Characterization of blood-brain barrier permeability to PYY3-36 in the mouse

Peptide YY3-36 (PYY) has emerged as an important signal in the gut-brain axis, with peripherally administered PYY affecting feeding and brain function. For these effects to be direct, PYY would have to cross the blood-brain barrier (BBB). Here, we determined the permeability of the BBB to PYY radioactively labeled with 131I (I-PYY). Multiple-time regression analysis showed the unidirectional influx rate (Ki) from blood-to-brain for I-PYY to be 0.49 +/- 0.19 microl/g-min, a rate similar to that previously measured for leptin. Influx was not inhibited by 1 microg/mouse of unlabeled PYY, suggesting PYY crosses the BBB by transmembrane diffusion. About 0.176% of the i.v.-injected dose of I-PYY was taken up by brain, an amount similar to that for other peptides important in gut-brain communication. Capillary depletion showed that 69% of I-PYY crossed the BBB to enter the parenchymal space of the brain, and high-performance liquid chromatography demonstrated that the radioactivity in this space represented intact I-PYY. After intracerebroventricular injection, I-PYY crossed from brain to blood by the mechanism of bulk flow. We conclude that PYY crosses in both the blood-to-brain and brain-to-blood directions by nonsaturable mechanisms. Passage across the BBB provides a mechanism by which blood-borne PYY can affect appetite and brain function.     

Differential transport of a secretin analog across the blood-brain and blood-cerebrospinal fluid barriers of the mouse

Secretin is a gastrointestinal peptide belonging to the vasoactive intestinal peptide (VIP)/glucagon/pituitary adenylate cyclase-activating polypeptide (PACAP) family recently suggested to have therapeutic effects in autism. A direct effect on brain would require secretin to cross the blood-brain barrier (BBB), an ability other members of the VIP/PACAP family have. Herein, we examined whether a secretin analog (SA) radioactively labeled with (131)I (I-SA) could cross the BBB of 4-week-old mice. We found I-SA was rapidly cleared from serum with fragments not precipitating with acid appearing in brain and serum. Levels of radioactivity were corrected to reflect only intact I-SA as estimated by acid precipitation. After i.v. injection, I-SA was taken up by brain at a modest rate of 0.9 to 1.5 microl/g-mm. Capillary depletion, brain perfusion, and high-performance liquid chromatography were used to confirm the passage of intact I-SA across the BBB. I-SA entered every brain region, with the highest uptake into the hypothalamus and cerebrospinal fluid (CSF). Unlabeled SA (10 microg/mouse) did not inhibit uptake by brain but did inhibit clearance from blood and uptake by the CSF, colon, kidney, and liver. The decreased clearance of I-SA from blood increased the percentage of the i.v. injected dose taken up per brain (%Inj/g) from about 0.118 to 0.295%Inj/g. In conclusion, SA crosses the vascular barrier by a nonsaturable process and the choroid plexus by a saturable process in amounts that for other members of its family produce central nervous system (CNS) effects. This passage provides a pathway through which peripherally administered SA could affect the CNS.     

Insulin in the brain: There and back again

Insulin performs unique functions within the CNS. Produced nearly exclusively by the pancreas, insulin crosses the blood-brain barrier (BBB) using a saturable transporter, affecting feeding and cognition through CNS mechanisms largely independent of glucose utilization. Whereas peripheral insulin acts primarily as a metabolic regulatory hormone, CNS insulin has an array of effects on brain that may more closely resemble the actions of the ancestral insulin molecule. Brain endothelial cells (BECs), the cells that form the vascular BBB and contain the transporter that translocates insulin from blood to brain, are themselves regulated by insulin. The insulin transporter is altered by physiological and pathological factors including hyperglycemia and the diabetic state. The latter can lead to BBB disruption. Pericytes, pluripotent cells in intimate contact with the BECs, protect the integrity of the BBB and its ability to transport insulin. Most of insulin's known actions within the CNS are mediated through two canonical pathways, the phosphoinositide-3 kinase (PI3)/Akt and Ras/mitogen activated kinase (MAPK) cascades. Resistance to insulin action within the CNS, sometimes referred to as diabetes mellitus type III, is associated with peripheral insulin resistance, but it is possible that variable hormonal resistance syndromes exist so that resistance at one tissue bed may be independent of that at others. CNS insulin resistance is associated with Alzheimer's disease, depression, and impaired baroreceptor gain in pregnancy. These aspects of CNS insulin action and the control of its entry by the BBB are likely only a small part of the story of insulin within the brain.     

