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This study aimed to investigate the anti-depressant effect of hesperidin (Hsp) in streptozotocin (STZ)-induced diabetic rats. Additionally, the effect of Hsp on hyperglycaemia, oxidative stress, inflammation, brain-derived neurotrophic factor (BDNF), and brain monoamines in diabetic rats was also assessed. The Wistar rats in the experimental groups were rendered hyperglycaemic with a single dose of STZ (52.5 mg·(kg body mass)(-1), by intraperitoneal injection). The normal group received the vehicle only. Hyperglycaemic rats were treated with Hsp (25.0, 50.0, or 100.0 mg·(kg body mass)(-1)·day(-1), per oral) and fluoxetine (Flu) (5.0 mg·(kg body mass)(-1)·day(-1), per oral) 48 h after the STZ injection, for 21 consecutive days. The normal and STZ control groups received the vehicle (distilled water). Behavioral and biochemical parameters were then assessed. When Hsp was administered to the STZ-treated rats, this reversed the STZ-induced increase in immobility duration in the forced swimming test (FST) and attenuated hyperglycaemia, decreased malondialdehyde (MDA), increased reduced glutathione (GSH) decreased interleukin-6 (IL-6), and increased BDNF levels in the brain. Treatment with Hsp attenuated STZ-induced neurochemical alterations, as indicated by increased levels of monoamines in the brain, namely, norepinephrine (NE), dopamine (DA), and serotonin (5-hydroxytryptamine; 5-HT). All of these effects of Hsp were similar to those observed with the established anti-depressant Flu. This study shows that Hsp exerted anti-depressant effect in diabetic rats, which may have been partly mediated by its amelioration of hyperglycaemia as well as its anti-oxidant and anti-inflammatory activities, the enhancement of neurogenesis, and changes in the levels of monoamines in the brain.
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Antidepresivos/uso terapéutico , Conducta Animal/efectos de los fármacos , Depresión/tratamiento farmacológico , Diabetes Mellitus Experimental/tratamiento farmacológico , Hesperidina/uso terapéutico , Animales , Antidepresivos/farmacología , Monoaminas Biogénicas/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Depresión/psicología , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/psicología , Fluoxetina/farmacología , Fluoxetina/uso terapéutico , Glutatión/metabolismo , Hesperidina/farmacología , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Interleucina-6/metabolismo , Masculino , Malondialdehído/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , EstreptozocinaRESUMEN
Naringenin (NAR) has various biological activities but low bioavailability. The current study examines the effect of Naringenin-loaded hybridized nanoparticles (NAR-HNPs) and NAR on depression induced by streptozotocin (STZ) in rats. NAR-HNPs formula with the highest in vitro NAR released profile, lowest polydispersity index value (0.21 ± 0.02), highest entrapment efficiency (98.7 ± 2.01%), as well as an acceptable particle size and zeta potential of 415.2 ± 9.54 nm and 52.8 ± 1.04 mV, respectively, was considered the optimum formulation. It was characterized by differential scanning calorimetry, examined using a transmission electron microscope, and a stability study was conducted at different temperatures to monitor its stability efficiency showing that NAR-HNP formulation maintains stability at 4 °C. The selected formulation was subjected to an acute toxicological test, a pharmacokinetic analysis, and a Diabetes mellitus (DM) experimental model. STZ (50 mg/kg) given as a single i.p. rendered rats diabetic. Diabetic rat groups were allocated into 4 groups: one group received no treatment, while the remaining three received oral doses of unloaded HNPs, NAR (50 mg/kg), NAR-HNPs (50 mg/kg) and NAR (50 mg/kg) + peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist, GW9662 (1mg/kg, i.p.) for three weeks. Additional four non-diabetic rat groups received: distilled water (normal), free NAR, and NAR-HNPs, respectively for three weeks. NAR and NAR-HNPs reduced immobility time in forced swimming test and serum blood glucose while increasing serum insulin level. They also reduced cortical and hippocampal 5-hydroxyindoeacetic acid, 3,4-Dihydroxy-phenylacetic acid, malondialdehyde, NLR family pyrin domain containing-3 (NLRP3) and interleukin-1beta content while raised serotonin, nor-epinephrine, dopamine and glutathione level. PPAR-γ gene expression was elevated too. So, NAR and NAR-HNPs reduced DM-induced depression by influencing brain neurotransmitters and exhibiting anti-oxidant and anti-inflammatory effects through the activation PPAR-γ/ NLRP3 pathway. NAR-HNPs showed the best pharmacokinetic and therapeutic results.
