous system disorder, hepatic encephalopathy (HE), by affecting mitochondrial functions. Sirtuin-3 (SIRT3) is emerging as a master regulator of mitochondrial integrity, which is currently being focused as a pathogenic hotspot for HE. This article describes SIRT3 level versus mitochondrial dysfunction markers in the hippocampus of the control, the moderate-grade hepatic encephalopathy (MoHE), developed in thioacetamide-induced (100 mg/kg bw ip for 10 days) liver cirrhotic rats, and the MoHE rats treated with an SIRT3 activator, honokiol (HKL; 10 mg/kg bw ip), for 7 days from 8th day of the thioacetamide schedule. As compared with the control group rats, hippocampus mitochondria of MoHE rats showed a significant decline in SIRT3 expression and its activity with concordant enhancement of ROS and declined membrane permeability transitionand organelle viability scores. This was consistent with the declined mitochondrial thiol level and thiol-regenerating enzyme, isocitrate dehydrogenase 2. Also, significantly declined activities of electron transport chain complexes I, III, IV, and Q10 , decreased NAD+ /NADH and ATP/AMP ratios, and enhanced number of the shrunken mitochondria were recorded in the hippocampus of those MoHE rats. However, all these mitochondrial aberrations were observed to regain their normal profiles/levels, concordant to the enhanced SIRT3 expression and its activity due to treatment with HKL. The findings suggest a role of SIRT3 in mitochondrial structure-function derangements associated with MoHE pathogenesis and SIRT3 activation by HKL as a relevant strategy to protect mitochondrial integrity during ammonia neurotoxicity.

The possible effect of coenzyme Q10 and captopril on acetaminophen-induced encephalopathy in rats: possible influence on autophagy, antioxidant and Na+/K+ ATPase

IntroductionInduction of autophagy could protect against acetaminophen (APAP)-induced hepatotoxicity; however, little is known about the role of autophagy in APAP-induced encephalopathy (APAP-E). This study aimed to evaluate the effects of coenzyme Q10 (CoQ10) and captopril on APAP-E.Material and methodsForty-eight rats were randomly allotted to 4 equal groups: control, an APAP-E, coenzyme Q10-treated (CoQ10-treated), and captopril-treated groups. Behavioral tests were conducted. Serum ammonia and total antioxidant capacity (TAC) and hippocampal Na+/K+ ATPase activity were measured. The expression levels of hippocampal microtubule-associated protein light chain 3 (LC3-II) and beclin-1 mRNA were detected using quantitative polymerase chain reaction (qPCR). General histological, immunohistochemical staining for glial fibrillary acid protein (GFAP) and electron microscopy (EM) of the hippocampus were performed.ResultsIn the APAP-E group, serum ammonia was increased significantly, hippocampal LC3-II and beclin-1 mRNA were elevated insignificantly, while serum TAC and the activity of hippocampal Na+/K+ ATPase were reduced significantly compared with the control group. APAP-E rats showed remarkable degenerative changes in CA1 pyramidal neurons in the form of electron-dense cytoplasm with ill-defined nuclei and accumulation of lysosomal structure-like dense bodies. Increased immunoreactivity of astrocytes for GFAP was observed. Treatment with either CoQ10 or captopril significantly reduced ammonia levels, increased hippocampal LC3-II and beclin-1 mRNA, increased serum TAC and Na+/K+ ATPase activity, and noticeably ameliorated the hippocampal neuronal changes. EM revealed restoration of the normal structure of pyramidal neurons. These effects were more obvious in CoQ10-treated than captopril-treated rats.ConclusionsCoQ10 and captopril have neuroprotective effects on APAP-E via enhancing LC3-II, beclin-1 mRNA expression, serum TAC level and hippocampal Na+/K+ ATPase activity.