Peripheral markers of blood-brain barrier damage

Neurological diseases are often associated with cerebrovascular dysfunction and changes in blood-brain barrier (BBB) function. This is important for two seemingly conflicting reasons. On the one hand, a leaky BBB may lead to brain disease by allowing extravasation of cells and molecules normally segregated in the periphery, while on the other hand an intact BBB may hamper drug delivery to the ailing brain. Under both circumstances, it would be desirable to follow closely over time BBB "tightness". Several lines of evidence have suggested that the astrocytic protein S100beta is a potentially useful peripheral marker of BBB permeability. Other markers of brain-to-blood barriers have been recently discovered by a proteomic approach. These proteins are virtually absent in normal blood, appear in serum from patients with cerebral lesions, and can be easily detected. We will present clinical and laboratory evidence supporting the use of these markers as modern neurodiagnostic tools.     

A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier

The blood-brain barrier (BBB) protects the brain from toxic substances within the peripheral circulation. It maintains brain homeostasis and is a hurdle for drug delivery to the CNS to treat neurodegenerative diseases, including Alzheimer’s disease and brain tumors. The drug efflux transporter P-glycoprotein (P-gp) is highly expressed on brain endothelial cells and blocks the entry of most drugs delivered to the brain. Here, we show that activation of the A2A adenosine receptor (AR) with an FDA-approved A2A AR agonist (Lexiscan) rapidly and potently decreased P-gp expression and function in a time-dependent and reversible manner. We demonstrate that downmodulation of P-gp expression and function coincided with chemotherapeutic drug accumulation in brains of WT mice and in primary mouse and human brain endothelial cells, which serve as in vitro BBB models. Lexiscan also potently downregulated the expression of BCRP1, an efflux transporter that is highly expressed in the CNS vasculature and other tissues. Finally, we determined that multiple pathways, including MMP9 cleavage and ubiquitinylation, mediated P-gp downmodulation. Based on these data, we propose that A2A AR activation on BBB endothelial cells offers a therapeutic window that can be fine-tuned for drug delivery to the brain and has potential as a CNS drug-delivery technology.     

Intravenous human interleukin-1alpha impairs memory processing in mice: dependence on blood-brain barrier transport into posterior division of the septum

Peripherally administered cytokines profoundly affect the central nervous system (CNS). One mechanism by which they could affect the CNS is by crossing the blood-brain barrier (BBB) to interact directly with brain receptors. Human and murine IL-1alpha (hIL-1alpha; mIL-1alpha) are transported across the murine BBB with a high rate of transport into the posterior division of the septum (PDS), but it is unknown whether BBB transport is relevant to their actions. Here, we injected species-specific blocking antibodies into the PDS to determine whether transport across the BBB is required for blood-borne hIL-1alpha to affect memory. Retention was impaired in a dose-dependent manner when hIL-1alpha was injected either by tail vein (i.v.) or into the PDS, with the PDS route being 1000 times more potent. About 70% of the memory impairment induced by i.v. hIL-1alpha was reversed by injecting a blocking antibody (Ab) specific for hIL-1alpha into the PDS. This shows that much of the memory impairment induced by hIL-1alpha depends on its ability to cross the BBB. Ab specific for mIL-1alpha was also effective in reversing memory impairment, showing that hIL-1alpha releases mIL-1alpha from endogenous stores. Whether the mIL-1alpha was released from peripheral stores, which would require it to cross the BBB, or from brain stores is unknown. In conclusion, these results show that exogenous, blood-borne hIL-1alpha affects memory by releasing mIL-1alpha from endogenous stores and by crossing the BBB to act at sites within the PDS.     

