Serum IGF-1 levels correlate negatively to liver damage in diabetic rats

Abstract

Diabetes and insulin resistance frequently cause liver damage. Diabetes also causes reduction in liver and blood IGF-1 levels. We investigated the relation between liver damage and IGF-1 levels in diabetic rats. Fourteen Wistar albino rats were divided into control and diabetic groups. Diabetes was induced by streptozotocin. Rats were sacrificed for biochemical and histologic examinations 2 weeks after streptozotocin injection. Serum and liver IGF-1 levels were decreased, liver malondialdehyde (MDA) levels were increased, glutathione peroxidase (GPx) enzymes activities were decreased and serum alanine aminotransferase (ALT) levels were increased in diabetic group. Microscopic examination of liver revealed that normal tissue organization was disrupted in streptozotocin-induced diabetic rats. There was a strongly positive correlation between blood glucose levels and liver injury, and blood and liver IGF-1 levels. There was a strongly negative correlation between blood IGF-1 levels and hepatic injury. Our results suggest that reduction of blood IGF-1 levels correlates with hepatic injury and circulating IGF-1 levels may have predictive value for determining hepatic damage that results from diabetes. In addition, circulating IGF-1 levels are correlated with glutathione levels and the oxidative stress status of diabetic rat liver.     

Effects of carbon dioxide exposure on early brain development in rats

The developing brain is vulnerable to environmental factors. We investigated the effects of air that contained 0.05, 0.1 and 0.3% CO₂ on the hippocampus, prefrontal cortex (PFC) and amygdala. We focused on the circuitry involved in the neurobiology of anxiety, spatial learning, memory, and on insulin-like growth factor-1 (IGF-1), which is known to play a role in early brain development in rats. Spatial learning and memory were impaired by exposure to 0.3% CO₂ air, while exposure to 0.1 and 0.3% CO₂ air elevated blood corticosterone levels, intensified anxiety behavior, increased superoxide dismutase (SOD) enzyme activity and MDA levels in hippocampus and PFC; glutathione peroxidase (GPx) enzyme activity decreased in the PFC with no associated change in the hippocampus. IGF-1 levels were decreased in the blood, PFC and hippocampus by exposure to both 0.1 and 0.3% CO₂. In addition, apoptosis was increased, while cell numbers were decreased in the CA1 regions of hippocampus and PFC after 0.3% CO₂ air exposure in adolescent rats. A positive correlation was found between the blood IGF-1 level and apoptosis in the PFC. We found that chronic exposure to 0.3% CO₂ air decreased IGF-1 levels in the serum, hippocampus and PFC, and increased oxidative stress. These findings were associated with increased anxiety behavior, and impaired memory and learning.     

Astrocyte-Specific Overexpression of Insulin-Like Growth Factor-1 Protects Hippocampal Neurons and Reduces Behavioral Deficits following Traumatic Brain Injury in Mice

Traumatic brain injury (TBI) survivors often suffer from long-lasting cognitive impairment that stems from hippocampal injury. Systemic administration of insulin-like growth factor-1 (IGF-1), a polypeptide growth factor known to play vital roles in neuronal survival, has been shown to attenuate posttraumatic cognitive and motor dysfunction. However, its neuroprotective effects in TBI have not been examined. To this end, moderate or severe contusion brain injury was induced in mice with conditional (postnatal) overexpression of IGF-1 using the controlled cortical impact (CCI) injury model. CCI brain injury produces robust reactive astrocytosis in regions of neuronal damage such as the hippocampus. We exploited this regional astrocytosis by linking expression of hIGF-1 to the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter, effectively targeting IGF-1 delivery to vulnerable neurons. Following brain injury, IGF-1Tg mice exhibited a progressive increase in hippocampal IGF-1 levels which was coupled with enhanced hippocampal reactive astrocytosis and significantly greater GFAP levels relative to WT mice. IGF-1 overexpression stimulated Akt phosphorylation and reduced acute (1 and 3d) hippocampal neurodegeneration, culminating in greater neuron survival at 10d after CCI injury. Hippocampal neuroprotection achieved by IGF-1 overexpression was accompanied by improved motor and cognitive function in brain-injured mice. These data provide strong support for the therapeutic efficacy of increased brain levels of IGF-1 in the setting of TBI.     