Flavonoids from Barnebydendron riedelii leaf extract mitigate thioacetamide-induced hepatic encephalopathy in rats: The interplay of NF-κB/IL-6 and Nrf2/HO-1 signaling pathways

Phytochemical investigation of the butanol fraction (BUF) derived from the 70% aqueous methanolic leaf extract of Barnebydendron riedelii led to the isolation of three flavonoid glycosides; kaempferol-3-O-α-l-rhamnopyranosyl-(1 → 6)-β-d-glucopyranoside, quercetin-3-O-α-l-rhamnopyranosyl-(1 → 6)-β-d-galactopyranoside and quercetin-3-O-α-l-rhamnopyranosyl-(1 → 6)-β-d-glucopyranoside. Docking studies were fulfilled to validate the possible bio-properties of BUF toward nuclear factorkappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2). The protective role of BUF against behavioral, biochemical, molecular, histopathological and immunohistochemical alterations in thioacetamide (TAA)-induced hepatic encephalopathy in rats was investigated. The toxicological studies indicated that BUF was safe up to 2000 mg/kg bw. Prior to TAA intoxication, rats were orally treated with either BUF at multiple doses (70, 140 and 280 mg/kg bw) or lactulose (8 mL/kg bw) for 14 consecutive days. On the 13th and the 14th day, TAA (200 mg/kg bw/day) was intraperitoneally injected. The BUF significantly improved motor impairment, ameliorated cognitive deficits and attenuated TAA-induced hepatotoxicity. Moreover, BUF controlled the inflammatory processes by suppressing the hepatic inflammatory cytokine; interleukin-6 (IL-6) as well as its pro-inflammatory mediator; NF-κB supporting the molecular docking assessment. The brain neurotransmitters; dopamine, serotonin and noradrenaline, as well as ammonia levels were improved in BUF-treated TAA-intoxicated animals in a dose-dependent manner. Furthermore, BUF administration to TAA-intoxicated rats modulated the Nrf2 and heme oxygenase 1 (HO-1) genes expression in liver and brain tissues. The histological evaluation showed that pretreatment of TAA-intoxicated rats with BUF ameliorated the degenerative effects of TAA on liver and brain tissues as well as reduced the activation of cellular apoptotic marker; caspase-3 and glial fibrillary acidic protein (GFAP+) astrocytes. In conclusion, the observed hepato-neuroprotective effect of BUF is attributed to its flavonoidal content through its modulatory effects on of NF-κB/IL-6 and Nrf2/HO-1 signaling pathways.

Stanniocalcin 1 Inhibits the Inflammatory Response in Microglia and Protects Against Sepsis-Associated Encephalopathy.

Sepsis-associated encephalopathy is a serious consequence of sepsis, triggered by the host response against an infectious agent, that can lead to brain damage and cognitive impairment. Several mechanisms have been proposed in this bidirectional communication between the immune system and the brain after sepsis as neuroinflammation, oxidative stress, and mitochondrial dysfunction. Stanniocalcin-1 (STC-1), an endogen neuroprotective protein, acts as an anti-inflammatory and suppresses superoxide generation through induction of uncoupling proteins (UCPs) in the mitochondria. Here, we demonstrated a protective role of STC-1 on inflammatory responses in vitro, in activated microglia stimulated with LPS, and on neuroinflammation, oxidative stress, and mitochondrial function in the hippocampus of rats subjected to an animal model of sepsis by cecal ligation and puncture (CLP), as well the consequences on long-term memory. Recombinant human STC-1 (rhSTC1) suppressed the pro-inflammatory cytokine production in LPS-stimulated microglia without changing the UCP-2 expression. Besides, rhSTC1 injected into the cisterna magna decreased acute hippocampal inflammation and oxidative stress and increased the activity of complex I and II activity of mitochondrial respiratory chain and creatine kinase at 24h after sepsis. rhSTC1 was effective in preventing long-term cognitive impairment after CLP. In conclusion, rhSTC1 confers significant neuroprotection by inhibiting the inflammatory response in microglia and protecting against sepsis-associated encephalopathy in rats.