Mahogany (1377-1428) enters brain by a saturable transport system

The mouse mahogany gene encodes a protein that is involved in the suppression of diet-induced obesity. We studied the ability of its widely conserved C-terminal fragment to cross the blood-brain barrier (BBB) in mice. Multiple-time regression analysis showed that the entry rate (K(i)) of (125)I-mahogany (1377-1428) from blood-to-brain was 5.5 x 10(-4) ml/g. min. After coinjection of unlabeled mahogany (1377-1428), the K(i) was significantly decreased, showing the self-inhibition characteristic of a saturable transport mechanism. The excess mahogany (1377-1428) did not change the influx rate of (99m)Tcalbumin, the vascular control, indicating a lack of disruption of the BBB. Statistically significant cross-inhibition was not seen with agouti-related protein (83-132), melanin-concentrating hormone, epidermal growth factor, leptin, a melanocortin-4 receptor antagonist, or alpha-melanocyte-stimulating hormone. HPLC showed that most of the injected (125)I-mahogany (1377-1428) reached the brain intact, and capillary depletion with washout showed that most of it reached the parenchyma. There was no brain-to-blood efflux system for mahogany (1377-1428) but rather retention after i.c.v. administration, and the octanol/buffer partition coefficient showed low lipophilicity. Thus, the results show that the C-terminal peptide product encoded by the mahogany gene crosses the BBB by a transport mechanism that is saturable. The ability of this system to be regulated indicates the therapeutic potential of mahogany (1377-1428) in the treatment of obesity.     

Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells

Ghrelin, a recently described endogenous ligand for the growth hormone secretagogue receptor (GHS-R), is produced by stomach cells and is a potent circulating orexigen, controlling energy expenditure, adiposity, and growth hormone secretion. However, the functional role of ghrelin in regulation of immune responses remains undefined. Here we report that GHS-R and ghrelin are expressed in human T lymphocytes and monocytes, where ghrelin acts via GHS-R to specifically inhibit the expression of proinflammatory anorectic cytokines such as IL-1beta, IL-6, and TNF-alpha. Ghrelin led to a dose-dependent inhibition of leptin-induced cytokine expression, while leptin upregulated GHS-R expression on human T lymphocytes. These data suggest the existence of a reciprocal regulatory network by which ghrelin and leptin control immune cell activation and inflammation. Moreover, ghrelin also exerts potent anti-inflammatory effects and attenuates endotoxin-induced anorexia in a murine endotoxemia model. We believe this to be the first report demonstrating that ghrelin functions as a key signal, coupling the metabolic axis to the immune system, and supporting the potential use of ghrelin and GHS-R agonists in the management of disease-associated cachexia.     

P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model

Accumulation of amyloid-beta (Abeta) within extracellular spaces of the brain is a hallmark of Alzheimer disease (AD). In sporadic, late-onset AD, there is little evidence for increased Abeta production, suggesting that decreased elimination from the brain may contribute to elevated levels of Abeta and plaque formation. Efflux transport of Abeta across the blood-brain barrier (BBB) contributes to Abeta removal from the brain. P-glycoprotein (Pgp) is highly expressed on the luminal surface of brain capillary endothelial cells and contributes to the BBB. In Pgp-null mice, we show that [I]Abeta40 and [I]Abeta42 microinjected into the CNS clear at half the rate that they do in WT mice. When amyloid precursor protein-transgenic (APP-transgenic) mice were administered a Pgp inhibitor, Abeta levels within the brain interstitial fluid significantly increased within hours of treatment. Furthermore, APP-transgenic, Pgp-null mice had increased levels of brain Abeta and enhanced Abeta deposition compared with APP-transgenic, Pgp WT mice. These data establish a direct link between Pgp and Abeta metabolism in vivo and suggest that Pgp activity at the BBB could affect risk for developing AD as well as provide a novel diagnostic and therapeutic target.     

The physiology and potential clinical applications of ghrelin, a novel peptide hormone

Ghrelin, a peptide hormone originally identified as the endogenous ligand of the growth hormone secretagogue receptor, is secreted primarily from the stomach and secondarily from the small intestine and colon. Ghrelin may also be expressed in the pancreatic islets, hypothalamus, pituitary, and several tissues in the periphery. The growth hormone secretagogue receptor is widely expressed, suggesting diverse physiologic roles for ghrelin. A growing body of evidence suggests that, in addition to its predictable effect on growth hormone secretion, ghrelin has an important role in the short-term regulation of appetite and the long-term regulation of energy balance and glucose homeostasis. Recent studies have implicated ghrelin in the regulation of gastrointestinal, cardiovascular, and immune function and have suggested a role for ghrelin in bone physiology. The identification of obestatin, a novel peptide hormone derived from the same gene as ghrelin, has recently added further complexity to ghrelin physiology. Obestatin appears to have actions opposite of ghrelin on energy homeostasis and gastrointestinal function. Despite the rapid progress, many questions remain unanswered, including the regulation of ghrelin and obestatin secretion, the downstream pathways that mediate their effects, and their precise physiologic endocrine and paracrine roles. This review presents data on ghrelin structure, expression, and function, with emphasis placed on human studies, highlighting areas that require future investigation and providing speculation about potential clinical applications of ghrelin agonists or antagonists.     