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Antidepresivos , Diabetes Mellitus Experimental , Flavanonas , Proteína con Dominio Pirina 3 de la Familia NLR , Nanopartículas , PPAR gamma , Animales , Flavanonas/farmacología , Flavanonas/administración & dosificación , Flavanonas/química , PPAR gamma/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nanopartículas/química , Ratas , Masculino , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Depresión/metabolismo , Transducción de Señal/efectos de los fármacos , Estreptozocina , Ratas Wistar , AnilidasRESUMEN
Diabetic peripheral neuropathy (DPN) is a common diabetic complication. Chrysin (CHY) has many biological properties but poor oral bioavailability. This study investigates the effect of CHY and CHY-loaded nanovesicles (CHY-NVs) on streptozotocin (STZ)-induced DPN in rats. CHY-NVs were prepared by using film hydration method. The formula with the best entrapment efficiency%, lowest particle size, highest zeta potential, and highest in vitro CHY released profile was selected, characterized by Differential scanning calorimetry, Fourier transformation infrared spectroscopy analysis, and examined by Transmission electron microscope. Acute toxicity test, pharmacokinetic study and experimental model of diabetes mellitus were performed on the selected formulation. Wistar rats were considered diabetic by administration of a single intraperitoneal dose of STZ (50 mg/kg). 48 h after STZ administration, hyperglycemic rats were randomly assigned into four groups, one group of untreated hyperglycemic rats and the other three groups received daily oral doses of unloaded NVs, CHY-NVs (25 mg/kg), and CHY-NVs (50 mg/kg), respectively for 21 days. Moreover, five additional groups of healthy rats received: distilled water (control), free CHY, unloaded NVs, and CHY-NVs respectively for 21 days. CHY and CHY-NVs maintained body weight and reduced STZ-induced behavioral changes in rotarod, hind paw cold allodynia, tail cold allodynia, tail flick, and hot plate tests. CHY and CHY-NVs lowered blood glucose, glycated hemoglobin, elevated serum reduced glutathione (GSH), and reduced plasma malondialdehyde (MDA) levels. CHY-NVs elevated phosphatidylinositol 3-kinase (Pi3k), phosphorylated protein kinase B (p-AKT), and reduced nuclear factor kappa B (NF-κB), interleukin-6 (IL-6) in sciatic nerve homogenate. CHY and CHY-NVs increased nerve growth factor (NGF) and decreased glycogen synthase kinase-3ß (GSK-3ß) gene expressions in the sciatic nerve. In conclusion, CHY and CHY-NVs ameliorated STZ-induced DPN behavioral and histopathological changes via attenuating hyperglycemia, exerting anti-oxidant, anti-inflammatory effects, activating NGF/p-AKT/GSK-3ß pathway, and its anti-apoptotic effect. The best pharmacokinetic profile and therapeutic effect was observed in rats treated with CHY-loaded NVs.
