Ligand-specific recycling profiles determine distinct potential for chronic analgesic tolerance of delta-opioid receptor (DOPr) agonists.

δ-opioid receptor (DOPr) agonists have analgesic efficacy in chronic pain models but development of tolerance limits their use for long-term pain management. Although agonist potential for inducing acute analgesic tolerance has been associated with distinct patterns of DOPr internalization, the association between trafficking and chronic tolerance remains ill-defined. In a rat model of streptozotocin (STZ)-induced diabetic neuropathy, deltorphin II and TIPP produced sustained analgesia  following daily (intrathecal) i.t. injections over six days, whereas similar treatment with SNC-80 or SB235863 led to progressive tolerance and loss of the analgesic response. Trafficking assays in murine neuron cultures showed no association between the magnitude of ligand-induced sequestration and development of chronic tolerance. Instead, ligands that supported DOPr recycling were also the ones producing sustained analgesia over 6-day treatment. Moreover, endosomal endothelin-converting enzyme 2 (ECE2) blocker 663444 prevented DOPr recycling by deltorphin II and TIPP and precipitated tolerance by these ligands. In conclusion, agonists, which support DOPr recycling, avoid development of analgesic tolerance over repeated administration.

Reciprocal Regulatory Interaction between TRPV1 and Kinin B1 Receptor in a Rat Neuropathic Pain Model.

Kinins are mediators of pain and inflammation and evidence suggests that the inducible kinin B1 receptor (B1R) is involved in neuropathic pain (NP). This study investigates whether B1R and TRPV1 are colocalized on nociceptors and/or astrocytes to enable regulatory interaction either directly or through the cytokine pathway (IL-1ß, TNF-α) in NP. Sprague Dawley rats were subjected to unilateral partial sciatic nerve ligation (PSNL) and treated from 14 to 21 days post-PSNL with antagonists of B1R (SSR240612, 10 mg·kg-1, i.p.) or TRPV1 (SB366791, 1 mg·kg-1, i.p.). The impact of these treatments was assessed on nociceptive behavior and mRNA expression of B1R, TRPV1, TNF-α, and IL-1ß. Localization on primary sensory fibers, astrocytes, and microglia was determined by immunofluorescence in the lumbar spinal cord and dorsal root ganglion (DRG). Both antagonists suppressed PSNL-induced thermal hyperalgesia, but only SB366791 blunted mechanical and cold allodynia. SSR240612 reversed PSNL-induced enhanced protein and mRNA expression of B1R and TRPV1 mRNA levels in spinal cord while SB366791 further increased B1R mRNA/protein expression. B1R and TRPV1 were found in non-peptide sensory fibers and astrocytes, and colocalized in the spinal dorsal horn and DRG, notably with IL-1ß on astrocytes. IL-1ß mRNA further increased under B1R or TRPV1 antagonism. Data suggest that B1R and TRPV1 contribute to thermal hyperalgesia and play a distinctive role in allodynia associated with NP. Close interaction and reciprocal regulatory mechanism are suggested between B1R and TRPV1 on astrocytes and nociceptors in NP.

Tibial post fracture pain is reduced in kinin receptors deficient mice and blunted by kinin receptor antagonists.

BACKGROUND: Tibial fracture is associated with inflammatory reaction leading to severe pain syndrome. Bradykinin receptor activation is involved in inflammatory reactions, but has never been investigated in fracture pain. METHODS: This study aims at defining the role of B1 and B2-kinin receptors (B1R and B2R) in a closed tibial fracture pain model by using knockout mice for B1R (B1KO) or B2R (B2KO) and wild-type (WT) mice treated with antagonists for B1R (SSR 240612 and R954) and B2R (HOE140) or vehicle. A cyclooxygenase (COX) inhibitor (ketoprofen) and an antagonist (SB366791) of Transient Receptor Potential Vaniloid1 (TRPV1) were also investigated since these pathways are associated with BK-induced pain in other models. The impact on mechanical and thermal hyperalgesia and locomotion was assessed by behavior tests. Gene expression of B1R and B2R and spinal cord expression of c-Fos were measured by RT-PCR and immunohistochemistry, respectively. RESULTS: B1KO and B2KO mice demonstrated a reduction in post-fracture pain sensitivity compared to WT mice that was associated with decreased c-Fos expression in the ipsilateral spinal dorsal horn in B2KO. B1R and B2R mRNA and protein levels were markedly enhanced at the fracture site. B1R and B2R antagonists and inhibition of COX and TRPV1 pathways reduced pain in WT. However, the analgesic effect of the COX-1/COX-2 inhibitor disappeared in B1KO and B2KO. In contrast, the analgesic effect of the TRPV1 antagonist persisted after gene deletion of either receptor. CONCLUSIONS: It is suggested that B1R and B2R activation contributes significantly to tibial fracture pain through COX. Hence, B1R and B2R antagonists appear potential therapeutic agents to manage post fracture pain.