A functional role for sodium-dependent glucose transport across the blood-brain barrier during oxygen glucose deprivation

In the current study, we determined the functional significance of sodium-dependent/-independent glucose transporters at the neurovasculature during oxygen glucose deprivation (OGD). Confluent brain endothelial cells cocultured with astrocytes were exposed to varying degrees of in vitro stroke conditions. Glucose transporter (GLUT) 1 and sodium glucose cotransporter (SGLT) activity were investigated by luminal membrane uptake and transport studies using [(3)H]D-glucose and also by [(14)C]alpha-methyl D-glucopyranoside (AMG), a specific, nonmetabolized substrate of SGLT. In vivo middle cerebral artery occlusion experiments were tested to determine whether blood-brain barrier (BBB) SGLT activity was induced during ischemia. Increases in luminal D-glucose and AMG uptake and transport were observed with in vitro stroke conditions. Specific inhibitor experiments suggest a combined role for both SGLT and GLUT1 at the BBB during OGD. A time-dependent increase in the uptake of AMG was also seen in mice exposed to permanent focal ischemia, and this increase was sensitive to the SGLT inhibitor, phlorizin. Infarct and edema ratio during ischemia were significantly decreased by the inhibition of this transporter. These results show that both GLUT1 and SGLT play a role at the BBB in the blood-to-brain transport of glucose during ischemic conditions, and inhibition of SGLT during stroke has the potential to improve stroke outcome. Pharmacological modulation of this novel BBB transporter could prove to be a brain vascular target in stroke.     

Ghrelin is a physiological regulator of insulin release in pancreatic islets and glucose homeostasis

Ghrelin, an acylated 28-amino acid peptide, was isolated from the stomach as the endogenous ligand for the growth hormone (GH) secretagogue receptor (GHS-R). Circulating ghrelin is produced predominantly in the oxyntic mucosa of stomach. Ghrelin potently stimulates GH release and feeding, and exhibits positive cardiovascular effects, suggesting a possible clinical application. Low plasma ghrelin levels are associated with elevated fasting insulin levels and insulin resistance, suggesting both physiological and pathophysiological roles for ghrelin in glucose metabolism. Here, we review the physiological role of ghrelin in the regulation of insulin release and glucose metabolism, and a potential therapeutic avenue to treat type 2 diabetes by manipulating ghrelin and/or its signaling. Ghrelin inhibits insulin release in mice, rats and humans. The signal transduction mechanisms of ghrelin in islet β-cells are distinct from those utilized in GH-releasing and/or GHS-R-expressing cells. Ghrelin is expressed in pancreatic islets and released into pancreatic microcirculations. Pharmacological and genetic blockades of islet-derived ghrelin markedly augment glucose-induced insulin release in vitro. In high-fat diet-induced mildly obese mice, ghrelin-deficiency enhances insulin release and prevents impaired glucose tolerance. Thus, manipulation of insulinostatic function of ghrelin — GHS-R system, particularly that in islets, could optimize the amount of insulin release to meet the systemic demand, providing a potential therapeutic application to prevent type 2 diabetes.     

Systemic combinatorial peptide selection yields a non-canonical iron-mimicry mechanism for targeting tumors in a mouse model of human glioblastoma

The management of CNS tumors is limited by the blood-brain barrier (BBB), a vascular interface that restricts the passage of most molecules from the blood into the brain. Here we show that phage particles targeted with certain ligand motifs selected in vivo from a combinatorial peptide library can cross the BBB under normal and pathological conditions. Specifically, we demonstrated that phage clones displaying an iron-mimic peptide were able to target a protein complex of transferrin and transferrin receptor (TfR) through a non-canonical allosteric binding mechanism and that this functional protein complex mediated transport of the corresponding viral particles into the normal mouse brain. We also showed that, in an orthotopic mouse model of human glioblastoma, a combination of TfR overexpression plus extended vascular permeability and ligand retention resulted in remarkable brain tumor targeting of chimeric adeno-associated virus/phage particles displaying the iron-mimic peptide and carrying a gene of interest. As a proof of concept, we delivered the HSV thymidine kinase gene for molecular-genetic imaging and targeted therapy of intracranial xenografted tumors. Finally, we established that these experimental findings might be clinically relevant by determining through human tissue microarrays that many primary astrocytic tumors strongly express TfR. Together, our combinatorial selection system and results may provide a translational avenue for the targeted detection and treatment of brain tumors.     