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Diabetes Mellitus , Neuropatías Diabéticas , Ratas , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Ratas Wistar , Neuropatías Diabéticas/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/metabolismo , Factor de Crecimiento Nervioso , Hiperalgesia , EstreptozocinaRESUMEN
High consumption of industrialized food with high fat content is generally associated with insulin resistance, which in turn causes memory impairment and cognitive decline. Nicotinamide and ascorbic acid are among the promising neuroprotective molecules; however, an appreciable therapeutic activity necessitates the administration of a large dose of either. Therefore, the study aimed to assess if loading them in chitosan nanoparticles in doses 5-10 times lower than the unencapsulated forms would achieve comparable therapeutic results. Animals were fed a high-fat-high-fructose (HFHF) diet for 75 days. The vitamins in their conventional form (100 mg/kg) and the nanoparticles under investigation (10 and 20 mg/kg) were given orally concomitantly with the diet in the last 15 days. The intake of HFHF diet for 75 days led to an insulin-resistant state, with memory impairment, which was verified behaviorally through the object recognition test. This was accompanied by significant reduction in brain insulin-like growth factor 1 (IGF-1), increased acetylcholine esterase activity, increase in the serotonin and dopamine turnover ratio, and increase in oxidative stress and 8-OHdG, indicating cellular DNA fragmentation. Cellular energy was also decreased, and immunohistochemical examination verified the high immunoreactivity in both the cortex and hippocampus of the brain. The administration of nanoparticulated nicotinamide or ascorbic acid with a 10 times lesser dose than the unencapsulated forms managed to reverse all aforementioned harmful effects, with an even lesser immunoreactivity score than the unencapsulated form. Therefore, it can be concluded that nicotinamide or ascorbic acid chitosan nanoparticles can be recommended as daily supplements for neuroprotection in patients suffering from insulin resistance after conduction of clinical investigations.
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Depression is a major psychological disorder that contributes to global health problem. This study aimed to evaluate the anti-depressant effect of Cerebrolysin (CBL) in Reserpine-induced depressed rats, its effect on oxidative stress, inflammation, regulatory cyclic AMP-dependent response element binding protein (CREB)/brain derived neurotropic factor (BDNF) signaling pathways, brain monoamines and histopathological changes was assessed. Rats received either the vehicle or Reserpine (0.5 mg/kg, i.p.) for 14 days. The other three groups were pretreated with CBL (2.5, 5 ml/kg; i.p.) or fluoxetine (FLU) (5 mg/kg, p.o.), respectively for 14 days, 30 min before reserpine injection. Then analyses were conducted. CBL reversed Reserpine-induced reduction in latency to immobility and prolongation of immobility time in the forced swimming test (FST), reduced malondialdehyde (MDA), elevated reduced glutathione (GSH), reduced tumor necrosis factor-alpha (TNF-É), and elevated BDNF cortical and hippocampal brain contents. CBL elevated protein kinase A (PKA) and nuclear factor kappa-B (NF-κB) cortical and hippocampal protein expressions. CBL also ameliorated alterations in mRNA expressions of protein kinase B (AKT), CREB and BDNF in the cortical and hippocampal tissues. CBL elevated nor-epinephrine (NE), serotonin (5-HT), and dopamine (DA) and reduced 5-Hydroxyindoleacetic acid (5-HTAA), 3,4-Dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) cortical and hippocampal contents. CBL effects were in parallel to those observed with the standard anti-depressant drug, FLU. This study shows that CBL exerted anti-depressant effect evidenced by attenuation of oxidative stress and inflammation as well as enhancement of neurogenesis, amelioration of monoaminergic system and histopathological changes.
