LIPUS-SCs-Exo promotes peripheral nerve regeneration in cavernous nerve crush injury-induced ED rats via PI3K/Akt/FoxO signaling pathway

Objective

Clinical treatment of erectile dysfunction (ED) caused by cavernous nerve (CN) injury during pelvic surgery is difficult. Low-intensity pulsed ultrasound (LIPUS) can be a potential strategy for neurogenic ED (NED). However, whether Schwann cells (SCs) can respond to LIPUS stimulation signals is unclear. This study aims to elucidate the signal transmission between SCs paracrine exosome (Exo) and neurons stimulated by LIPUS, as well as to analyze the role and potential mechanisms of exosomes in CN repair after injury.

Methods

The major pelvic ganglion (MPG) neurons and MPG/CN explants were stimulated with LIPUS of different energy intensities to explore the appropriate LIPUS energy intensity. The exosomes were isolated and purified from LIPUS-stimulated SCs (LIPUS-SCs-Exo) and non-stimulated SCs (SCs-Exo). The effects of LIPUS-SCs-Exo on neurite outgrowth, erectile function, and cavernous penis histology were identified in bilateral cavernous nerve crush injury (BCNI)-induced ED rats.

Results

LIPUS-SCs-Exo group can enhance the axon elongation of MPG/CN and MPG neurons compared to SCs-Exo group in vitro. Then, the LIPUS-SCs-Exo group showed a stronger ability to promote the injured CN regeneration and SCs proliferation compared to the SCs-Exo group in vivo. Furthermore, the LIPUS-SCs-Exo group increased the Max intracavernous pressure (ICP)/mean arterial pressure (MAP), lumen to parenchyma and smooth muscle to collagen ratios compared to the SCs-Exo group in vivo. Additionally, high-throughput sequencing combined with bioinformatics analysis revealed the differential expression of 1689 miRNAs between the SCs-Exo group and the LIPUS-SCs-Exo group. After LIPUS-SCs-Exo treatment, the phosphorylated levels of Phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt) and forkhead box O (FoxO) in MPG neurons increased significantly compared to negative control (NC) and SCs-Exo groups.

Conclusion

Our study revealed that LIPUS stimulation could regulate the gene of MPG neurons by changing miRNAs derived from SCs-Exo, then activating the PI3K-Akt-FoxO signal pathway to enhance nerve regeneration and restore erectile function. This study had important theoretical and practical significance for improving the NED treatment.     

Loss of enteric neurons accompanied by decreased expression of GDNF and PI3K/Akt pathway in diabetic rats

Abstract  To investigate the enteric neuropathy in diabetic rats and the role of glia cell line-derived neurotrophic factor (GDNF) and its signalling pathway PI3K/Akt in regulating enteric neurons survival. Male Sprague–Dawley (SD) rats were randomly divided into normal control group, diabetic groups (rats with diabetes for 4, 8 and 12 weeks respectively). Proximal and distal colon specimens were obtained from each rat. Phosphoinositol-3-kinase signalling pathway was analysed by Akt phosphorylation. Protein gene product 9.5 (PGP9.5) used as a pan-neuronal marker. The expressions of GDNF, phospho-Akt (p-Akt), neuronal nitric oxide synthase (nNOS) neurons, cholinergic [choline acetyltransferase (CHAT) stained] neurons and total neurons were measured by immunohistochemical streptavidin-biotin complex (SABC) methods, Western blot and real-time polymerase chain reaction methods for each specimen. (i) Expression of GDNF was significantly decreased in diabetes 8 and 12 weeks group compared with the control group in both proximal ( P  < 0.01) and distal ( P  < 0.01) colon. The change of GDNF expression was greater in the 12 weeks group than that in the 8 weeks group ( P  < 0.05). There were no significant differences between the 4 weeks group and the control group in expression of GDNF ( P  > 0.05). (ii) The change trend of Akt phosphorylation was the same with GDNF. (iii) The numbers of nNOS, CHAT neurons and total neurons in proximal and distal colon were decreased significantly during the course of diabetes ( P  < 0.05). Diabetes can significantly induce enteric neuropathy. This change may be mediated, in partly, via a reduction of GDNF and its main downstream signalling pathway PI3K/Akt, which is a survival signal for enteric neurons.     

