大鼠眶额叶GABA及其B型受体在应激性抑郁行为发生中的作用及其影响机制

为了探讨眶额叶(orbital frontal cortex,OFC)GABA及其B型受体在应激性抑郁行为发生中的作用及其影响机制,实验采用强迫游泳方法建立急性应激抑郁模型。在OFC区微量注射γ-氨基丁酸(γ-aminobutyric acid,GABA)及其B型受体阻断剂,通过开场实验、强迫游泳方式检测动物行为学表现,用免疫组织化学染色和Western blotting方法检测OFC区Kalirin表达,用高尔基染色法观察锥体细胞树突和树突棘。结果显示:强迫游泳应激引起动物抑郁样行为表现,同时,OFC区Kalirin阳性颗粒数及表达量显著减少,且锥体细胞树突棘密度下降;OFC区微量注射GABA具有抗抑郁效应,使OFC区Kalirin表达显著升高,锥体细胞树突棘密度增加;GABA-B型受体阻断剂CGP35348可以抑制GABA的这种效应。由此可见,通过强迫游泳应激诱发的抑郁样的行为变化与OFC区Kalirin表达减少和神经元树突棘密度降低有关,GABA可能通过GABA-B型受体增加OFC区Kalirin表达,以防止神经元退行性变化而产生抗抑郁作用。     

SIRT2 Plays Significant Roles in Lipopolysaccharides-Induced Neuroinflammation and Brain Injury in Mice

Several recent studies have suggested seemingly contrasting roles of SIRT2 in inflammation: Our previous cell culture study has indicated that SIRT2 siRNA-produced decrease in SIRT2 levels can lead to significant inhibition of lipopolysaccharides (LPS)-induced activation of BV2 microglia, suggesting that SIRT2 is required for LPS-induced microglial activation. In contrast, some studies have suggested that SIRT2 deficiency can lead to increased inflammation. In our current study, we used a mouse model of neuroinflammation to determine the roles of SIRT2 in LPS-induced inflammation. We found that administration of SIRT2 inhibitor AGK2 can significantly decrease LPS-induced increases in CD11b signals and the mRNA of TNF-α and IL-6. We further found that AGK2 can block LPS-induced nuclear translocation of NFκB. In addition, our study has shown that AGK2 can decrease not only LPS-induced increase in TUNEL signals—a marker of apoptosis-like damage, but also LPS-induced increases in the levels of active Caspase-3 and Bax. Collectively, our current in vivo study, together with our previous cell culture study, has suggested that SIRT2 is required for LPS-induced neuroinflammation and brain injury.

     

Endogenous brain IL-1 mediates LPS-induced anorexia and hypothalamic cytokine expression

The present study was designed to determine the role of endogenous brain interleukin (IL)-1 in the anorexic response to lipopolysaccharide (LPS). Intraperitoneal administration of LPS (5-10 microgram/mouse) induced a dramatic, but transient, decrease in food intake, associated with an enhanced expression of proinflammatory cytokine mRNA (IL-1beta, IL-6, and tumor necrosis factor-alpha) in the hypothalamus. This dose of LPS also increased plasma levels of IL-1beta. Intracerebroventricular pretreatment with IL-1 receptor antagonist (4 microgram/mouse) attenuated LPS-induced depression of food intake and totally blocked the LPS-induced enhanced expression of proinflammatory cytokine mRNA measured in the hypothalamus 1 h after treatment. In contrast, LPS-induced increases in plasma levels of IL-1beta were not altered. These findings indicate that endogenous brain IL-1 plays a pivotal role in the development of the hypothalamic cytokine response to a systemic inflammatory stimulus.     

Adenosine A2A receptors control neuroinflammation and consequent hippocampal neuronal dysfunction