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Aminoácidos/farmacología , Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Reserpina/farmacología , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Depresión/metabolismo , Modelos Animales de Enfermedad , Dopamina/metabolismo , Fluoxetina/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Inflamación/metabolismo , Masculino , FN-kappa B/metabolismo , Neurogénesis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Wistar , Serotonina/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Fibrosis represents a common outcome of almost all chronic liver diseases and leads to an impairment of liver function that requires medical intervention. The current study aimed to evaluate the potential anti-fibrotic effect of Saccharomyces cervisciae cell wall extract (SCCWE) against thioacetamide (TAA)-induced liver fibrosis in rats (200mg/kg b.w. i.p. twice weekly for 6 weeks) using Ursodeoxycholic acid (UDCA) as a reference anti-fibrotic product. SCCWE at two doses (50 and 100 mg/kg) significantly ameliorated the rise in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamide transferase (GGT) activities, total bilirubin and direct bilirubin, increased total protein and albumin. SCCWE significantly reduced glutathione depletion (GSH), Nitric oxide (NOx) and malondialdehyde (MDA), thioredoxin (Trx) contents and elevated nuclear factor erythroid 2-related factor 2 (Nrf-2) content. Its anti-inflammatory effects were confirmed by observing a decrease in nuclear factor-κB (NF- κß), interleukin-1b (IL-1ß) and inducible nitric oxide synthase (iNOS) content. The anti-fibrotic effects of SCCWE were explored by assessing fibrosis related markers as it significantly reduced transform growth factor-ß (TGF-ß) and autotaxin (ATX) contents. Administration of SCCWE significantly decreased matrix metalloproteinase-3 and 9 (MMP-3 and -9). Furthermore, it also decreased alpha smooth muscle actin (α-SMA) and caspase-3 as assessed immunohistochemically those results were similar to that of the standard drug UDCA. This study shows that SCCWE protects against TAA-induced liver fibrosis in rats, through attenuating oxidative stress, and inflammation, ameliorating MMPs, combating apoptosis and thereby fibrotic biomarkers in addition to improving histopathological changes.
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Cardiovascular disease represents a vital global disease burden. This study aims to assess the possible cardioprotective effect of thymol against adrenaline-induced myocardial injury (MI) in rats. Furthermore the effect of thymol on cardiac function biomarkers, electrocardiogram (ECG) alterations, oxidative stress, inflammation, apoptosis and histopathological changes was assessed. MI was induced by adrenaline (2 mg/kg, s.c.) injected as a single dose for 2 consecutive days (24 h apart). Normal and control groups received the vehicle for 21 consecutive days. The other 3 groups were orally administered thymol (15, 30, 60 mg/kg) for 21 consecutive days and on day 22, adrenaline was injected as a single dose for 2 consecutive days. Then ECG examination, biochemical, histopathological, immunohistochemical analyses were carried out. Thymol reversed adrenaline-induced reduction of heart rate, prolongation of RR interval and elevation of ST interval. Thymol pretreatment significantly reduced serum aspartate dehydrogenase (AST), lactate dehydrogenase (LDH), and creatine kinase (CK) levels in MI rats. Oral pretreatment with thymol increased reduced glutathione (GSH), reduced malondialdehyde (MDA), nuclear factor-kappa B (NF-κB), and interleukin-1ß (IL-1ß) cardiac contents in MI rats. Additionally, thymol administration significantly decreased protein expression of caspase-3, increased Bcl-2 protein expression in cardiac tissue and ameliorated histopathological changes. This study reveals that thymol exerted cardioprotective effect against adrenaline-induced MI in rats evidenced by improving cardiac function, attenuating ECG and histopathological changes which may be partly mediated through its anti-oxidant, anti-inflammatory and anti-apoptotic effect.
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OBJECTIVE: Evaluation of traditionally used royal jelly (RJ) for the management of hepato-renal damage and gastrointestinal ulcerations caused by diclofenac. METHODS: Forty adult male Wistar rats were allocated into four groups. Rats of the 1st group received only saline and served as normal group. The remaining 3 groups received diclofenac (50 mg/kg/day, I.P.) for 7 days. Group 2 served as diclofenac-control group. Groups 3 and 4 received RJ (150 and 300 mg/kg/day, P.O.) respectively for 30 days. Twenty-four hours after the last treatment, blood samples were collected, rats were sacrificed, and livers, kidneys, stomachs & intestines were harvested. Stomachs and intestines were tested for ulcer counts. Serum levels of AST, ALT, creatinine and urea were investigated. Hepatic, renal, gastric and intestinal tissue contents of myeloperoxidase (MPO) and prostaglandin-E2 (PGE2) were measured. Histopathological examinations were also performed followed by immunohistochemical determination of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression. RESULTS: Diclofenac administration caused significant deterioration of all the above mentioned parameters. RJ improved hepatic and renal functions. Gastric and intestinal ulcer counts were significantly ameliorated. Hepatic, renal, gastric and intestinal tissue PGE-2 contents and COX-2 expression were significantly elevated. RJ also significantly reduced MPO content and iNOS expression as compared to diclofenac-control group. Improvements of the histopathological pictures of hepatic, renal, gastric and intestinal tissues were also apparent. CONCLUSION: The study demonstrates promising protective effects of RJ against diclofenac-induced hepato-renal damage and gastrointestinal ulceration in rats.