Does sumatriptan cross the blood–brain barrier in animals and man?

Sumatriptan, a relatively hydrophilic triptan, based on several animal studies has been regarded to be unable to cross the blood–brain barrier (BBB). In more recent animal studies there are strong indications that sumatriptan to some extent can cross the BBB. The CNS adverse events of sumatriptan in migraine patients and normal volunteers also indicate a more general effect of sumatriptan on CNS indicating that the drug can cross the BBB in man. It has been discussed whether a defect in the BBB during migraine attacks could be responsible for a possible central effect of sumatriptan in migraine. This review suggests that there is no need for a breakdown in the BBB to occur in order to explain a possible central CNS effect of sumatriptan.     

Group A Streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells

Group A streptococcal (GAS) infection induces the production of Abs that cross-react with host neuronal proteins, and these anti-GAS mimetic Abs are associated with autoimmune diseases of the CNS. However, the mechanisms that allow these Abs to cross the blood-brain barrier (BBB) and induce neuropathology remain unresolved. We have previously shown that GAS infection in mouse models induces a robust Th17 response in nasal-associated lymphoid tissue (NALT). Here, we identified GAS-specific Th17 cells in tonsils of humans naturally exposed to GAS, prompting us to explore whether GAS-specific CD4⁺ T cells home to mouse brains following i.n. infection. Intranasal challenge of repeatedly GAS-inoculated mice promoted migration of GAS-specific Th17 cells from NALT into the brain, BBB breakdown, serum IgG deposition, microglial activation, and loss of excitatory synaptic proteins under conditions in which no viable bacteria were detected in CNS tissue. CD4⁺ T cells were predominantly located in the olfactory bulb (OB) and in other brain regions that receive direct input from the OB. Together, these findings provide insight into the immunopathology of neuropsychiatric complications that are associated with GAS infections and suggest that crosstalk between the CNS and cellular immunity may be a general mechanism by which infectious agents exacerbate symptoms associated with other CNS autoimmune disorders.     

Ghrelin,growth and obesity

The objective of this paper is to review the current evidence of a novel gastric hormone ghrelin. Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R) that potently stimulates growth hormone (GH) release. The discovery of ghrelin opens up a new regulatory system for the GH secretion. Surprisingly, recent studies in rodents suggest that peripherally or centrally administrated ghrelin, independent of GH, decreases fat oxidation and increases food intake and adiposity. In addition, plasma ghrelin levels are lower in obese human subjects. Ghrelin might participate in meal initiation and may signal to the hypothalamus when an increase in the metabolic efficiency is needed. However, the role of ghrelin in the regulation of body weight in humans is unknown. Whether ghrelin's somatotrophic effect surpasses its adipogenic effect in the prolonged administration determines its effect on energy balance. New interesting implications for ghrelin have recently been suggested. For instance, ghrelin's cardiovascular effects might have clinical relevance. Furthermore, ghrelin might be involved in the growth of some neoplasms. In conclusion, ghrelin, a new somatotrophic, orexigenic and adipogenic peptide hormone, links the regulatory systems for growth and energy balance.     

Ghrelin,growth and obesity

The objective of this paper is to review the current evidence of a novel gastric hormone ghrelin. Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R) that potently stimulates growth hormone (GH) release. The discovery of ghrelin opens up a new regulatory system for the GH secretion. Surprisingly, recent studies in rodents suggest that peripherally or centrally administrated ghrelin, independent of GH, decreases fat oxidation and increases food intake and adiposity. In addition, plasma ghrelin levels are lower in obese human subjects. Ghrelin might participate in meal initiation and may signal to the hypothalamus when an increase in the metabolic efficiency is needed. However, the role of ghrelin in the regulation of body weight in humans is unknown. Whether ghrelin's somatotrophic effect surpasses its adipogenic effect in the prolonged administration determines its effect on energy balance. New interesting implications for ghrelin have recently been suggested. For instance, ghrelin's cardiovascular effects might have clinical relevance. Furthermore, ghrelin might be involved in the growth of some neoplasms. In conclusion, ghrelin, a new somatotrophic, orexigenic and adipogenic peptide hormone, links the regulatory systems for growth and energy balance.     