The blockade of adenosine A(2A) receptors (A2AR) affords a robust neuroprotection in different noxious brain conditions. However, the mechanisms underlying this general neuroprotection are unknown. One possible mechanism could be the control of neuroinflammation that is associated with brain damage, especially because A2AR efficiently control peripheral inflammation. Thus, we tested if the intracerebroventricular injection of a selective A2AR antagonist (SCH58261) would attenuate the changes in the hippocampus triggered by intraperitoneal administration of lipopolysaccharide (LPS) that induces neuroinflammation through microglia activation. LPS administration triggers an increase in inflammatory mediators like interleukin-1β that causes biochemical changes (p38 and c-jun N-terminal kinase phosphorylation and caspase 3 activation) contributing to neuronal dysfunction typified by decreased long-term potentiation, a form of synaptic plasticity. Long-term potentiation, measured 30 min after the tetanus, was significantly lower in LPS-treated rats compared with control-treated rats, while SCH58261 attenuated the LPS-induced change. The LPS-induced increases in phosphorylation of c-jun N-terminal kinase and p38 and activation of caspase 3 were also prevented by SCH58261. Significantly, SCH58261 also prevented the LPS-induced recruitment of activated microglial cells and the increase in interleukin-1β concentration in the hippocampus, indicating that A2AR activation is a pivotal step in mediating the neuroinflammation triggered by LPS. These results indicate that A2AR antagonists prevent neuroinflammation and support the hypothesis that this mechanism might contribute for the ability of A2AR antagonists to control different neurodegenerative diseases known to involve neuroinflammation.     

Endotoxin administration increases hypothalamic somatostatin mRNA through nitric oxide release

Acute inflammation induced by endotoxin (LPS) administration inhibits insulin-like growth factor (IGF-I) and growth hormone (GH) secretion. The aim of this study was to elucidate the role of glucocorticoids and nitric oxide (NO) in the effect of LPS on hypothalamic somatostatin gene expression. Adult male Wistar rats were injected with different doses of LPS (5, 10 and 100 microg/kg). Rats received two i.p. injections of LPS (at 17:30 and 8:30 h the following day) and were killed 4 h after the second injection. LPS administration at the dose of 100 microg/kg increased the hypothalamic somatostatin mRNA content, as well as the serum concentrations of corticosterone. Glucocorticoids do not seem to be involved in LPS-induced increase in hypothalamic somatostatin mRNA since adrenalectomy did not prevent this effect. In order to analyze the possible effect of NO, aminoguanidine, an inducible nitric oxide synthase inhibitor, was injected (100 mg/kg s.c.) simultaneously with LPS injection. Aminoguanidine administration did not modify somatostatin mRNA in saline injected rats, but it prevented LPS-induced increase in hypothalamic somatostatin mRNA. These data suggest that the stimulatory effect of endotoxin on hypothalamic somatostatin gene expression is not mediated by glucocorticoids, but instead by the increase in NO release.     

Indoleamine 2,3-dioxygenase mediates anhedonia and anxiety-like behaviors caused by peripheral lipopolysaccharide immune challenge

This article is part of a Special Issue "Neuroendocrine-Immune Axis in Health and Disease." Upregulation of indoleamine 2,3-dioxygenase (IDO) by proinflammatory cytokines has been implicated as a biological mediator of inflammation-related mood disorders. Clinical reports on this neuro-immune interaction remain correlative, while mechanism-centered preclinical experiments have focused on a relatively narrow, and somewhat controversial, survey of depression-like behaviors that include the forced swim and tail suspension tests. Here, we sought to determine whether peripheral immune challenge with Escherichia coli, lipopolysaccharides (LPS) precipitates the development of translationally relevant depression-like behaviors and to investigate the role of IDO in mediating these LPS-induced behaviors. Intraperitoneal injection of C57BL/6J mice with LPS resulted in a robust, but transient, reduction in exploratory locomotor activity (eLMA) that returned to near baseline levels by 24h. Sucrose preference, a preclinical correlate of anhedonia, was diminished by more than 20% in LPS-treated compared to saline-treated control mice, and LPS induced a significant increase in anxiety-like behavior at 24h that was independent eLMA. Pretreatment of mice with an IDO inhibitor, 1-methyltryptophan (1MT), ablated the anxiogenic effects of LPS, while having no impact on sickness associated changes in body weight or eLMA. Additionally, 1MT pretreatment attenuated the LPS-induced reduction in sucrose preference, which was also confirmed in IDO-1 null mice. Interestingly, acute systemic administration of l-kynurenine, the enzymatic product of IDO, precipitated an anhedonic and anxiogenic effect in na?ve mice without effect on eLMA. In a preclinical model, these data implicate IDO as a pivotal mediator of LPS-induced depression- and anxiety-like behavior.     