Protective Effects of Cornel Iridoid Glycoside in Rats After Traumatic Brain Injury

Cornel iridoid glycoside (CIG) is the active ingredient extracted from Cornus officinalis. Our previous studies showed that CIG had protective effects on several brain injury models. In the present study, we aimed to examine the effects and elucidate the mechanisms of CIG against traumatic brain injury (TBI). TBI was induced in the right cerebral cortex of male adult rats. The neurological and cognitive functions were evaluated by modified neurological severity score (mNSS) and object recognition test (ORT), respectively. The level of serum S100β was measured by an ELISA method. Nissl staining was used to estimate the neuron survival in the brain. The expression of proteins was determined by western blot and/or immunohistochemical staining. We found that intragastric administration of CIG in TBI rats ameliorated the neurological defects and cognitive impairment, and alleviated the neuronal loss in the injured brain. In the acute stage of TBI (24–72 h), CIG decreased the level of S100β in the serum and brain, increased the ratio of Bcl-2/Bax and decreased the expression of caspase-3 in the injured cortex. Moreover, the treatment with CIG for 30 days increased the levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), enhanced the expression of synapsin I, synaptophysin and postsynaptic density protein 95 (PSD-95), and inhibited the apoptosis-regulating factors in the chronic stage of TBI. The present study demonstrated that CIG had neuroprotective effects against TBI through inhibiting apoptosis in the acute stage and promoting neurorestoration in the chronic stage. The results suggest that CIG may be beneficial to TBI therapy.     

20‐HETE synthesis inhibition attenuates traumatic brain injury–induced mitochondrial dysfunction and neuronal apoptosis via the SIRT1/PGC‐1α pathway: A translational study

Objectives20‐hydroxyeicosatetraenoic acid (20‐HETE) is a metabolite of arachidonic acid catalysed by cytochrome P450 enzymes and plays an important role in cell death and proliferation. We hypothesized that 20‐HETE synthesis inhibition may have protective effects in traumatic brain injury (TBI) and investigated possible underlying molecular mechanisms.Materials and methodsNeurologic deficits, and lesion volume, reactive oxygen species (ROS) levels and cell death as assessed using immunofluorescence staining, transmission electron microscopy and Western blotting were used to determine post‐TBI effects of HET0016, an inhibitor of 20‐HETE synthesis, and their underlying mechanisms.ResultsThe level of 20‐HETE was found to be increased significantly after TBI in mice. 20‐HETE synthesis inhibition reduced neuronal apoptosis, ROS production and damage to mitochondrial structures after TBI. Mechanistically, HET0016 decreased the Drp1 level and increased the expression of Mfn1 and Mfn2 after TBI, indicating a reversal of the abnormal post‐TBI mitochondrial dynamics. HET0016 also promoted the restoration of SIRT1 and PGC‐1α in vivo, and a SIRT1 activator (SRT1720) reversed the downregulation of SIRT1 and PGC‐1α and the abnormal mitochondrial dynamics induced by 20‐HETE in vitro. Furthermore, plasma 20‐HETE levels were found to be higher in TBI patients with unfavourable neurological outcomes and were correlated with the GOS score.ConclusionsThe inhibition of 20‐HETE synthesis represents a novel strategy to mitigate TBI‐induced mitochondrial dysfunction and neuronal apoptosis by regulating the SIRT1/PGC‐1α pathway.     