Mechanism of resveratrol on ameliorating the cognitive dysfunction induced by sepsis associated encephalopathy in rats

To explore the mechanism of resveratrol on ameliorating the cognitive dysfunction induced by sepsis associated encephalopathy (SAE) in rats. The 12 weeks old male Sprague-dawley (SD) male rats were randomly divided into sham group, sepsis group and resveratrol group, with 30 rats in each group. The rat model of sepsis was made by injecting LPS (10 mg/kg) into tail vein. The rats in sham group was given the same amount of normal saline (NS). After LPS injection, resveratrol (8 mg×kg-1×d-1) was intraperitoneally injected once daily for 2 days in the resveratrol group; the same amount of NS was given to the sepsis group and sham group. At 24 hours after model establishment, the cognitive function of the experimental rats was assessed by the Morris water maze test. The blood-brain barrier (BBB) permeability was evaluated by the brain water content (BWC) and Evans blue (EB) test. The protein expressions of matrix metalloproteinase 9 (MMP-9), Occludin and Claudin-5 in cortical tissue were detected by Western Blot. Double immunofluorescence was used to verify the co-localization of MMP-9 protein and the marker protein of astrocyte GFAP in the cortical tissue of rats. Compared with the sham group, the escape latency in the sepsis group was significantly longer [48-hour escape latency (s): 56.56±6.43 vs. 36.62±3.32, 72-hour escape latency (s): 57.72±7.23 vs. 26.46±4.24, both P < 0.01], the BWC and extravasation of EB were increased [BWC: (84.56±2.03)% vs. (76.82±2.22)%, EB (μg/g): 17.56±2.28 vs. 6.25±1.36, both P < 0.01], the expression of MMP-9 protein was increased (MMP-9/β-actin: 0.73±0.01 vs. 0.24±0.01, P < 0.01), the protein expressions of Occludin and Claudin-5 were decreased (Occludin/β-actin: 0.45±0.02 vs. 0.86±0.04, Claudin-5/β-actin: 0.62±0.03 vs. 0.96±0.05, both P < 0.01). At the same time, the co-localization expression of MMP-9 protein and the astrocytes of the cortical were increased [MMP-9 fluorescence intensity (AU): 38.66±4.26 vs. 17.23±3.04, MMP-9 positive cells: (26.92±1.77)% vs. (12.82±1.46)%, both P < 0.01]. Compared with the sepsis group, the escape latency in resveratrol group was significantly shorter [48-hour escape latency (s): 41.42±6.27 vs. 56.56±6.43, 72-hour escape latency (s): 33.46±7.17 vs. 57.72±7.23, both P < 0.01], the BWC and extravasation of EB were decreased [BWC: (77.15±2.27)% vs. (84.56±2.03)%, EB (μg/g): 7.74±1.88 vs. 17.56±2.28, both P < 0.01], the expression of MMP-9 protein was decreased (MMP-9/β-actin: 0.25±0.01 vs. 0.73±0.01, P < 0.01), the protein expressions of Occludin and Claudin-5 were increased (Occludin/β-actin: 0.82±0.03 vs. 0.45±0.02, Claudin-5/β-actin: 0.92±0.04 vs. 0.62±0.03, both P < 0.01). At the same time, the co-localization expression of MMP-9 protein and the astrocytes of the cortical were decreased [MMP-9 fluorescence intensity (AU): 19.44±4.37 vs. 38.66±4.26, MMP-9 positive cells: (13.11±1.29)% vs. (26.92±1.77)%, both P < 0.01]. Resveratrol can inhibit the expression of MMP-9 protein in the astrocytes of the cortical cortex of rats, and then reduce the degradation of tight junction proteins of Occludin and Claudin-5, thereby reducing BBB permeability and eventually ameliorate the cognitive dysfunction induced by SAE.

Synergistic effect of aminoguanidine and l-carnosine against thioacetamide-induced hepatic encephalopathy in rats: behavioral, biochemical, and ultrastructural evidence.

Hepatic encephalopathy depicts the cluster of neurological alterations that occur during acute or chronic hepatic injury. Hyperammonemia, inflammatory injury, and oxidative stress are the main predisposing factors for the direct and indirect changes in cerebral metabolism causing encephalopathy. The aim of this study was to evaluate the possible synergistic effect between aminoguanidine (AG; 100 mg/kg, p.o.) and l-carnosine (CAR; 200 mg/kg, p.o.) on hepatic encephalopathy that was induced by thioacetamide (TAA; 100 mg/kg, i.p.) administered three times weekly for six weeks. Behavioral changes, biochemical parameters, histopathological analysis, and immunohistochemical and ultrastructural studies were conducted 24h after the last treatment. Combining AG with CAR improved TAA-induced locomotor impairment and motor incoordination evidenced by reduced locomotor activity and decline in motor skill performance, as well as ameliorated cognitive deficits. Moreover, both drugs restored the levels of serum hepatic enzymes and serum and brain levels of ammonia. In addition, the combination significantly modulated hepatic and brain oxidative stress biomarkers, inflammatory cytokines, and cleaved caspase-3 expression. Furthermore, they succeeded in activating nuclear erythroid 2-related factor 2 (Nrf2) expression and heme oxygenase-1 (HO-1) activity and ameliorating markers of hepatic encephalopathy, including hepatic necrosis and brain astrocyte swelling. This study shows that combining AG with CAR exerted a new intervention for hepatic and brain damage in hepatic encephalopathy due to their complementary antioxidant, anti-inflammatory effects and hypoammonemic effects via Nrf2/HO-1 activation and NO inhibition.