TNF is a key mediator of septic encephalopathy acting through its receptor, TNF receptor-1

In this study, we demonstrate that mice deficient in TNFR1 (TNFR1(-/-)) were resistant to LPS-induced encephalopathy. Systemic administration of lipopolysaccharide (LPS) induces a widespread inflammatory response similar to that observed in sepsis. Following LPS administration TNFR1(-/-) mice had less caspase-dependent apoptosis in brain cells and fewer neutrophils infiltrating the brain (p<0.039), compared to control C57Bl6 (TNFR1(+/+)) mice. TNFR1-dependent increase in aquaporin (AQP)-4 mRNA and protein expression was observed with a concomitant increase in water content, in brain (18% increase in C57Bl6 mice treated with LPS versus those treated with saline), similar to cerebral edema observed in sepsis. Furthermore, absence of TNFR1 partially but significantly reduced the activation of astrocytes, as shown by immunofluorescence and markedly inhibited iNOS mRNA expression (p<0.01). Septic encephalopathy is a devastating complication of sepsis. Although, considerable work has been done to identify the mechanism causing the pathological alterations in this setting, the culprit still remains an enigma. Our results demonstrate for the first time that endotoxemia leads to inflammation in brain, with alteration in blood-brain barrier, up-regulation of AQP4 and associated edema, neutrophil infiltration, astrocytosis, as well as apoptotic cellular death, all of which appear to be mediated by TNF-alpha signaling through TNFR1.     

Inflammation-induced behavioral changes is driven by alterations in Nrf2-dependent apoptosis and autophagy in mouse hippocampus: Role of fluoxetine

Inflammation has been associated with the progression of many neurological diseases. Peripheral inflammation has also been vaguely linked to depression-like symptoms in animal models, but the underlying pathways that orchestrate inflammation-induced behavioral or molecular changes in the brain are still elusive. We have recently shown that intraperitoneal injections of lipopolysaccharide (LPS) to Swiss albino mice triggers systemic inflammation, leading to an activated immune response along with changes in monoamine levels in the brain. Herein we pinpoint the fundamental pathways linking peripheral inflammation and depression-like behavior in a mouse model, thereby identifying suitable targets of intervention to combat the situation. We show that LPS-induced peripheral inflammation provoked a depression-like behavior in mice and a distinct pro-inflammatory bias in the hippocampus, as evident from increased microglial activation and elevated levels of pro-inflammatory cytokines IL-6 and TNF-α, and activation of NFκB-p65 pathway. Significant alterations in Nrf2-dependent cellular redox status, coupled with altered autophagy and increased apoptosis were noticed in the hippocampus of LPS-exposed mice. We and others have previously shown that, fluoxetine (an anti-depressant) has effective anti-inflammatory and antioxidant properties by virtue of its abilities to regulate NFκB and Nrf2 signaling. We observed that treatment with fluoxetine or the Nrf2 activator tBHQ (tert-butyl hydroquinone), could reverse depression-like-symptoms and mitigate alterations in autophagy and cell death pathways in the hippocampus by activating Nrf2-dependent gene expressions. Taken together, the data suggests that systemic inflammation potentiates Nrf2-dependent changes in cell death and autophagy pathway in the hippocampus, eventually leading to major pathologic sequelae associated with depression. Therefore, targeting Nrf2 could be a novel approach in combatting depression and ameliorating its associated pathogenesis.     

In utero transplantation of neural stem cells ameliorates maternal inflammation-induced prenatal white matter injury

Prenatal white matter injury is a serious problem due to maternal inflammation leading to postnatal disabilities. In this study, we used the periventricular leukomalacia (PVL) model as a common prenatal white matter injury by maternal administration of lipopolysaccharide (LPS). Neural stem cells (NSCs) have shown therapeutic ability in neurological disorders through a different mechanism such as immunomodulation. Here, we studied the preventive potential of NSCs following in utero transplantation into the embryonic lateral ventricle in an LPS-induced white matter injury model. Pregnant animals were divided into three groups and received phosphate buffered saline, LPS, or LPS + NSCs. The brains of offspring were obtained and evaluated by real-time polymerase chain reaction (PCR), immunohistochemy, enzyme-linked immunosorbent assay (ELISA), terminal deoxynucleotidyl transferase-mediated biotinylated-dUTP nick-end labeling (TUNEL), and caspase-3 activity assay. The LPS-induced maternal inflammation degenerated the myelin sheath in the offspring periventricular region which was associated with an increased microglial number, oligodendrocytes degeneration, proinflammatory cytokine secretion, and cell apoptosis. The transplanted NSCs homed into the brain and ameliorated the evaluated parameters. The expression of proinflammatory cytokines interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), cell apoptosis and caspase-3 activity were inhibited by NSCs. In addition, Olig2 and myelin basic protein immunohistochemy staining showed that prenatal NSCs transplantation augmented the myelination in the periventricular white matter of offspring. In conclusion, we think that prenatal therapeutic strategies, such as in utero NSCs transplantation, may prevent prenatal white matter injury after birth.     