PI3K/Akt通路在创伤性脑损伤中的表达及抗凋亡作用

目的 研究创伤性脑损伤(TBI)后脑组织中Akt 蛋白磷酸化激活情况及其在神经细胞凋亡中的作用.方法 24 只雄性Wistar 大鼠,采用自由落体颅脑损伤模型随机分成假手术组、外伤后1 h、3 h、6 h、12 h、1 d、3 d、7 d 组.于相应时间点处死后行蛋白免疫印迹法(western blot)检测磷酸化A...     

基于PI3K/Akt通路研究右美托咪定对癫痫持续状态大鼠海马神经元自噬的调节作用

目的 探讨右美托咪定(Dexmedetomidine,Dex)对癫痫持续状态(Status epilepticus,SE)大鼠海马神经元自噬的调节作用及对磷脂酰肌醇-3-羟激酶/蛋白激酶B(PI3K/Akt)信号通路的影响。方法 采用戊四氮(PTZ)点燃制备SE大鼠模型,随机分为模型组(M组)、Dex低剂量(Dex-L)组、Dex高剂量(Dex-H)组、Dex-H +LY294002(Dex-H+LY)组,另取正常SD大鼠为对照组(NC组),每组各15只; Dex-L组、Dex-H组分别腹腔注射Dex 25、100 μg/kg; Dex-H+LY组脑室注射5 μL PI3K抑制剂LY294002+腹腔注射Dex 100 μg/kg,NC组、M组大鼠腹腔注射等量生理盐水; 观察大鼠行为学表现并进行脑电图描记; 原位末端标记法(TUNEL)检测各组大鼠海马神经元凋亡情况; 免疫印迹(WB)检测各组大鼠海马组织中LC3、PI3K、p-PI3K、Akt、p-Akt蛋白表达水平。结果 NC组大鼠脑电图无异常放电现象,主要以α、β波为主; M组大鼠出现大量阵发性棘波、高幅尖波、棘慢复合波、尖慢复合波等; Dex-L组、Dex-M组大鼠癫痫发作减少或波幅降低; Dex-H+LY组大鼠癫痫样放电较Dex-H组明显增加。与NC组比较,M组大鼠海马神经元凋亡细胞数、海马LC3-Ⅱ蛋白表达显著增加,海马LC3-Ⅰ,p-PI3K/PI3K,p-Akt/Akt蛋白表达水平显著降低(P<0.05); 与M组比较,Dex-L组、Dex-H组大鼠海马神经元凋亡细胞数、海马LC3-Ⅱ蛋白表达依次减少(P<0.05),海马LC3-Ⅰ,p-PI3K/PI3K,p-Akt/Akt蛋白表达水平依次增高(P<0.05); 与Dex-H组比较,Dex-H+LY组大鼠海马神经元凋亡细胞数、海马LC3-Ⅱ蛋白表达显著增加,海马LC3-Ⅰ,p-PI3K/PI3K,p-Akt/Akt蛋白表达水平显著降低(P<0.05)。结论 Dex可能通过促进PI3K/Akt信号通路激活来抑制SE大鼠海马神经元过度自噬,减轻神经元凋亡,发挥抗惊厥及脑保护作用。     

Analysis of the NF-kappa B and PI 3-kinase/Akt survival pathways in nerve growth factor-dependent neurons

Nerve growth factor (NGF) readdition to NGF-deprived neurons can halt Jun N-terminal kinase (JNK) activation, cytochrome c release, and cell death through mechanisms that may involve phosphatidylinositol (PI) 3-kinase, Akt, and nuclear factor kappa B (NF-kappaB). We found that expression of the NF-kappaB protein c-Rel in NGF-deprived neurons blocks cytochrome c release but does not inhibit c-Jun phosphorylation. Conversely, inhibition of NF-kappaB in NGF-maintained neurons promotes cytochrome c release and cell death. In contrast to c-Rel, activated PI 3-kinase and Akt inhibit c-Jun phosphorylation but have only a small effect on cytochrome c release. Finally, although c-Rel can protect neurons from death caused by inhibitors of PI 3-kinase or Akt, NF-kappaB function is not critical for Akt-promoted survival. These results suggest that the PI 3-kinase/Akt and NF-kappaB survival pathways target distinct cell death events in neurons.     