Progesterone modulation of α5 nAChR subunits influences anxiety‐related behavior during estrus cycle

Smokers often report an anxiolytic effect of cigarettes. In addition, stress‐related disorders such as anxiety, post‐traumatic stress syndrome and depression are often associated with chronic nicotine use. To study the role of the α5 nicotinic acetylcholine receptor subunit in anxiety‐related responses, control and α5 subunit null mice (α5^?/?) were subjected to the open field activity (OFA), light–dark box (LDB) and elevated plus maze (EPM) tests. In the OFA and LDB, α5^?/? behaved like wild‐type controls. In the EPM, female α5^?/? mice displayed an anxiolytic‐like phenotype, while male α5^?/? mice were undistinguishable from littermate controls. We studied the hypothalamus–pituitary–adrenal axis by measuring plasma corticosterone and hypothalamic corticotropin‐releasing factor. Consistent with an anxiolytic‐like phenotype, female α5^?/? mice displayed lower basal corticosterone levels. To test whether gonadal steroids regulate the expression of α5, we treated cultured NTera 2 cells with progesterone and found that α5 protein levels were upregulated. In addition, brain levels of α5 mRNA increased upon progesterone injection into ovariectomized wild‐type females. Finally, we tested anxiety levels in the EPM during the estrous cycle. The estrus phase (when progesterone levels are low) is anxiolytic‐like in wild‐type mice, but no cycle‐dependent fluctuations in anxiety levels were found in α5^?/? females. Thus, α5‐containing neuronal nicotinic acetylcholine receptors may be mediators of anxiogenic responses, and progesterone‐dependent modulation of α5 expression may contribute to fluctuations in anxiety levels during the ovarian cycle.     

Hypolipoproteinemia and hyperinflammatory cytokines in serum of severe and moderate traumatic brain injury (TBI) patients

Traumatic brain injury (TBI) acts as an inducer of the inflammatory reaction expressed by the release of pro-inflammatory cytokines (interleukin-1beta [IL-1beta], interleukin-6 [IL-6] and interleukin-8 [IL-8]), and causes metabolic alterations in the early, post-traumatic state, either in the brain or/and the systemic circulation. The metabolic changes involve carbohydrates, proteins and lipids. We focused on the serum lipid profile, the impact of trauma on lipoproteins, and their subsequent effects, on inflammation. We investigated the role of cytokines and serum lipids, in patient outcome, reviewing 30-day mortality and the Glasgow Coma Scale (GCS). A total of 75 patients with severe or moderate TBI (GCS 相似文献   

特发性矮小症患儿治疗前后血清IGF-1、IGFBP-3、25（OH）D、皮质醇水平变化及其与体格发育和骨龄的相关性分析

摘要 目的：探究特发性矮小症（ISS）患儿治疗前后血清胰岛素样生长因子1（IGF-1）、胰岛素样生长因子结合蛋白3（IGFBP-3）、25羟维生素D[25（OH）D]、皮质醇水平变化及其与体格发育和骨龄的相关性。方法：选取安徽省儿童医院于2017年7月～2021年3月收治的88例ISS患儿作为研究组。另选取同期体检健康儿童88例作为对照组。比较两组血清IGF-1、IGFBP-3、25（OH）D及皮质醇水平。比较ISS患儿治疗前后血清IGF-1、IGFBP-3、25（OH）D及皮质醇水平,体格指标以及骨龄指标。通过Pearson相关性分析ISS患儿血清IGF-1、IGFBP-3、25（OH）D及皮质醇水平与体格指标、骨龄指标的相关性。结果：研究组患儿血清IGF-1、IGFBP-3、25（OH）D水平均低于对照组,而皮质醇水平高于对照组（均P＜0.05）。ISS患儿治疗后血清IGF-1、IGFBP-3、25（OH）D水平均高于治疗前,而皮质醇水平低于治疗前（均P＜0.05）。ISS患儿治疗后身高、体重、骨龄年龄差（BAD）、骨龄指数（BAI）以及体质指数（BMI）均高于治疗前（均P＜0.05）。经Pearson相关性分析发现：ISS患儿血清IGF-1、IGFBP-3、25（OH）D水平与身高、体重、BAD、BAI以及BMI均呈正相关;皮质醇与身高、体重、BAD、BAI以及BMI均呈负相关（均P＜0.05）。结论：ISS患儿血清IGF-1、IGFBP-3、25（OH）D水平异常降低,皮质醇水平升高,且上述四项指标均和身高、体重、BAD以及BAI有关。     