Argan Oil as an Effective Nutri-Therapeutic Agent in Metabolic Syndrome: A Preclinical Study.

The present study aims at examining the effects of argan oil on the three main cardiovascular risk factors associated with metabolic syndrome (hypertension, insulin resistance and obesity) and on one of its main complications, neuropathic pain. Male Sprague-Dawley rats had free access to a drinking solution containing 10% d-glucose or tap water for 12 weeks. The effect of argan oil was compared to that of corn oil given daily by gavage during 12 weeks in glucose-fed rats. Glucose-fed rats showed increases in systolic blood pressure, epididymal fat, plasma levels of triglycerides, leptin, glucose and insulin, insulin resistance, tactile and cold allodynia in association with a rise in superoxide anion production and NADPH oxidase activity in the thoracic aorta, epididymal fat and gastrocnemius muscle. Glucose-fed rats also showed rises in B1 receptor protein expression in aorta and gastrocnemius muscle. Argan oil prevented or significantly reduced all those anomalies with an induction in plasma adiponectin levels. In contrast, the same treatment with corn oil had a positive impact only on triglycerides, leptin, adiponectin and insulin resistance. These data are the first to suggest that argan oil is an effective nutri-therapeutic agent to prevent the cardiovascular risk factors and complications associated with metabolic syndrome.

Cellular localisation of the kinin B1R in the pancreas of streptozotocin-treated rat and the anti-diabetic effect of the antagonist SSR240612.

The mechanism by which kinin B1 receptor (B1R) contributes to type 1 diabetes is addressed by determining the impact of its inhibition on diabetes and on its pancreatic expression and cellular localisation on immunocompetent cells and primary sensory C-fibres. Rats were made diabetic with streptozotocin (STZ). On day 4, they were treated daily for 7 days with a B1R antagonist (SSR240612, 10 mg/kg) or its vehicle. The surviving ß-cells were measured by immunostaining. The expression of B1R, iNOS, TNF-α, macrophages, TCD4+, CGRP and TRPV1 was measured by Western blotting, qRT-PCR and immunofluorescence. Macrophages and TCD4+ lymphocytes were absent in control, but distributed abundantly in the pancreas of STZ-diabetic rats. B1R was upregulated on these immune cells infiltrating the diabetic rat pancreas while it was not expressed on primary sensory C-fibres even if the expression of TRPV1 and CGRP was enhanced. SSR240612 prevented the infiltration of macrophages and TCD4+ lymphocytes and the upregulation of B1R, iNOS, TNF-α and TRPV1. SSR240612 corrected hyperglycaemia and hypoinsulinaemia by improving the Langerhans islets survival or regeneration. It is concluded that kinin B1R antagonism exerts anti-diabetic action by preventing the infiltration of immune cells in the pancreas and by preserving the integrity of Langerhans islets ß-cells.

Beneficial effects of kinin B1 receptor antagonism on plasma fatty acid alterations and obesity in Zucker diabetic fatty rats.

Kinins are the endogenous ligands of the constitutive B2 receptor (B2R) and the inducible B1 receptor (B1R). Whereas B2R prevents insulin resistance, B1R is involved in insulin resistance and metabolic syndrome. However, the contribution of B1R in type 2 diabetes associated with obesity remains uncertain. The aim of the present study was to examine the impact of 1-week treatment with a selective B1R antagonist (SSR240612, 10 mg/kg per day, by gavage) on hyperglycemia, hyperinsulinemia, leptinemia, body mass gain, and abnormal plasma fatty acids in obese Zucker diabetic fatty (ZDF) rats. Treatment with SSR240612 abolished the body mass gain and reduced polyphagia, polydipsia, and plasma fatty acid alterations in ZDF rats without affecting hyperglycemia, hyperinsulinemia, and hyperleptinemia. The present study suggests that the upregulated B1R plays a role in body mass gain and circulating fatty acid alterations in ZDF rats. However, mechanisms other than B1R induction would be implicated in glucose metabolism disorder in ZDF rats, based on the finding that SSR240612 did not reverse hyperglycemia and hyperinsulinemia.

The kallikrein-kinin system in diabetic retinopathy.