雷公藤内酯对癫痫大鼠神经元PI3K/Akt/mTOR蛋白的影响

目的 通过检测癫痫大鼠海马神经元PI3K、Akt和mTOR蛋白表达,探讨雷公藤内酯抑制癫痫大鼠神经元凋亡的分子机制.方法 30只大鼠随机分为对照组、海人酸组、雷公藤内酯干预组,免疫组化法检测各组大鼠海马神经元PI3K、Akt和mTOR蛋白的表达情况.结果 海人酸组神经元胞体皱缩,形态不规则,数量减少,而雷公藤内酯干预组神经元的数量和形态与对照组相似,海人酸组海马神经元PI3K、Akt、mTOR蛋白表达与对照组比较均减少,而雷公藤内酯干预组海马神经元的PI3K、Akt、mTOR蛋白表达均较海人酸组增加,差异均有统计学意义(P＜0.05).结论 雷公藤内酯可能通过上调PI3K/Akt/mTOR信号通路蛋白表达对癫痫大鼠海马神经元发挥保护作用.     

雷公藤内酯对癫痫大鼠神经元P13K／Akt／mTOR蛋白的影响

目的通过检测癫痫大鼠海马神经元P13K、Akt和mTOR蛋白表达,探讨雷公藤内酯抑制癫痫大鼠神经元凋亡的分子机制。方法30只大鼠随机分为对照组、海人酸组、雷公藤内酯干预组,免疫组化法检测各组大鼠海马神经元P13K、Akt和mTOR蛋白的表达情况。结果海人酸组神经元胞体皱缩,形态不规则,数量减少,而雷公藤内酯干预组神经元的数量和形态与对照组相似,海人酸组海马神经元P13K、Akt、ITITOR蛋白表达与对照组比较均减少,而雷公藤内酯干预组海马神经元的P13K、Akt、mTOR蛋白表达均较海人酸组增加,差异均有统计学意义（P〈0．05）。结论雷公藤内酯可能通过上调P13K／Akt／mTOR信号通路蛋白表达对癫痫大鼠海马神经元发挥保护作用。     

Interleukin-1 induces c-Fos immunoreactivity in primary afferent neurons of the vagus nerve

Peripheral administration of bacterial endotoxin, an immune stimulant, induces evidence of activation in vagal primary afferent neurons. To determine whether interleukin-1β (IL-1β) is part of the molecular pathway leading to this activation, we assessed the expression of the neuronal activation marker c-Fos in vagal primary afferent neurons after intraperitoneal injections of IL-1β (2 μg/kg). IL-1β, but not vehicle, induced c-Fos expression, demonstrating that IL-1β is likely an important signal from the immune system to the vagus nerve, and thus the brain.     

孕酮通过PI3K/Akt信号通路减轻新生大鼠缺血缺氧性脑损伤

目的探讨孕酮是否通过PI3K/Akt信号通路减轻新生大鼠缺血缺氧性脑损伤。方法取40只7 d龄新生Wistar大鼠随机分成4组:假手术组:仅做颈部切口,不做缺氧缺血处理;模型组:按动物模型的方法进行缺氧缺血处理;孕酮组:动物进行缺氧缺血处理且在缺氧前30 min按8 mg/kg腹腔注射孕酮溶液;抑制剂组:在建立缺血缺氧性脑损伤模型前30 min,按16μg/kg剂量在大鼠左侧海马区注射Wortmannin。电镜观察新生鼠缺氧缺血性脑损伤神经元的变化,采用免疫组织化学法检测海马pAkt及NF-κB的蛋白表达,应用Western blot检测海马pAkt及NF-κB的蛋白含量。结果 24 h后假手术组神经元结构基本正常,模型组神经元由于缺氧缺血损伤呈空化改变,给予孕酮后的缺氧缺血神经元受损情况改善,空化现象减少,应用抑制剂神经元空化改变明显。缺氧缺血后海马神经元pAkt蛋白表达减少,NF-κB表达增加;孕酮预处理可增加pAkt的表达,降低NF-κB表达;使用抑制剂组pAkt蛋白表达减少,NF-κB表达增加。结论孕酮可通过激活PI3K/Akt信号通路,增加pAkt的水平,抑制NF-κB表达,减轻缺血缺氧性脑损伤中的炎症反应,发挥脑保护作用。     