Correlations between brain catecholamines,neurosecretion, and serum corticoid levels in osmotically stressed mallard ducks (Anas platyrhynchos)

The effects of depleting brain catecholamines with a combined treatment of reserpine and alpha-methyl-p-tyrosine on serum corticosterone levels and release of immunoreactive neurophysin from the median eminence, in osmotically stressed and unstressed mallard ducks, were studied. Corticoid levels in salt loaded birds were more than three times that of unstressed birds. The combined treatment of reserpine and alpha-methyl-p-tyrosine significantly decreased the concentration of brain monoamines in all experimental groups and raised serum corticoid levels in non-stressed birds to the same level found in the osmotically stressed animals. Immunoreactive neurophysin in the zona externa of the median eminence was depleted in all birds subjected to either osmotic stress and/or reserpine treatment but not in unstressed control birds. These preliminary data indicate that catecholamines may exert an inhibitory influence on both ACTH release from the anterior pituitary and neurophysin from the median eminence and that these two events may in some way be interrelated in the duck.     

The effects of α-lipoic acid on immature rats with traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality during childhood. TBI enhances formation of reactive oxygen species that cause neuron damage and apoptosis. α-Lipoic acid (LA) is a free radical scavenger and biological antioxidant. We investigated the effects of LA treatment on the parietal and prefrontal cortex, and on the hippocampal regions of the brain in 7-day-old rat pups that had been subjected to contusion injury. Forty-two male rats were divided randomly into a control group, a TBI group and a TBI + LA treated group. LA was administered 30 min after TBI through an intragastric tube once daily for 2 days. Forty-eight hours after TBI, the animals were sacrificed and tissues were examined for apoptosis and density of neurons. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) and active caspase-3 immunostaining were used to detect apoptosis. Glutathione peroxidase (GPx), superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels also were measured. Histological evaluation showed that LA treatment significantly reduced TBI-induced neuronal death in the hippocampus, prefrontal and parietal cortex; TUNEL- and caspase-3-positive cells also were decreased in the same regions. In addition, LA administration increased GPx and SOD activity in the prefrontal cortex. It appears that LA may be beneficial for TBI in rats.     

Possible role of brain norepinephrine in the hypothalamic hypophyseal adrenal system.

Intracisternal injection of bethanidine in rats decreased brain norepinephrine turnover without affecting its endogenous level, and increased both cardiac norepinephrine turnover and serum corticosterone level. A negative correlation was observed between brain norepinephrine turnover rate and serum corticosterone level. On the other hand, when cardiac norepinephrine turnover was suppressed by intraperitoneal injection of bethanidine, serum corticosterone did not change significantly. Next, ether inhalation was added after intracisternal injection of bethanidine. Then, serum corticosterone increased more even brain norepinephrine turnover was suppressed only slightly. These data may indicate that serum corticosterone increases by selective decrease in brain norepinephrine turnover via the humoral route; from the hypothalamus down to the adrenal cortex. Inversely, intracisternal injection of corticosterone increased brain norepinephrine turnover. These results suggest that brain norepinephrine may play an inhibitory role in the tonic regulation of CRF-ACTH secretion in the higher center than the hypothalamus and there may be a closed-loop feedback system between brain norepinephrine and serum corticosterone.     

Anxiolytic effects of a novel herbal treatment in mice models of anxiety

AimsAnxiety and stress disorders are currently among the ten most important public health concerns, and in recent years, have reached epidemic proportions. The current success rate of treatments for anxiety disorders is not high, reaching 50% at most. These treatments are also associated with a wide variety of side effects. The aim of the present study was to investigate the anxiolytic properties of a novel herbal treatment produced in our laboratory compared to a conventional treatment for anxiety disorders, namely SSRIs.Main methodsAnxiety-like behavior was evaluated in adult mice exposed to stress during childhood following 1, 2 and 3 weeks of treatment with the novel herbal treatment or escitalopram, using the novel open field and the elevated plus maze paradigms. The behavioral evaluation in these mice was followed by a biochemical assessment of their brain hippocampal BDNF levels and blood corticosterone levels.Key findingsThe study showed that (1) the novel herbal treatment reduced anxiety-like behaviors in both behavioral tests. Interestingly, this reduction was observed only following a 3-week treatment; (2) following the novel treatment, corticosterone levels in the plasma of treated mice were reduced and this reduction was similar to the one observed following escitalopram treatment; and (3) BDNF levels in the hippocampus of mice treated both with the novel herbal treatment and escitalopram were increased.SignificanceThese behavioral and biological findings indicate that our novel herbal compound has the potential of being highly efficacious in treating anxiety disorders.     