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ETHNOPHARMACOLOGICAL RELEVANCE: Cymbopogon citratus (lemongrass) is commonly used in teas, soups and treat inflammatory-based ailments, vascular and nervous disorders. AIM OF THE STUDY: The study aimed to evaluate the neuroprotective effect of Cymbopogon citratus leaves through scientific protocol. The effect of aqueous (AE) and ethanolic (EE) extracts was evaluated against AlCl3-induced Alzheimer's disease (AD) in rats. Metabolic profiling of the plant, isolation of bioactive compounds and standardization of the active fraction were investigated. MATERIALS AND METHODS: AE of Cymbopogon citratus leaves was prepared as per traditional method (infusion), EE was prepared by repeated maceration in 90% ethanol, bioactive fraction (BAEE) was obtained from EE and the active compounds thereof were obtained by column chromatography. Metabolic profiling of Cymbopogon citratus was performed by UPLC-Orbitrap HRMS and HPLC was used for standardization. AlCl3-induced Alzheimer's rats were used to assess neuroprotective effect of the extracts. Neuroprotective mechanism(s) of Cymbopogon citratus extracts was clarified through histopathological examination of brain tissues, estimation of AD biochemical markers, oxidative stress and neuroinflammation in brain homogenates. In addition, antioxidant (using DPPH assay) and anticholinesterase (using modified Ellman's method) activities were investigated. RESULTS: AlCl3-treated rats (17â¯mg/kg/day) showed histopathological alteration in brain tissues together with elevated levels of Aß, tau proteins, MDA, NF-kB and IL-6. However, treatment with AE and EE of Cymbopogon citratus leaves prevented the pathological changes and maintained the levels of oxidative stress and inflammatory markers. In addition, BAEE significantly inhibited acetylcholinesterase enzyme (2.11⯱â¯0.11â¯mg/ml) and exhibited a strong antioxidant activity (24.99⯱â¯0.00⯵g/ml). UPLC-MS of Cymbopogon citratus leaves showed peaks for twenty-eight compounds, twenty-one of them were identified. Three flavonoids; isoorientin, isoschaftoside and luteolin-7-O-neohesperidoside were isolated from BAEE as major constituents. The powdered leaves of Cymbopogon citratus was found to contain remarkable amounts of caffeic acid (3.49â¯mg/g dry wt.) and isoorientin (7.37â¯mg/g dry wt.) as determined by HPLC. CONCLUSION: Cymbopogon citratus ethanolic extract attenuates AlCl3-induced neurotoxicity in rats through inhibition of oxidative stress and inflammatory markers. This effect could possibly attributed, in part to its high content of phenolic acids and flavonoids. Accordingly, we recommend Cymbopogon citratus leaves for protection against AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Cymbopogon/química , Extractos Vegetales/farmacología , Cloruro de Aluminio , Enfermedad de Alzheimer/inducido químicamente , Animales , Antioxidantes/farmacología , Egipto , Flavonoides/farmacología , Proteína Ácida Fibrilar de la Glía/metabolismo , Hipocampo/metabolismo , Hipocampo/patología , Interleucina-6/metabolismo , Masculino , FN-kappa B/metabolismo , Hojas de la Planta/química , Ratas , Ratas WistarRESUMEN
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 (200â¯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, 100â¯mg/kg) and starting from day 17, rats received i.p. dose of TAA (200â¯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.