Diabetic retinopathy (DR) is a major microvascular complication associated with type 1 and type 2 diabetes mellitus, which can lead to visual impairment and blindness. Current treatment strategies for DR are mostly limited to laser therapies, steroids, and anti-VEGF agents, which are often associated with unwanted side effects leading to further complications. Recent evidence suggests that kinins play a primary role in the development of DR through enhanced vascular permeability, leukocytes infiltration, and other inflammatory mechanisms. These deleterious effects are mediated by kinin B1 and B2 receptors, which are expressed in diabetic human and rodent retina. Importantly, kinin B1 receptor is virtually absent in sane tissue, yet it is induced and upregulated in diabetic retina. These peptides belong to the kallikrein-kinin system (KKS), which contains two separate and independent pathways of regulated serine proteases, namely plasma kallikrein (PK) and tissue kallikrein (TK) that are involved in the biosynthesis of bradykinin (BK) and kallidin (Lys-BK), respectively. Hence, ocular inhibition of kallikreins or antagonism of kinin receptors offers new therapeutic avenues in the treatment and management of DR. Herein, we present an overview of the principal features and known inflammatory mechanisms associated with DR along with the current therapeutic approaches and put special emphasis on the KKS as a new and promising therapeutic target due to its link with key pathways directly associated with the development of DR.

Cognitive and cerebrovascular improvements following kinin B1 receptor blockade in Alzheimer's disease mice.

BACKGROUND: Recent evidence suggests that the inducible kinin B1 receptor (B1R) contributes to pathogenic neuroinflammation induced by amyloid-beta (Aß) peptide. The present study aims at identifying the cellular distribution and potentially detrimental role of B1R on cognitive and cerebrovascular functions in a mouse model of Alzheimer's disease (AD). METHODS: Transgenic mice overexpressing a mutated form of the human amyloid precursor protein (APPSwe,Ind, line J20) were treated with a selective and brain penetrant B1R antagonist (SSR240612, 10 mg/kg/day for 5 or 10 weeks) or vehicle. The impact of B1R blockade was measured on i) spatial learning and memory performance in the Morris water maze, ii) cerebral blood flow (CBF) responses to sensory stimulation using laser Doppler flowmetry, and iii) reactivity of isolated cerebral arteries using online videomicroscopy. Aß burden was quantified by ELISA and immunostaining, while other AD landmarks were measured by western blot and immunohistochemistry. RESULTS: B1R protein levels were increased in APP mouse hippocampus and, prominently, in reactive astrocytes surrounding Aß plaques. In APP mice, B1R antagonism with SSR240612 improved spatial learning, memory and normalized protein levels of the memory-related early gene Egr-1 in the dentate gyrus of the hippocampus. B1R antagonism restored sensory-evoked CBF responses, endothelium-dependent dilations, and normalized cerebrovascular protein levels of endothelial nitric oxide synthase and B2R. In addition, SSR240612 reduced (approximately 50%) microglial, but not astroglial, activation, brain levels of soluble Aß1-42, diffuse and dense-core Aß plaques, and it increased protein levels of the Aß brain efflux transporter lipoprotein receptor-related protein-1 in cerebral microvessels. CONCLUSION: These findings show a selective upregulation of astroglial B1R in the APP mouse brain, and the capacity of the B1R antagonist to abrogate amyloidosis, cerebrovascular and memory deficits. Collectively, these findings provide convincing evidence for a role of B1R in AD pathogenesis.

Prevention of Inflammation, Neovascularization, and Retinal Dysfunction by Kinin B1 Receptor Antagonism in a Mouse Model of Age-Related Macular Degeneration.

The kallikrein-kinin system (KKS) contributes to vascular inflammation and neovascularization in age-related macular degeneration (AMD), particularly via the kinin B1 receptor (B1R). The aim of the present study was to determine the protective effects of the topical administration of the B1R antagonist (R-954) on inflammation, neovascularization, and retinal dysfunction in a murine model of neovascular AMD. Choroidal neovascularization (CNV) was induced in C57BL6 mice using an argon laser. A treatment with ocular drops of R-954 (100 µg/15 µL, twice daily in both eyes), or vehicle, was started immediately on day 0, for 7, 14, or 21 days. CNV, invasive microglia, and B1R immunoreactive glial cells, as well as electroretinography alterations, were observed within the retina and choroid of the CNV group but not in the control group. The staining of B1R was abolished by R-954 treatment as well as the proliferation of microglia. R-954 treatment prevented the CNV development (volume: 20 ± 2 vs. 152 ± 5 × 104 µm3 in R-954 vs. saline treatment). R-954 also significantly decreased photoreceptor and bipolar cell dysfunction (a-wave amplitude: -47 ± 20 vs. -34 ± 14 µV and b-wave amplitude: 101 ± 27 vs. 64 ± 17 µV in R-954 vs. saline treatment, day 7) as well as angiogenesis tufts in the retina. These results suggest that self-administration of R-954 by eye-drop treatment could be a promising therapy in AMD to preserve retinal health and vision.