Enhanced serum glucocorticoid levels mediate the reduction of serosal mast cell numbers in diabetic rats.

Rats turned diabetic by treatment with alloxan exhibit a significant reduction in serosal mast cell numbersin parallel with decreased insulin levels in the plasma. Our aim was to investigate the putative involvement of endogenous glucocorticoid hormone in this phenomenon. The findings indicated that rats treated with alloxan responded with an increase in levels of serum corticosterone concomitantly with decreased mast cell numbers in the pleural space. We found that either surgical bilateral adrenalectomy or pretreatment with the steroid antagonist RU 486 (20 mg/kg, i.p.) impaired the drop in pleural mast cell counts in alloxinated rats. Administration of insulin (15 U/kg) prevented the increase in corticosterone levels and restored pleural mast cell levels in diabetic animals. In addition, treatment of naive rats with corticosterone (0.5 mg/kg, s.c.) or dexamethasone (0.1 mg/kg, s.c.), for 3 consecutive days, led to a reduction in the number of mast cells recovered from the pleural cavity as noted in diabetic animals. In contrast, insulin reduced serum corticosterone levels and induced a significant elevation in pleural mast cell numbers in naive rats. We conclude that there is a causative relationship between increased levels of glucocorticoids and down-regulation of mast cell numbers associated with the diabetic state, both phenomena clearly sensitive to insulin.     

Participation of progesterone receptors in plus-maze behavior in female mice

The current study tested delayed effect pf progesterone on the anxiety level of female mice. The elevated plus maze (EPM) behavior was assessed in ovariectomized mice injected for 7 days with estradiol benzoate and progesterone or progesterone alone after 6 hrs of the last treatment. One group of ovariectomized mice was injected with progesterone receptor blocker Mifepristone before 2 hrs of the last treatment. The immunocytochemistry method was used to visualize cells in different brain areas having immunoreactivity (ir) for progesterone receptors. In the EPM, progesterone administration significantly increased the anxiety levels of ovariectomized mice as compared with estradiol benzoate and progesterone administration. The participation of nuclear progesterone receptors in anxiety levels regulation is confirmed by high correlation of the change of progesterone receptor-ir cell number in some brain areas and anxiety levels. Mifepristone decreased anxiety levels and progesterone receptor-ir cell number in both groups of mice that suggests involvement of genomic mechanisms in anxiety regulation in female mice.     

NAAG peptidase inhibitor increases dialysate NAAG and reduces glutamate, aspartate and GABA levels in the dorsal hippocampus following fluid percussion injury in the rat

Traumatic brain injury (TBI) produces a rapid and excessive elevation in extracellular glutamate that induces excitotoxic brain cell death. The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) is reported to suppress neurotransmitter release through selective activation of presynaptic group II metabotropic glutamate receptors. Therefore, strategies to elevate levels of NAAG following brain injury could reduce excessive glutamate release associated with TBI. We hypothesized that the NAAG peptidase inhibitor, ZJ-43 would elevate extracellular NAAG levels and reduce extracellular levels of amino acid neurotransmitters following TBI by a group II metabotropic glutamate receptor (mGluR)-mediated mechanism. Dialysate levels of NAAG, glutamate, aspartate and GABA from the dorsal hippocampus were elevated after TBI as measured by in vivo microdialysis. Dialysate levels of NAAG were higher and remained elevated in the ZJ-43 treated group (50 mg/kg, i.p.) compared with control. ZJ-43 treatment also reduced the rise of dialysate glutamate, aspartate, and GABA levels. Co-administration of the group II mGluR antagonist, LY341495 (1 mg/kg, i.p.) partially blocked the effects of ZJ-43 on dialysate glutamate and GABA, suggesting that NAAG effects are mediated through mGluR activation. The results are consistent with the hypothesis that inhibition of NAAG peptidase may reduce excitotoxic events associated with TBI.     