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Flavonoides/uso terapéutico , Encefalopatía Hepática/prevención & control , Sustancias Protectoras/uso terapéutico , Tioacetamida/toxicidad , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Caspasa 3/metabolismo , Citocinas/metabolismo , Flavonoides/farmacología , Expresión Génica/efectos de los fármacos , Glutatión/metabolismo , Encefalopatía Hepática/inducido químicamente , Encefalopatía Hepática/patología , Encefalopatía Hepática/veterinaria , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Malondialdehído/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Despite its poor bioavailability, curcumin is a promising natural polyphenol targeting NF-κß. NF-κß is a target for new therapeutics because it plays a pivotal role in the pathophysiology of Alzheimer disease (AD). In contrast, ambrsoin, a sesquiterpene lactone which is a potent NF-κß inhibitor, is scarcely studied in AD models. The current work aims to assess the efficacy of ambrosin as a possible remedy for AD. In silico studies showed that bioavailability and BBB permeability could be favorable for ambrosin over curcumin. Memory impairment was induced in mice by single intraperitoneal injection of LPS (0.4 mg/kg). Treated groups received curcumin (100 mg/kg) or ambrosin at doses (5 or 10 mg/kg) for 7 days. Mice in treated groups showed a significant improvement in memory functions during Morris water maze and object recognition tests. Curcumin and ambrosin (10 mg/kg) inhibited the upsurge of NF-κßp65 transcript and protein levels. Consequently, downstream pro-inflammatory and nitrosative mediators were inhibited, namely, TNF-α, IL-1ß, COX-2 and iNOS. BACE1 was inhibited, thereby reducing amyloid plaques (Aß) deposition and eventually reducing inflammation and apoptosis of neurons as revealed by immunohistopathological examination. In conclusion, ambrosin can be repurposed as AD remedy after further pharmacokinetic/pharamacodynamic assessments. It could serve as an additional lead drug for AD therapeutics.
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Curcumina/farmacología , Trastornos de la Memoria/etiología , Trastornos de la Memoria/metabolismo , Memoria/efectos de los fármacos , FN-kappa B/antagonistas & inhibidores , Sesquiterpenos de Guayano/farmacología , Péptidos beta-Amiloides/metabolismo , Animales , Apoptosis/efectos de los fármacos , Biomarcadores , Curcumina/química , Citocinas/metabolismo , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/efectos adversos , Masculino , Aprendizaje por Laberinto , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/psicología , Ratones , Estructura Molecular , FN-kappa B/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Sesquiterpenos de Guayano/química , Transducción de Señal/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
In liver fibrosis, conversion of fibroblasts to profibrogenic myofibroblasts significantly drives the development of the disease. A crucial role of cyclic adenosine monophosphate (cAMP) in regulation of fibroblast function has been reported. Increase in cAMP levels has been found to decrease fibroblast proliferation, inhibit their conversion to myofibroblast, and stimulate their death. cAMP is generated by adenyl cyclase (AC), and degraded by cyclic nucleotide phosphodiesterase (PDE). In this study, the antifibrotic effect of a PDE inhibitor, cilostazol (Cilo), on a rat model of liver fibrosis induced by thioacetamide (TAA) was investigated. Four groups of rats were used; the first group received the vehicles and served as the normal control group, while liver fibrosis was induced in the other groups using (TAA, 200 mg/kg/biweekly for 8 successive weeks, ip). The last two groups were treated with Cilo (50 and 100 mg/kg/day, po, respectively). Induction of liver fibrosis in TAA-treated rats was observed as evidenced by the biochemical and histopathological findings. On the other hand, a potent antifibrotic effect was observed in the groups treated with Cilo, with preference to the higher dose. In these groups, a significant increase in the liver content of cAMP was demonstrated that was accompanied by reduction in the hepatic expression of key fibrogenic cytokines, growth factors, and inflammatory biomarkers, including interleukin-6, tumor necrosis factor-alpha, nuclear factor kappa B, and transforming growth factor-beta as compared to TAA group. Moreover, amelioration of TAA-induced oxidative stress and apoptosis in the liver has been observed. These findings reveal the antifibrotic effect of Cilo against TAA-induced liver fibrosis in rats, and suggest regulation of cAMP pathway, together with the modulation of oxidative stress, inflammation, and apoptosis as mechanistic cassette underlines this effect.