Chronic lithium administration attenuates up-regulated brain arachidonic acid metabolism in a rat model of neuroinflammation

Neuroinflammation, caused by a 6-day intracerebroventricular infusion of lipopolysaccharide (LPS) in rats, is associated with the up-regulation of brain arachidonic acid (AA) metabolism markers. Because chronic LiCl down-regulates markers of brain AA metabolism, we hypothesized that it would attenuate increments of these markers in LPS-infused rats. Incorporation coefficients k* of AA from plasma into brain, and other brain AA metabolic markers, were measured in rats that had been fed a LiCl or control diet for 6 weeks, and subjected in the last 6 days on the diet to intracerebroventricular infusion of artificial CSF or of LPS. In rats on the control diet, LPS compared with CSF infusion increased k* significantly in 28 regions, whereas the LiCl diet prevented k* increments in 18 of these regions. LiCl in CSF infused rats increased k* in 14 regions, largely belonging to auditory and visual systems. Brain cytoplasmic phospholipase A(2) activity, and prostaglandin E(2) and thromboxane B(2) concentrations, were increased significantly by LPS infusion in rats fed the control but not the LiCl diet. Chronic LiCl administration attenuates LPS-induced up-regulation of a number of brain AA metabolism markers. To the extent that this up-regulation has neuropathological consequences, lithium might be considered for treating human brain diseases accompanied by neuroinflammation.     

Lipopolysaccharide-Induced Striatal Nitrosative Stress and Impaired Social Recognition Memory Are Not Magnified by Paraquat Coexposure

Systemic inflammation triggered by lipopolysaccharide (LPS) administration disrupts blood–brain barrier (BBB) homeostasis in animal models. This event leads to increased susceptibility of several encephalic structures to potential neurotoxicants present in the bloodstream. In this study, we investigated the effects of alternate intraperitoneal injections of LPS on BBB permeability, social recognition memory and biochemical parameters in the striatum 24 h and 60 days after treatments. In addition, we investigated whether the exposure to a moderate neurotoxic dose of the herbicide paraquat could potentiate LPS-induced neurotoxicity. LPS administration caused a transient disruption of BBB integrity, evidenced by increased levels of exogenously administered sodium fluorescein in the striatum. Also, LPS exposure caused delayed impairment in social recognition memory (evaluated at day 38 after treatments) and increase in the striatal levels of 3-nitrotyrosine. These events were observed in the absence of significant changes in motor coordination and in the levels of tyrosine hydroxylase (TH) in the striatum and substantia nigra. PQ exposure, which caused a long-lasting decrease of striatal mitochondrial complex I activity, did not modify LPS-induced behavioral and striatal biochemical changes. The results indicate that systemic administration of LPS causes delayed social recognition memory deficit and striatal nitrosative stress in adult mice and that the coexposure to a moderately toxic dose of PQ did not magnify these events. In addition, PQ-induced inhibition of striatal mitochondrial complex I was also not magnified by LPS exposure, indicating the absence of synergic neurotoxic effects of LPS and PQ in this experimental model.

     

Sulforaphane, a natural constituent of broccoli, prevents cell death and inflammation in nephropathy