PI3K/Akt/mTOR信号传导通路与人脑胶质瘤恶性进展及预后的相关研究

目的 探讨磷脂酰肌醇3-激酶(PI3K),磷酸化蛋白激酶B(p-AKT)和磷酸化哺乳动物雷帕霉素靶蛋白(p-mTOR)在人脑胶质瘤组织中的表达及其与人脑胶质瘤恶性进展和预后的相关性.方法 选取南京医科大学附属淮安第一医院神经外科自2004年9月至2008年9月间手术切除并经病理证实的人脑胶质瘤标本88例,另取非肿瘤组织中的正常脑组织标本20例作为对照.采用免疫组织化学染色检测脑胶质瘤组织和正常脑组织中PI3K、p-AKT及p-mTOR的表达,并统计分析其与患者的临床病理学特征及预后的关系.结果 PI3K、p-AKT、p-mTOR在脑胶质瘤组织中的阳性表达率均显著高于正常脑组织,差异有统计学意义(PI3K:x2=14.028,P=0.009;p-AKT:x2=15.132,P=0.008和mTOR:x2=15.293,P=0.008);不同病理分级、治疗前KPS评分以及临床分期脑胶质瘤组织中PI3K、p-AKT和p-mTOR阳性表达率的差异均有统计学意义(P＜0.05);PI3K、p-AKT、p-mTOR阳性表达组患者的5年总体生存率均显著低于其阴性表达组(PI3K:x2=8.381,P=0.026;p-AKT:x2=12.923,P=0.011;mTOR:x2=13.252,P=0.013).结论 PI3K/Akt/mTOR信号传导通路在脑胶质瘤组织中被过度激活,与肿瘤的恶性程度密切相关,可以作为判断脑胶质瘤患者预后的生物学指标.

Abstract：

Objective To investigate the protein expression of phosphatidylinositol 3-kinase (PI3K), phosphorylated Akt B (p-Akt) and p-mTOR in human gliomas, and evaluate their clinical significance in clinicopathological status and prognosis of these patients with gliomas. Methods Eighty-eight patients, admitted to our hospital from September 2004 to September 2008, were chosen in our study; these patients were performed surgical resection and the samples were pathologically confirmed as gliomas. Another 20 samples, cut from the normal brain tissue were adopted as controls.Immunohistochemistry was employed to examine the protein expression of PI3K, p-AKT and p-mTOR.Then, the correlation of their expression with the clinicopathological features of the gliomas and prognosis of the patients was further analyzed. Results The positive expression rates of PI3K in gliomas and normal brain tissues were 68.18% (60/88) and 18.18% (16/88), respectively; those of p-AKT were 73.86% (65/88) and 17.05% (15/88), respectively;, those of p-mTOR were 75.00% (66/88) and 18.18% (16/88), respectively; the expression levels of these 3 proteins were all significantly higher than those in normal brain tissues (PI3K: x2=14.028, P=0.009; p-AKT: x2=15.132, P=0.008 and mTOR:x2=15.293, P=0.008). The positive expression rates of PI3K, p-AKT and p-mTOR were significantly different in the gliomas with pathological grades, different scores of Karnofsky performance status and different clinical stages (P＜0.05). In addition, the 5-year overall survival rate in PI3K-positive group,p-AKT-positive group and p-mTOR-positive group was significantly lower than in those negative groups (PI3K: x2=8.381, P=0.026; p-AKT: x2=12.923, P=0.011; mTOR: x2=13.252, P=0.013). Conclusion PI3K/Akt/mTOR signal transduction pathway is over-activated in gliornas, which is closely correlated to the grade-malignancy; and the positive expression of PI3K, p-AKT and p-mTOR may predict the poor prognosis of the patients with gliomas.     