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Cilostazol/uso terapéutico , Cirrosis Hepática/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Biomarcadores/análisis , AMP Cíclico/metabolismo , Inflamación/tratamiento farmacológico , Hígado/metabolismo , Cirrosis Hepática/inducido químicamente , Estrés Oxidativo/efectos de los fármacos , Ratas , Tioacetamida/toxicidad , Regulación hacia ArribaRESUMEN
AIM: This study aims to elucidate the possible ameliorative effect of silymarin on scopolamine-induced dementia using the object recognition test (ORT) in rats. METHODS: The study was extended to demonstrate the role of cholinergic activity, oxidative stress, neuroinflammation, brain neurotransmitters and histopathological changes in the anti-amnestic effect of silymarin in demented rats. Wistar rats were pre-treated with silymarin (200, 400, 800 mg/kg) or donepezil (10 mg/kg) orally for 14 consecutive days. Dementia was induced after the last drug administration by a single intraperitoneal dose of scopolamine (16 mg/kg). Then behavioural, biochemical, histopathological, and immunohistochemical analyses were then performed. RESULTS: Rats pre-treated with silymarin counteracted scopolamine-induced non-spatial working memory impairment in the ORT and decreased acetylcholinesterase (AChE) activity, reduced malondialdehyde (MDA), elevated reduced glutathione (GSH), restored gamma-aminobutyric acid (GABA) and dopamine (DA) contents in the cortical and hippocampal brain homogenates. Silymarin reversed scopolamine-induced histopathological changes. Immunohistochemical analysis showed that silymarin mitigated protein expression of the glial fibrillary acidic protein (GFAP) and nuclear factor kappa-B (NF-κB) in the brain cortex and hippocampus. All these effects of silymarin were similar to that of the standard anti-amnestic drug, donepezil. CONCLUSION: This study reveals that the ameliorative effect of silymarin on scopolamine-induced dementia in rats using the ORT maybe in part mediated by, enhancement of cholinergic activity, anti-oxidant and anti-inflammatory activities as well as mitigation in brain neurotransmitters and histopathological changes.
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Stroke is the leading cause of death worldwide. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of anti-diabetic drugs for treatment of type-2 diabetes mellitus. The aim of this study is to evaluate the possible neuroprotective effect of a dipeptidyl peptidase-4 inhibitor, vildagliptin, independent of its anti-diabetic properties in non-diabetic rats subjected to cerebral ischemia. Anesthetized Wistar rats were subjected to either left middle cerebral artery occlusion (MCAO) or sham operation followed by reperfusion after 30 min of MCAO. The other three groups were orally administered vildagliptin at 3 dose levels (2.5, 5, 10 mg/kg) for 3 successive weeks before subjected to left focal cerebral ischemia/reperfusion and till the end of the study. Neurological deficit scores and motor activity were assessed 24 h following reperfusion. Forty-eight hours following reperfusion, rats were euthanized and their left brain hemispheres were harvested and used in biochemical, histopathological, and immunohistochemical investigations. Vildagliptin pretreatment improved neurological deficit score, locomotor activity, and motor coordination in MCAO rats. Moreover, vildagliptin reduced malondialdehyde (MDA), elevated reduced glutathione (GSH), phosphotylinosital 3 kinase (PI3K), phosphoryated of protein kinase B (p-AKT), and mechanistic target of rapamycin (mTOR) brain contents in addition to reducing protein expression of caspase-3. Also, vildagliptin showed a dose-dependent attenuation in neuronal cell loss and histopathological alterations in MCAO rats. This study proves that vildagliptin exerted a neuroprotective effect in a dose-dependent manner as shown in the attenuation of the infarct area, neuronal cell loss, and histopathological damage in MCAO rats, which may be mediated by attenuating neuronal and motor deficits, its antioxidant property, activation of the PI3K/AKT/mTOR pathway, and its anti-apoptotic effect.