Thymus atlanticus: A Source of Nutrients with Numerous Health Benefits and Important Therapeutic Potential for Age-Related Diseases.

Thymus atlanticus (Lamiaceae) is a plant endemic to the Mediterranean basin that is found in significant quantities in the arid regions of Morocco. Thymus atlanticus is used in traditional medicine to treat infectious and non-infectious diseases. It is also used for the isolation of essential oils and for the seasoning of many dishes in the Mediterranean diet. The major constituents of Thymus atlanticus are saponins, flavonoids, tannins, alkaloids, various simple and hydroxycinnamic phenolic compounds, and terpene compounds. Several of these compounds act on signaling pathways of oxidative stress, inflammation, and blood sugar, which are parameters often dysregulated during aging. Due to its physiochemical characteristics and biological activities, Thymus atlanticus could be used for the prevention and/or treatment of age-related diseases. These different aspects are treated in the present review, and we focused on phytochemistry and major age-related diseases: dyslipidemia, cardiovascular diseases, and type 2 diabetes.

The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors.

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.16177. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Bradykinin inhibits high glucose- and growth factor-induced collagen synthesis in mesangial cells through the B2-kinin receptor.

Mesangial matrix expansion is an early lesion leading to glomeruloclerosis and chronic renal diseases. A beneficial effect is achieved with angiotensin I-converting enzyme inhibitors (ACEI), which also favor bradykinin (BK) B2 receptor (B2R) activation. To define the underlying mechanism, we hypothesized that B2R activation could be a negative regulator of collagen synthesis in mesangial cells (MC). We investigated the effect of BK on collagen synthesis and signaling in MC. Inflammation was evaluated by intercellular adhesion molecule-1 (ICAM-1) expression. BK inhibited collagen I and IV synthesis stimulated by high glucose, epithelial growth factor (EGF), and transforming growth factor-ß (TGF-ß) but did not alter ICAM-1. Inhibition of collagen synthesis was B2R but not B1R mediated. PKC or phosphatidylinositol 3-kinase (PI3K) inhibitors mimicked the BK effect. B2R activation inhibited TGF-ß- and EGF-induced Erk1/2, Smad2/3, Akt S473, and EGFR phosphorylation. A phosphatase inhibitor prevented BK effects. The in vivo impact of B2R on mesangial matrix expansion was assessed in streptozotocin-diabetic rodents. Deletion of B2R increased mesangial matrix expansion and albuminuria in diabetic mice. In diabetic rats, matrix expansion and albuminuria were prevented by ACEI but not by ACEI and B2R antagonist cotreatment. Consistently, the lowered BK content of diabetic glomeruli was restored by ACEI. In conclusion, deficient B2R activation aggravated mesangial matrix expansion in diabetic rodents whereas B2R activation reduced MC collagen synthesis by a mechanism targeting Erk1/2 and Akt, common pathways activated by EGF and TGF-ß. Taken together, the data support the hypothesis of an antifibrosing effect of B2R activation.

Activation of kinin B1 receptor evokes hyperthermia through a vagal sensory mechanism in the rat.

BACKGROUND: Kinins are mediators of pain and inflammation. Their role in thermoregulation is, however, unknown despite the fact the B1 receptor (B1R) was found implicated in lipopolysaccharide (LPS)-induced fever. The aim of this study was to investigate the mechanism by which peripheral B1R affects body core temperature in a rat model known to show up-regulated levels of B1R. METHODS: Male Sprague-Dawley rats received streptozotocin (STZ, 65 mg/kg; i.p.) to enhance B1R expression. Control rats received the vehicle only. One week later, rectal temperature was measured in awake rats after i.p. injection of increasing doses (0.01 to 5 mg/kg) of des-Arg(9)-Bradykinin (BK) and Sar-[D-Phe(8)]des-Arg(9)-BK (B1R agonists) or BK (B2R agonist). The mechanism of B1R-induced hyperthermia was addressed using specific inhibitors and in rats subjected to subdiaphragmatic vagal nerve ligation. B1R mRNA level was measured by quantitative Real Time-polymerase chain reaction (qRT-PCR) and B1R was localized by confocal microscopy. RESULTS: B1R agonists (0.1 to 5 mg/kg) showed transient (5- to 30-minute) and dose-dependent increases of rectal temperature (+1.5°C) in STZ-treated rats, but not in control rats. BK caused no effect in STZ and control rats. In STZ-treated rats, B1R agonist-induced hyperthermia was blocked by antagonists/inhibitors of B1R (SSR240612), cyclooxygenase-2 (COX-2) (niflumic acid) and nitric oxide synthase (NOS) (L-NAME), and after vagal nerve ligation. In contrast, COX-1 inhibition (indomethacin) had no effect on B1R agonist-induced hyperthermia. In STZ-treated rats, B1R mRNA was significantly increased in the hypothalamus and the vagus nerve where it was co-localized with calcitonin-gene-related peptide in sensory C-fibers. CONCLUSION: B1R, which is induced in inflammatory diseases, could contribute to hyperthermia through a vagal sensory mechanism involving prostaglandins (via COX-2) and nitric oxide.