Cisplatin (cis-diamminedichloroplatinum II, CIS) is a potent and widely used chemotherapeutic agent to treat various malignancies, but its therapeutic use is limited because of dose-dependent nephrotoxicity. Cell death and inflammation play a key role in the development and progression of CIS-induced nephropathy. Sulforaphane (SFN), a natural constituent of cruciferous vegetables such as broccoli, Brussels sprouts, etc., has been shown to exert various protective effects in models of tissue injury and cancer. In this study, we have investigated the role of prosurvival, cell death and inflammatory signaling pathways using a rodent model of CIS-induced nephropathy, and explored the effects of SFN on these processes. Cisplatin triggered marked activation of stress signaling pathways [p53, Jun N-terminal kinase (JNK), and p38-α mitogen-activated protein kinase (MAPK)] and promoted cell death in the kidneys (increased DNA fragmentation, caspases-3/7 activity, terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick-end labeling), associated with attenuation of various prosurvival signaling pathways [e.g., extracellular signal-regulated kinase (ERK) and p38-β MAPK]. Cisplatin also markedly enhanced inflammation in the kidneys [promoted NF-κB activation, increased expression of adhesion molecules ICAM and VCAM, enhanced tumor necrosis factor-α (TNF-α) levels and inflammatory cell infiltration]. These effects were significantly attenuated by pretreatment of rodents with SFN. Thus, the cisplatin-induced nephropathy is associated with activation of various cell death and proinflammatory pathways (p53, JNK, p38-α, TNF-α and NF-κB) and impairments of key prosurvival signaling mechanisms (ERK and p38-β). SFN is able to prevent the CIS-induced renal injury by modulating these pathways, providing a novel approach for preventing this devastating complication of chemotherapy.     

Site-specific modulation of LPS-induced fever and interleukin-1 beta expression in rats by interleukin-10

Bacterial lipopolysaccharide (LPS) induces fever that is mediated by pyrogenic cytokines such as interleukin (IL)-1 beta. We hypothesized that the anti-inflammatory cytokine IL-10 modulates the febrile response to LPS by suppressing the production of pyrogenic cytokines. In rats, intravenous but not intracerebroventricular infusion of IL-10 was found to attenuate fever induced by peripheral administration of LPS (10 microg/kg iv). IL-10 also suppressed LPS-induced IL-1 beta production in peripheral tissues and in the brain stem. In contrast, central administration of IL-10 attenuated the febrile response to central LPS (60 ng/rat icv) and decreased IL-1 beta production in the hypothalamus and brain stem but not in peripheral tissues and plasma. Furthermore, intravenous LPS upregulated expression of IL-10 receptor (IL-10R1) mRNA in the liver, whereas intracerebroventricular LPS enhanced IL-10R1 mRNA in the hypothalamus. We conclude that IL-10 modulates the febrile response by acting in the periphery or in the brain dependent on the primary site of inflammation and that its mechanism of action most likely involves inhibition of local IL-1 beta production.     

Bexarotene Improve Depression-Like Behaviour in Mice by Protecting Against Neuro-inflammation and Synaptic Damage

The growing number of evidences suggest that neuroinflammation and synaptic damage are closely related to the onset of depression. Bexarotene (Bex), a retinoid X receptor agonist, is an U.S. Food and Drug Administration-approved drug for the treatment of cutaneous T-cell lymphoma that has recently been reported to have anti-inflammatory and neuroprotective effects in several models of neurological disease including Parkinson’s disease, Alzheimer’s disease, and so forth. However, the effect of Bex on depression remains unclear. In this study, we investigated effect of Bex on depression-like behaviour in mice induced by lipopolysaccharide (LPS) or corticosterone (CORT). Our results showed that treatment with Bex for 15 days significantly improved LPS-induced depression-like behaviour in social interaction test and CORT-induced depression-like behaviour in forced swimming test and tail suspension test in mice. We found that the Bex treatment depressed the increase in the number of activated microglia and astrocytes in the frontal cortex, and the increase in the levels of inflammatory cytokines TNF-α, IL-1β and IL-6 in LPS-injected mice. Furthermore, Bex treatment also rescued the decrease in the expression of BDNF, and inhibition of CREB/BDNF/ERK pathway, and improved the expression of synaptic related protein in CORT-induced mice. Based on these results, it is possible that Bex reversed depression-like behaviour in mice by reducing neuroinflammation and protecting against synaptic damage induced by LPS or CORT.

     

Repeated LPS Injection Induces Distinct Changes in the Kynurenine Pathway in Mice