Dentin hypersensitivity induces anxiety and increases corticosterone serum levels in rats

Aims

Investigate the relationships between experimentally induced dentin hypersensitivity (DH) with behavioral, endocrine and dentin erosion data.

Methods

Male Wistar rats divided into four groups, two controls and two experimental, received tap water or isotonic solution (Gatorade®, lemon, pH 2.7) for 30 or 45 days. The DH test was performed by a cold water stimulus on molars. A score (0–3) was given to the rats' pain response. Anxiety was evaluated by the elevated plus maze model and by serum corticosterone levels. The dentin erosion was observed by scanning electron microscopy (SEM). Anatomopathological studies were performed on the stomach, adrenal, kidney, and liver.

Results

Relative to control groups, experimental rats showed: 1) increased hypersensitivity scores (control group, 0; experimental groups, 2 (limits 0.5–3) on the 30th day and 2 (limits 1–3) on the 45th day); 2) reduced percentage of time and entries in the open arms and in serum corticosterone levels; 3) totally exposed dentinal tubules on the 30th day in SEM analysis of the teeth; and 4) no alterations in the anatomopathological and histological evaluations.

Conclusions

The treatment with isotonic solution for 30 days was able to induce DH after erosive challenge and severe DH was observed after isotonic solution treatment for 45 days. The pain induced by cold stimuli was consistent with the grade of DH. The close relationships between dental erosion, response to pain, serum levels of corticosterone and the EPM behavior responses reveal the effects of DH at several levels.     

Alterations in serum and brain trace element levels after antidepressant treatment

We have studied the effect of chronic treatment with imipramine, citalopram and electroconvulsive shock (ECS) on serum and brain zinc levels in rats. Chronic treatment with citalopram (but not with imipramine or ECS) significantly (approx 20%) increased the serum zinc level. Chronic treatment with both drugs slightly (by approx 10%) increase the zinc level in the hippocampus and slightly decreased it in the cortex, cerebellum and basal forebrain. Calculation of the ratio hippocampus/brain region within each group demonstrated a significantly (approx 20%) higher value after treatment with either imipramine or citalopram. Moreover, chronic ECS induced a significant increase (by 30%) in the zinc level in the hippocampus and also a slight increase (by 11–15%) in the other brain regions. Thus, these different antidepressant therapies induced an elevation of the hippocampal zinc concentration, which indicates a significant role of zinc in the mechanism of antidepressant therapy.     

tBHQ和SFN在创伤性脑损伤小鼠中的疗效比较性分析

目的:探讨叔丁基对苯二酚(t BHQ)和莱菔硫烷(SFN)在患有创伤性脑损伤大鼠的疗效差异性。方法:80只健康成年的雄性SD大鼠分为假手术组、常规损伤组、t BHQ治疗组和SFN治疗组,使用电子颅脑损伤仪(e CCI)制备TBI模型。其中t BHQ治疗组在伤前24 h大鼠腹腔注射三次t BHQ(50 mg/kg),每8 h一次;SFN治疗组在伤后15 min给予腹腔注射SFN(5 mg/kg)。给药24 h后,采用m NSS方法评价各组大鼠神经功能缺损状况,利用干湿称量法计算脑含水量,Western blot和ELISA方法分别测定大鼠脑组织的NOX2和Nrf2的表达水平。结果:损伤发生后第24 h,t BHQ治疗组和SFN治疗组在m NSS评分((4.5±0.71)vs(9.2±0.79),(6.0±0.82)vs(9.2±0.79))、脑水肿(79.4%vs 85.6%,80.3%vs 85.6%)、NOX2和Nrf2(0.93 ng/m L vs 0.81 ng/m L,0.87 ng/m L vs 0.81 ng/m L)表达上与常规损伤组差异明显,而t BHQ治疗组和SFN治疗组间在m NSS评分((4.5±0.71)vs(6.0±0.82))、NOX2和Nrf2(0.93 ng/m L vs 0.87 ng/m L)表达上差异显著。结论:在大鼠TBI模型中,t BHQ和SFN均可以有效的降低机体自身的氧化应激作用,并改善神经功能,但t BHQ的疗效要好于SFN。     