IRE1\u03b1 inhibition attenuates neuronal pyroptosis via miR-125/NLRP1 pathway in a neonatal hypoxic-ischemic encephalopathy rat model

BackgroundInhibition of inositol-requiring enzyme-1 alpha (IRE1α), one of the sensor signaling proteins associated with endoplasmic reticulum (ER) stress, has been shown to alleviate brain injury and improve neurological behavior in a neonatal hypoxic-ischemic encephalopathy (HIE) rat model. However, there is no information about the role of IRE1α inhibitor as well as its molecular mechanisms in preventing neuronal pyroptosis induced by NLRP1 (NOD-, LRR- and pyrin domain-containing 1) inflammasome. In the present study, we hypothesized that IRE1α can degrade microRNA-125-b-2-3p (miR-125-b-2-3p) and activate NLRP1/caspased-1 pathway, and subsequently promote neuronal pyroptosis in HIE rat model.MethodsTen-day old unsexed rat pups were subjected to hypoxia-ischemia (HI) injury, and the inhibitor of IRE1α, STF083010, was administered intranasally at 1 h after HI induction. AntimiR-125 or NLRP1 activation CRISPR was administered by intracerebroventricular (i.c.v) injection at 24 h before HI induction. Immunofluorescence staining, western blot analysis, reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), brain infarct volume measurement, neurological function tests, and Fluoro-Jade C staining were performed.ResultsEndogenous phosphorylated IRE1α (p-IRE1α), NLRP1, cleaved caspase-1, interleukin-1β (IL-1β), and interleukin-18 (IL-18) were increased and miR-125-b-2-3p was decreased in HIE rat model. STF083010 administration significantly upregulated the expression of miR-125-b-2-3p, reduced the infarct volume, improved neurobehavioral outcomes and downregulated the protein expression of NLRP1, cleaved caspase-1, IL-1β and IL-18. The protective effects of STF083010 were reversed by antimiR-125 or NLRP1 activation CRISPR.ConclusionsIRE1α inhibitor, STF083010, reduced neuronal pyroptosis at least in part via miR-125/NLRP1/caspase-1 signaling pathway after HI.Graphical

Diallyl sulfide alleviates cyclophosphamide-induced nephropathic encephalopathy in rats

Diallyl sulfide (DAS) is a garlic-derived organosulfur compound. The current study was planned to evaluate the protecting effects of DAS against cyclophosphamide (CP)-induced nephropathic encephalopathy. DAS (100 mg/kg) was orally administered for 4 days, 60 min after the last dose, rats were injected with CP (150 mg/kg). DAS treatment before CP significantly decreased serum urea, creatinine, sodium, potassium, calcium, blood urea nitrogen (BUN), C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-1β (IL-1ß) and tumor necrosis factor-alpha (TNF-α) compared with CP-treated rats. DAS treatment decreased malondialdehyde (MDA) and increased superoxide dismutase (SOD) and reduced glutathione (GSH) levels in the renal tissues and significantly attenuated the elevated neurotransmitters N-methyl-D-aspartate/adenosine triphosphate (NMDA), γ-aminobutyric acid (GABA) levels and remarkably restored neuronal nitric oxide (NO) level and nitric oxide synthase (nNOS) activity in the brain compared to CP-treated rats. DAS for 4 consecutive days before CP showed moderate positive immunohistochemically expression of the glial fibrillary acidic protein (GFAP) in the brain and kidney tissues comparable to CP-treated rats. DAS afforded renal and neuroprotection against CP-induced nephropathic encephalopathy due to its capacity to ameliorates the afore-mentioned biochemical parameters which were supported by histopathological and immunohistochemically examination.