The immune system has been recognized as a potential contributor to psychiatric disorders. In animals, lipopolysaccharide (LPS) is used to induce inflammation and behaviors analogous to some of the symptoms in these disorders. Recent data indicate that the kynurenine pathway contributes to LPS-induced aberrant behaviors. However, data are inconclusive regarding optimal LPS dose and treatment strategy. Here, we therefore aimed to evaluate the effects of single versus repeated administration of LPS on the kynurenine pathway. Adult C57BL6 mice were given 0.83 mg/kg LPS as a single or a repeated injection (LPS + LPS) and sacrificed after 24, 48, 72, or 120 h. Mice receiving LPS + LPS had significantly elevated brain kynurenine levels at 24 and 48 h, and elevated serum kynurenine at 24, 48 and 72 h. Brain kynurenic acid and quinolinic acid were significantly increased at 24 and 48 h in mice receiving LPS + LPS, whereas serum kynurenic acid levels were significantly decreased at 24 h. The increase of brain kynurenic acid by LPS + LPS was likely unrelated to the higher total dose as a separate group of mice receiving 1.66 mg/kg LPS as single injection 24 h prior to sacrifice did not show increased brain kynurenic acid. Serum quinolinic acid levels were not affected by LPS + LPS compared to vehicle. Animals given repeated injections of LPS showed a more robust induction of the kynurenine pathway in contrast to animals receiving a single injection. These results may be valuable in light of data showing the importance of the kynurenine pathway in psychiatric disorders.     

A dual role of 12/15-lipoxygenase in LPS-induced acute renal inflammation and injury

Recent studies suggest a potential role of bioactive lipids in acute kidney injury induced by lipopolysaccharide (LPS). The current study was designed to determine the profiling activities of various polyunsaturated fatty acid (PUFA) metabolizing enzymes, including lipoxygenases (LO), cyclooxygenase, and cytochrome P450 in the plasma of LPS-injected mice using LC-MS. Heat map analysis revealed that out of 126 bioactive lipids screened, only the 12/15-LO metabolite, 12-HETE, had a significant (2.24 ± 0.4) fold increase relative to control (P = 0.0001) after Bonferroni Correction (BCF α = 0.003). We then determined the role of the 12/15-LO in LPS-induced acute kidney injury using genetic and pharmacological approaches. Treatment of LPS injected mice with the 12/15-LO inhibitor, baicalein, significantly reduced levels of renal injury and inflammation markers including urinary thiobarbituric acid reactive substance (TBARs), urinary monocyte chemoattractant protein-1 (MCP-1), renal interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Similarly, knocking-out of 12/15-LO reduced levels of renal inflammation and injury markers elicited by LPS injection. Next, we tested whether exogenous supplementation with docosahexaenoic acid (DHA) as a substrate would divert the role of 12/15-LO from being pro-inflammatory to anti-inflammatory via increased production of the anti-inflammatory metabolite. DHA treatment restored the decreased in plasma level of resolvin D2 (RvD2) and reduced renal injury in LPS-injected mice whereas DHA treatment failed to provide any synergistic effects in reducing renal injury in LPS injected 12/15-LO knock-out mice. The ability of RvD2 to protect kidney against LPS-induced renal injury was further confirmed by exogenous RvD2 which significantly reduced the elevation in renal injury in LPS injected mice. These data suggest a double-edged sword role of 12/15-LO in LPS-induced acute renal inflammation and injury, depending on the type of substrate available for its activity.     

Anti-Inflammatory Effects of Angiotensin Receptor Blockers in the Brain and the Periphery

In addition to regulating blood pressure, Angiotensin II (Ang II) exerts powerful pro-inflammatory effects in hypertension through stimulation of its AT₁ receptors, most clearly demonstrated in peripheral arteries and in the cerebral vasculature. Administration of Ang II receptor blockers (ARBs) decreases hypertension-related vascular inflammation in peripheral organs. In rodent models of genetic hypertension, ARBs reverse the inflammation in the cerebral microcirculation. We hypothesized that ARBs could be effective in inflammatory conditions beyond hypertension. Our more recent studies, summarized here, indicate that this is indeed the case. We used the model of systemic administration of the bacterial endotoxin lipopolysaccharide (LPS). LPS produces a robust initial inflammatory reaction, the innate immune response, in peripheral organs and in the brain. Pretreatment with the ARB candesartan significantly diminishes the response to LPS, including reduction of pro-inflammatory cytokine release to the general circulation and decreased production and release of the pro-inflammatory adrenal hormone aldosterone. In addition, the ARB very significantly decreased the LPS-induced gene expression of pro-inflammatory cytokines and microglia activation in the brain. Our results demonstrate that AT₁ receptor activity is essential for the unrestricted development of full-scale innate immune response in the periphery and in the brain. ARBs, due to their immune response-limiting properties, may be considered as therapeutically useful in a number of inflammatory diseases of the peripheral organs and the brain.