Pharmacokinetic analysis of the blood-brain barrier transport of 125I-amyloid beta protein 40 in wild-type and Alzheimer's disease transgenic mice (APP,PS1) and its implications for amyloid plaque formation

Amyloid plaques are formed in the extracellular space of Alzheimer's disease (AD) brain due to the accumulation of amyloid beta (Abeta) proteins such as Abeta40. The relationship between Abeta40 pharmacokinetics and its accumulation within and clearance from the brain in both wild-type (WT) and AD transgenic mice (APP,PS1) was studied to understand the mechanism of amyloid plaque formation and the potential use of Abeta40 as a probe to target and detect amyloid plaques. In both WT and APP,PS1 mice, the (125)I-Abeta40 tracer exhibited biexponential disposition in plasma with very short first and second phase half-lives. The (125)I-Abeta40 was significantly metabolized in the liver kidney > spleen. Coadministration of exogenous Abeta40 inhibited the plasma clearance and the uptake of (125)I-Abeta40 at the blood-brain barrier (BBB) in WT animals but did not affect its elimination from the brain. The (125)I-Abeta40 was shown to be metabolized within and effluxed from the brain parenchyma. The rate of efflux from APP,PS1 brain slices was substantially lower compared with WT brain slices. Since the Abeta40 receptor at the BBB can be easily saturated, the blood-to-brain transport of Abeta40 is less likely to be a primary contributor to the amyloid plaque formation in APP,PS1 mice. The decreased elimination of Abeta40 from the brain is most likely responsible for the amyloid plaque formation in the brain of APP,PS1 mice. Furthermore, inadequate targeting of Abeta40 to amyloid plaques, despite its high BBB permeability, is due to the saturability of Abeta40 transporter at the BBB and its metabolism and efflux from the brain.     

Hyperglycaemia suppresses the secretion of ghrelin,a novel growth-hormone-releasing peptide: responses to the intravenous and oral administration of glucose

Ghrelin is a novel growth hormone (GH)-releasing peptide, isolated from the stomach, which may also cause a positive energy balance by stimulating food intake and reducing fat utilization. However, whether glucose influences the release of ghrelin remains unknown. Accordingly, we examined circulating levels of ghrelin and GH in response to the intravenous or oral administration of 50 g of glucose in eight healthy humans. After the administration of intravenous glucose (50 g), the plasma ghrelin level decreased significantly from 127+/-9 to 98+/-9 fmol/ml (P<0.01), associated with an increase in plasma glucose from 85+/-3 to 357+/-19 mg/dl (P<0.01). Ingestion of 50 g of glucose decreased the plasma ghrelin level significantly from 134+/-12 to 97+/-15 fmol/ml (P<0.01), associated with an increase in plasma glucose from 93+/-3 to 166+/-10 mg/dl (P<0.01). The decrease in the plasma ghrelin level lasted for more than 30 min after recovery of the plasma glucose level. In conclusion, ghrelin secretion may be suppressed, at least in part, by an increased plasma glucose level in healthy humans.     

Ghrelin ameliorates atherosclerosis by inhibiting endoplasmic reticulum stress

The effects of ghrelin, a peptide hormone, on atherogenesis are mainly beneficial. This study aimed to investigate whether ghrelin ameliorates atherosclerosis (AS) by preventing endoplasmic reticulum stress (ERS). AS was induced by a high‐fat diet in ApoE^?/? mice. AS lesions in aortas were detected by Oil Red O staining, and the inner diameter and intima‐media thickness (IMT) of the abdominal aorta were analyzed by ultrasonography. The protein expression of the ERS markers, 78‐kDa glucose‐regulated protein, C/EBP homologous protein, and active caspase‐12, was detected by Western blot analysis. High‐fat diet‐fed ApoE^?/? mice showed AS lesions and increased aortic IMT. Ghrelin ameliorated these findings. Moreover, the protein expression of ERS markers was upregulated in the AS aorta and downregulated by ghrelin treatment. The above beneficial effects of ghrelin on AS and ERS were blocked by the ERS inducer, tunicamycin. In rat aortic endothelial cells, oxidized low‐density lipoprotein and tunicamycin triggered ERS, which could be inhibited by ghrelin pretreatment. These results suggest that ghrelin can ameliorate activation of ERS, which may be the beneficial effect of ghrelin on AS. Ghrelin may be a new target and strategy for prevention and therapy of AS.