基于PI3K/Akt通路探讨氯吡格雷对脑缺血再灌注损伤大鼠的神经保护作用

目的基于磷酯酰激醇3-激酶/蛋白激酶B(PI3K/Akt)通路探讨氯吡格雷对脑缺血再灌注损伤大鼠的神经保护作用.方法建立脑缺血再灌注大鼠模型,随机分为模型组、氯吡格雷组、LY294002(PI3K抑制剂)组、氯吡格雷+LY294002组,每组12只,另取12只SD大鼠设为假手术组.分组处理后,所有大鼠进行神经功能缺损评分并尾静脉取血,处死大鼠,HE染色检测各组大鼠神经元病理情况;三苯基氯化四氮唑(TTC)染色检测各组大鼠脑组织梗死面积;ELISA检测血清中中枢神经特异性蛋白(S100β)、神经元特异性烯醇化酶(NSE)、白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)水平;蛋白免疫印迹法检测脑组织中PI3K/Akt通路蛋白表达情况.结果与假手术组相比,模型组大鼠脑组织神经元出现坏死、核收缩变小等病理变化,神经功能缺损评分、脑梗死面积、血清中S100β、NSE、IL-6及TNF-α水平均明显升高(P<0.05),脑组织中p-PI3K/PI3K、p-Akt/Akt明显降低(P<0.05);与模型组相比,氯吡格雷组大鼠神经元病理损伤减轻,神经功能缺损评分、脑梗死面积、血清中S100β、NSE、IL-6及TNF-α水平均降低(P<0.05),脑组织中p-PI3K/PI3K、p-Akt/Akt升高(P<0.05);LY294002组大鼠神经元病理损伤加重,神经功能缺损评分、脑梗死面积、血清中S100β、NSE、IL-6及TNF-α水平均升高(P<0.05),脑组织中p-PI3K/PI3K、p-Akt/Akt降低(P<0.05).与LY294002组相比,氯吡格雷+LY294002组大鼠神经元病理损伤减轻,神经功能缺损评分、脑梗死面积、血清中S100β、NSE、IL-6及TNF-α水平均降低(P<0.05),脑组织中p-PI3K/PI3K、p-Akt/Akt升高(P<0.05).与氯吡格雷组相比,氯吡格雷+LY294002组大鼠神经元病理损伤加重,神经功能缺损评分、脑梗死面积、血清中S100β、NSE、IL-6及TNF-α水平均升高(P<0.05),脑组织中p-PI3K/PI3K、p-Akt/Akt降低(P<0.05).结论氯吡格雷可通过激活PI3K/Akt通路减轻大鼠脑缺血再灌注损伤,保护脑组织.     

白藜芦醇通过激活PI3K/Akt信号通路减轻大鼠脑缺血再灌注损伤

目的 探讨PI3K/Akt信号通路在白藜芦醇减轻大鼠脑缺血再灌注损伤中的作用。方法 将48只成年SD大鼠随机分为假手术组、模型组、白藜芦醇组、LY294002组（Akt抑制剂）,每组12只。利用线栓法制备大鼠脑缺血再灌注损伤模型,造模后24 h进行大鼠神经功能损伤评分和检测脑梗死体积、脑组织髓过氧化物酶（MPO）的活性,免疫印迹法检测脑组织p-Akt、t-Akt的表达水平,ELISA法检测脑组织肿瘤坏死因子-α（TNF-α）的含量。结果 与假手术组相比,模型组大鼠神经功能损伤评分、脑梗死体积、缺血脑组织MPO活性和TNF-α含量均明显增高（P<0.05）,缺血脑组织p-Akt表达水平也明显增高（P<0.05）;与模型组相比,白藜芦醇显著降低大鼠神经功能损伤评分、脑梗死体积、缺血脑组织MPO活性和TNF-α含量（P<0.05）,也显著降低缺血脑组织p-Akt表达水平（P<0.05）;脑室内注射LY294002,显著抑制白藜芦醇的这些作用（P<0.05）。结论 白藜芦醇通过激活PI3K/Akt信号通路减轻大鼠脑缺血再灌注损伤。     

阿司匹林通过抑制PI3K/Akt/mTOR 通路治疗癫痫 大鼠反复自发发作

目的 研究阿司匹林治疗癫痫大鼠反复自发发作的分子信号通路.方法 80只SD大鼠,75只随机分为5组,分别为(1)对照组(C组);(2)癫痫组(S组):匹鲁卡品诱导癫痫;(3)癫痫+慢病毒转染组(ST组):海马注射慢病毒转染shRNA[沉默磷脂酰肌醇激酶(PI3K)的p85亚基];(4)癫痫+阿司匹林组(SA组):腹腔注射阿司匹林20mg/kg;(5)癫痫+雷帕霉素组(SR组):腹腔注射雷帕霉素6mg/kg.剩余5只大鼠分入验证组,用于慢病毒转染的验证.建模后2周,检测各组大鼠癫痫发作的时间和频率,以及海马内环氧化酶-2(COX-2)、白介素1β(IL-1β)、PI3K的p85亚基(p85)、蛋白激酶B(Akt)、核糖体蛋白S6激酶(p70S6K)和微管相关蛋白2(MAP2)的表达水平.利用免疫组化染色,检测p70S6K在各组大鼠海马内的表达量.结果 (1)S组癫痫发作的时间和发作频率均显著高于SA、SR和ST组(P<0.05),而3个干预组间差异无统计学意义(P>0.05);(2)S组COX-2、IL-1β、p85、Akt、p70S6K和MAP2蛋白水平均显著高于C组(P<0.05);ST和SR组p85、Akt、p70S6K、MAP2蛋白水平均显著低于S组(P<0.05);SA组COX-2、IL-1β、p85、Akt、p70S6K、MAP2蛋白水平均显著低于S组(P<0.05);SA组的p85、Akt、p70S6K、MAP2蛋白水平与SR组差异无统计学意义(P>0.05).结论 阿司匹林可能通过抑制PI3K/Akt/mTOR通路和MAP2的表达来治疗癫痫大鼠反复自发发作.     