Amelioration of thioacetamide-induced hepatic encephalopathy in rats by low-dose gamma irradiation.

Brain affection is a common symptom of liver insufficiency. This study aimed to evaluate the role of low-dose γ irradiation (LDR) as a potential therapeutic agent in thioacetamide (TAA)-induced hepatic encephalopathy (HE) in rats. Effects of local and whole-body irradiation (0.5Gy) on rat brain/liver were evaluated following the induction of HE by TAA (200mg/kg/day/for 3 successive days). Serum activities of aspartate transaminase (AST) and alanine transaminase (ALT) and ammonia level were assessed. The effect of HE on brain was evaluated through the determination of brain contents of malondialdehyde (MDA), reduced glutathione (GSH), tumor necrosis factor-alpha (TNF-α), and interleukin-1beta (IL-1β) and glutathione peroxidase (GPx) activity. Moreover, apoptotic and inflammatory changes in brain and liver tissues were assessed together with alpha-smooth muscle actin (α-SMA); fibrosis marker. Results showed correction of the biochemical parameters which was supported by the results of the immunohistochemical examinations. LDR is a promising hepato- and neurotherapy against HE.

HUC-MSCs Exert a Neuroprotective Effect via Anti-apoptotic Mechanisms in a Neonatal HIE Rat Model

In this study, we investigated how human umbilical cord mesenchymal stem cells exerted a neuroprotective effect via antiapoptotic mechanisms in a neonatal hypoxic-ischemic encephalopathy rat model. A total of 78 10-day old (P10) rats were used. After human umbilical cord mesenchymal stem cells were collected from human umbilical cords and amplified in culture, they were administered to rat subjects 1 h after induced hypoxic-ischemic encephalopathy treatment. The short-term (48 h) and long-term (28 day) outcomes were evaluated after human umbilical cord mesenchymal stem cells treatment using neurobehavioral function assessment. Triphenyltetrazolium chloride monohydrate staining was performed at 48 h. Beclin-2 and caspase-3 levels were evaluated with Western blot and real time polymerase chain reaction at 48 h. Human umbilical cord mesenchymal stem cells were collected and administrated to hypoxic-ischemic encephalopathy pups by intracerebroventricular injection. Hypoxic-ischemic encephalopathy typically induced significant delay in development and caused impairment in both cognitive and motor functions in rat subjects. Human umbilical cord mesenchymal stem cells were shown to ameliorate hypoxic-ischemic encephalopathy-induced damage and improve both cognitive and motor functions. Although hypoxic-ischemic encephalopathy induced significant expression of caspase-3 and Beclin-2, human umbilical cord mesenchymal stem cells decreased the expression of both of them. Human umbilical cord mesenchymal stem cells may serve as a potential treatment to ameliorate brain injury in hypoxic-ischemic encephalopathy patients.

Comparison of different durations of mild hypothermia on neuroprotection in septic rats

Objective To investigate the protective effect of mild hypothermia on septic rats and to find suitable hypothermia duration time. Methods After cecal ligation and puncture (or sham), male Sprague-Dawley rats were divided into a sham operation group(Sham group, n=20), a normal temperature group[Norm group, (37.0±0.2) °C, n=43], and hypothermia group (34.0±0.5) °C[a hypothermia 6 h group (Hypo 6 group, n=41), a hypothermia 12 h group (Hypo 12 group, n=33), a hypothermia 24 h group (Hypo 24 group, n=27)], and the electrodes were placed on the head 10 days before the operation. Electrocardiogram (EEG) and behavioral tests were performed before and 24 h after surgery. The blood samples were collected 24 h after surgery. The blood levels of S100β protein were detected by enzyme-linked immunosorbent assay (ELISA) to determine the degree of brain damage. Results Twenty rats in each group survived. The survival rates of Sham group, Norm group and Hypo 6, 12 and 24 groups were 100% (20/20), 46.51% (20/43), 48.78% (20/41), 60.61% (20/33) and 74.07% (20/27), the survival rate of Hypo 24 group was significantly higher than that of Norm group and Hypo 6 group (P 0.05). Compared with the Sham group, rats in Norm group and Hypo groups presented remarkably lowerd neurobiological scores 24 h after surgery(P 0.05), and no significant difference was found between Hypo 12 and Hypo 6 groups (P>0.05). Compared with the sham groups, remarkly higher levels of plasma S100β protein and EEG δ waves were detected in the operation group(P 0.05), and no significant difference between Hypo 6 and Hypo 12 groups (P>0.05). According to the biological score and EEG monitoring results, sepsis-associated encephalopathy was was detected in 13(65%), 13(65%), 11(55%), and 8(40%) rats in the Norm group, Hypo 6, 12, 24 groups, and no statistically significant differences in the incidence was found among the groups(P>0.05). Conclusions Although mild hypothermia cannot reduce the incidence of sepsis-associated encephalopathy in rats with sepsis, it can reduce there brain damage, and protect the brain as hypothermia time extends. Key words: Hypothermia; Sepsis; Sepsis-associated encephalopathy; Neuroprotection