The role of estrogen and progesterone, administered alone and in combination, in modulating cytokine concentration following traumatic brain injury

Cytokines play an important role in the pathophysiology of traumatic brain injury (TBI). This study was designed to determine the effects of administering progesterone (P) and estrogen (E), alone and in combination, on brain water content, blood-brain barrier (BBB) disturbance, and brain level of cytokines following diffuse TBI. Ovariectomized rats were divided into 9 groups, treated with vehicle, E1, E2, P1, P2, E1+P1, E1+P2, E2+P1, and E2+P2. Levels of BBB disruption (5 h), cytokines, and water content (24 h) were evaluated after TBI induced by the Marmarou method. Physiological (E1 and P1) and pharmacological (E2 and P2) doses of estrogen and progesterone were administered 30 min after TBI. Water content in the E1+P2-treated group was higher than in the E1-treated group. The inhibitory effect of E2 on water content was reduced by adding progesterone. The inhibitory effect of E1 and E2 on Evans blue content was reduced by treatment with E1+P1 and E2+P2, respectively. The brain level of IL-1β was reduced in E1 and E2, after TBI. In the E2+P2-treated group, this level was higher than in the E2-treated group. The brain level of TGF-β was also elevated by the administration of progesterone and estrogen alone, and reduced when the hormones were administered in combination. In conclusion, a combined administration of progesterone and estrogen inhibited the decreasing effects of administration of progesterone and estrogen alone on water content and BBB disruption that mediated to change the proinflammatory cytokines.     

I. inflexus (Thunb.) Kudo extract improves atopic dermatitis and depressive-like behavior in DfE-induced atopic dermatitis-like disease

BackgroundAtopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease, which is caused by several genetic, immunological, and environmental factors. In addition to skin manifestations, AD is associated with an increased risk of depression and suicidal ideation. Furthermore, this association is underappreciated and therefore insufficiently studied.Hypothesis/PurposeWe investigated the association between AD and depression and the effect of I. inflexus (Thunb.) Kudo extract (IIE) treatment in a Dermatophagoides farinae extract (DfE)-induced mouse model of AD.Study DesignWe evaluated the effects of IIE on depressive behavior in AD mice using four experimental groups: normal (untreated), AD mice (untreated Dfe-induced), IIE-treated (Dfe-induced AD mice), and positive control (tacrolimus-treated Dfe-induced AD mice).MethodsAn AD model was established by the application of 4% sodium dodecyl sulfate to the shaved dorsal neck skin and ears of NC/Nga mice 1 h before application of 100 mg DfE twice per week for 3 weeks. After the first week of DfE application, mice were treated with IIE every day for the remaining 2 weeks. We performed behavioral testing, histology, ELISA, and western blotting to assess depressive-like behavior and neuroinflammatory responses and to measure IgE, histamine, corticosterone, and serotonin levels.ResultsCompared with normal mice, AD mice showed more scratching behavior, increased ear swelling, and higher serum levels of IgE and histamine. AD mice also exhibited evidence of depressive-like behavior in the open-field and sucrose preference tests as well as altered serum corticosterone and brain serotonin concentrations. Histopathological analyses revealed increased infiltration of inflammatory cells and mast cells into the skin and ear tissue and elevated microglia activation and neuroinflammatory response in the brains of AD mice. Topical application of IIE reversed the effects of AD on scratching behavior, ear swelling, open-field locomotion, sucrose preference, and levels of IgE, histamine, corticosterone, serotonin, and inflammatory markers. Moreover, IIE treatment reduced inflammatory cytokine responses in keratinocyte cells.ConclusionIIE is a candidate anti-AD therapy due to its ability to exert neuroprotective and antidepressant effects.