α-细辛醚对氯化锂-匹罗卡品致痫大鼠PI3K/ Akt /mTOR通路的调节作用

目的 探讨α- 细辛醚对癫痫大鼠学习记忆的影响及分子机制。方法 SD 大鼠随机分成 生理盐水组、癫痫组、α-细辛醚组,采用氯化锂-匹罗卡品注射诱导大鼠癫痫造模,α-细辛醚组造模 前用α-细辛醚干预28 d。水迷宫检测大鼠空间学习记忆能力,Western blot方法检测大鼠海马组织PI3K、 Akt、mTOR蛋白表达,采用RT-PCR技术检测大鼠海马组织PI3K、Akt、mTOR 的 mRNA表达。结果 水 迷宫实验结果显示α-细辛醚能够改善大鼠的学习记忆能力;Western blot 结果显示,癫痫组海马组织 PI3K、p-Akt、mTOR 蛋白表达较生理盐水组降低（P＜ 0. 05） ,α-细辛醚组海马组织的各蛋白表达较癫 痫组增加（P＜ 0. 05）。RT-PCR 结果显示,癫痫组海马组织PI3K、p-Akt、mTOR mRNA表达水平与生理盐 水组比较显著降低（P＜ 0. 05）,α-细辛醚组海马组织PI3K、p-Akt 的mRNA表达水平与癫痫组比较显著 增高（P＜ 0. 05） 。结论 α-细辛醚能够改善氯化锂-匹罗卡品致痫大鼠学习记忆,其分子机制可能与 上调PI3K/Akt /mTOR 表达有关。     

Novel pathway for LPS-induced afferent vagus nerve activation: possible role of nodose ganglion

The afferent vagus nerve has been suggested to be an important component for transmitting peripheral immune signals to the brain. However, there is inconsistent evidence showing that subdiaphragmatic vagotomy did not inhibit the brain mediated behavioral and neural effects induced by the peripheral application of lipopolysaccharide (LPS). LPS triggers innate immune cells through Toll-like receptor 4 (TLR4). In the present study, we found that TLR4 mRNA and protein was expressed in the rat nodose ganglion. Thus, it is suggested that LPS could activate afferent vagus nerve at the level of nodose ganglion, which exists centrally from the subdiaphragmatic level of vagus nerve. The results could provide evidence for the novel pathway of LPS-induced afferent vagus nerve activation.     

Effects of afferent and efferent denervation of vagal nerve on endotoxin-induced oxidative stress in rats

This study investigated the role of vagal innervation in oxidative stress after systemic administration of lipopolysaccharide (LPS) endotoxin. Control rats and rats subjected to bilateral subdiaphragmatic vagotomy, perivagal capsaicin application (5 mg/ml) or cholinergic receptor blockade with subcutaneous atropine (1 mg/kg), were intraperitoneally injected with 300 μg/kg of LPS and euthanized 4 h later. Results indicated that; (1) surgical vagotomy and sensory denervation by perivagal capsaicin increased brain oxidative stress and decreased reduced glutathione in basal condition (saline-treated rats) and following endotoxin challenge; (2) oxidative stress decreased after cholinergic blockade with atropine in endotoxemic rats; (3) nitric oxide decreased by abdominal vagotomy, sensory deafferentation and cholinergic blockade after endotoxin injection; (4) liver lipid peroxidation decreased after surgical vagotomy and cholinergic blockade but increased after sensory deafferentation; (5) liver reduced glutathione decreased following vagotomy and sensory denervation in basal state and by cholinergic blockade in basal state and during endotoxemia; (6) nitric oxide increased by vagotomy in basal state and by sensory denervation and cholinergic blockade in basal state and during endotoxemia; (7) liver histological damage increased by subdiaphragmatic vagotomy, sensory denervation or cholinergic blockade. These findings suggest that: (1) sensory fibers (signals from the periphery) running in the vagus nerves are important in maintaining the redox status of the brain; (2) capsaicin vagal sensory nerves are likely to maintain nitric oxide tone in basal conditions; (3) the vagus nerve modulates liver redox status and nitric oxide release, (4) the vagus nerve mediates protective role in the liver with both cholinergic and capsaicin-sensitive mechanisms being involved.