Protective role of chrysin on thioacetamide-induced hepatic encephalopathy in rats

Hepatic encephalopathy (HE) is a serious neuropsychiatric syndrome due to either acute or chronic hepatic failure. This study aimed to investigate the possible neuroprotective effect of chrysin, a natural flavenoid on thioacetamide (TAA)-induced hepatic encephalopathy in rats. Also the effect of chrysin on motor impairment, cognitive deficits, oxidative stress, neuroinflammation, apoptosis and histopathological damage was assessed. HE was induced in Wistar rats by intraperitoneal (i.p.) injection of TAA (200 mg/kg) for three alternative days. Normal and control groups received the vehicle for 21 days. Chrysin was administered orally for 21 days (25, 50, 100 mg/kg) and starting from day 17, rats received i.p. dose of TAA (200 mg/kg) at three alternative days. Then behavioral, biochemical, histopathological and immunohistochemical analyses were conducted. Chrysin improved TAA-induced motor incoordination as it reduced final falling latency time in rotarod test, ameliorated cognitive deficits in object recognition test (ORT) and attenuated serum ammonia, hepatic liver enzymes namely, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), reduced malondialdehyde (MDA), elevated reduced glutathione (GSH), reduced nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) brain contents. Chrysin administration also reduced Toll-4 receptor (TLR-4) gene expression, caspase-3 protein expression, hepatic necrosis and astrocyte swelling. This study depicts that chrysin exerted neuroprotective effect in TAA-induced HE rats, evidenced by improvement of cognitive deficits, motor incoordination and histopathological changes such as astrocyte swelling and vacuolization; hallmarks in HE, via reducing hyperammonia, ameliorating hepatic function, in addition to its anti-oxidant, inactivation of TLR-4/NF-κB inflammatory pathway, and anti-apoptotic effects.

THE COMPARATIVE ANALYSIS OF THE ULTRASTRUCTURAL REACTION OF NEO- AND PALLEOCORTEX OF BRAIN ON ACUTE CEREBRAL DISORDER IN BASSIN OF CAROTID ARTERIES ON BACKGROUND OF DIABETIC ENCEPHALOPATHY IN RATS

The aim of the study. The objective is to perform the comparativ analysis the ultrastructural reactions of tissues of neocortex and fields of hippocampus in rats with diabetic encephalopathy to acute cerebrovascular disorder in the bassin of carotid arteries. Material and methods. Diabetes mellitus was modeled by single intraperitoneal administration of the streptozotocin (Sigma, Aldrich, 60 mg / kg) to white nonlinear male rats in age two months, and acute cerebrovascular disorder was performed by a 20-minute clipsing of both common carotid arteries under intraperitoneal anesthesia, with reperfusion for 1 hour. The fragments of the brain containing the hippocampus and the cortex of the frontal and occipital brain lobes were taken, and after appropriate fixation and wiring, ultrathin sections were made, which were stained with 1% aqueous uranyl acetate solution, contrasted by lead citrate and studied using an electron microscope PEM-125K. Results. The diabetic encephalopathy in rats exacerbates destructive changes of all structural components of the gray matter of the cortex of the investigated brain lobes and the fields of the hippocampus in the form of violations of the internal structure and shape of the nerve cells and the appearance of neurocytes with hypo and hyperchromia of neuro-and karyoplasma in varying degrees of severity, violation of the structure of cellular organelles and decrease their number, appearance of perivascular edema, that is caused by ischemia-reperfusion of the brain. Among the all studied structures, the field of the hippocampus CA3 is the least sensitive to the indicated intervention. Conclusions. Diabetic encephalopathy creates pathomorphological preconditions for the deteriorated course of ischemic-reperfusion injury of the brain, especially in the structures of the neocortex and the fields of the hippocampus CA1 and CA2.

Role of the indoleamine-2,3-dioxygenase/kynurenine pathway of tryptophan metabolism in behavioral alterations in a hepatic encephalopathy rat model

BackgroundThis study aims to explore the role of indoleamine-2,3-dioxygenase (IDO)/kynurenine (KYN) pathway of tryptophan (TRY) metabolism in behavioral alterations observed in hepatic encephalopathy (HE) rats.MethodsExpression levels of proinflammatory cytokines were tested by QT-PCR and ELISA, levels of IDOs were tested by QT-PCR and Western blot, and levels of 5-hydroxytryptamine (5-HT), KYN, TRY, 3-hydroxykynurenine (3-HK), and kynurenic acid (KA) in different brain regions were estimated using HPLC. Effects of the IDO direct inhibitor 1-methyl-l-tryptophan (1-MT) on cognitive, anxiety, and depressive-like behavior were evaluated in bile duct ligation (BDL) rats.ResultsIncreased serum TNF-α, IL-1β, and IL-6 levels were shown in rats 7 days after BDL, and these increases were observed earlier than those in the brain, indicating peripheral immune activation may result in central upregulation of proinflammatory cytokines. Moreover, BDL rats showed a progressive decline in memory formation, as well as anxiety and depressive-like behavior. Further study revealed that IDO expression increased after BDL, accompanied by a decrease of 5-HT and an increase of KYN, as well as abnormal expression of 3-HK and KA. The above results affected by BDL surgery were reversed by IDO inhibitor 1-MT treatment.ConclusionTaken together, these findings indicate that (1) behavioral impairment in BDL rats is correlated with proinflammatory cytokines; (2) TRY pathway of KYN metabolism, activated by inflammation, may play an important role in HE development; and (3) 1-MT may serve as a therapeutic agent for HE.

Improvement of the Modeling and Diagnosis of Hepatic Encephalopathy in Rats

Improvement of the Modeling and Diagnosis of Hepatic Encephalopathy in Rats

Erratum to: A Therapeutic Insight of Niacin and Coenzyme Q10 against Diabetic Encephalopathy in Rats.

Erratum to: A Therapeutic Insight of Niacin and Coenzyme Q10 against Diabetic Encephalopathy in Rats.

Hepato- and neuro-protective influences of biopropolis on thioacetamide-induced acute hepatic encephalopathy in rats.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that ultimately occurs as a complication of acute or chronic liver failure; accompanied by hyperammonemia. This study aimed to evaluate the potential of biopropolis as a hepato- and neuro-protective agent using thioacetamide (TAA)-induced acute HE in rats as a model. Sixty Wistar rats were divided into 5 groups: Group 1 (normal control) received only saline and paraffin oil. Group 2 (hepatotoxic control) received TAA (300 mg/kg, once). Groups 3, 4, and 5 received TAA followed by vitamin E (100 mg/kg) and biopropolis (100 and 200 mg/kg), respectively, daily for 30 days. Evidences of HE were clearly detected in TAA-hepatotoxic group including significant elevation in the serum level of ammonia, liver functions, increased oxidative stress in liver and brain, apoptotic DNA fragmentation and overexpression of iNOS gene in brain tissue. The findings for groups administered biopropolis, highlighted its efficacy as a hepato- and neuro-protectant through improving the liver functions, oxidative status and DNA fragmentation as well as suppressing the brain expression of iNOS gene. In conclusion, biopropolis, at a dose of 200 mg/kg per day protected against TAA-induced HE through its antioxidant and antiapoptotic influence; therefore, it can be used as a protective natural product.