Activation of TRPV1 by capsaicin induces functional kinin B(1) receptor in rat spinal cord microglia.

BACKGROUND: The kinin B(1) receptor (B(1)R) is upregulated by pro-inflammatory cytokines and oxydative stress, which are enhanced by transient receptor potential vanilloid subtype 1 (TRPV1) activation. To examine the link between TRPV1 and B(1)R in inflammatory pain, this study aimed to determine the ability of TRPV1 to regulate microglial B(1)R expression in the spinal cord dorsal horn, and the underlying mechanism. METHODS: B(1)R expression (mRNA, protein and binding sites) was measured in cervical, thoracic and lumbar spinal cord in response to TRPV1 activation by systemic capsaicin (1-50 mg/kg, s.c) in rats pre-treated with TRPV1 antagonists (capsazepine or SB-366791), the antioxidant N-acetyl-L-cysteine (NAC), or vehicle. B(1)R function was assessed using a tail-flick test after intrathecal (i.t.) injection of a selective B(1)R agonist (des-Arg(9)-BK), and its microglial localization was investigated by confocal microscopy with the selective fluorescent B(1)R agonist, [Nα-bodipy]-des-Arg(9)-BK. The effect of i.t. capsaicin (1 µg/site) was also investigated. RESULTS: Capsaicin (10 to 50 mg/kg, s.c.) enhanced time-dependently (0-24h) B(1)R mRNA levels in the lumbar spinal cord; this effect was prevented by capsazepine (10 mg/kg, i.p.; 10 µg/site, i.t.) and SB-366791 (1 mg/kg, i.p.; 30 µg/site, i.t.). Increases of B(1)R mRNA were correlated with IL-1ß mRNA levels, and they were significantly less in cervical and thoracic spinal cord. Intrathecal capsaicin (1 µg/site) also enhanced B(1)R mRNA in lumbar spinal cord. NAC (1 g/kg/d × 7 days) prevented B(1)R up-regulation, superoxide anion production and NF-kB activation induced by capsaicin (15 mg/kg). Des-Arg(9)-BK (9.6 nmol/site, i.t.) decreased by 25-30% the nociceptive threshold at 1 min post-injection in capsaicin-treated rats (10-50 mg/kg) while it was without effect in control rats. Des-Arg(9)-BK-induced thermal hyperalgesia was blocked by capsazepine, SB-366791 and by antagonists/inhibitors of B(1)R (SSR240612, 10 mg/kg, p.o.), glutamate NMDA receptor (DL-AP5, 10 µg/site, i.t.), substance P NK-1 receptor (RP-67580, 10 µg/site, i.t.) and nitric oxide synthase (L-NNA, 10 µg/site, i.t.). The B(1)R fluorescent agonist was co-localized with an immunomarker of microglia (Iba-1) in spinal cord dorsal horn of capsaicin-treated rats. CONCLUSION: This study highlights a new mechanism for B(1)R induction via TRPV1 activation and establishes a link between these two pro-nociceptive receptors in inflammatory pain.

Suppression of vascular inflammation by kinin B1 receptor antagonism in a rat model of insulin resistance.

BACKGROUND: Kinin B1 receptor (B1R) intervenes in a positive feedback loop to amplify and perpetuate the vascular oxidative stress in glucose-fed rats, a model of insulin resistance. This study aims at determining whether B1R blockade could reverse vascular inflammation in this model. METHODS/RESULTS: Young male Sprague-Dawley rats were fed with 10% D-glucose or tap water (controls) for 8 weeks, and during the last week, rats were administered the B1R antagonist SSR240612 (10 mg/kg/day, gavage) or the vehicle. The outcome was determined on glycemia, insulinemia, insulin resistance (homeostasis model assessment index), and on protein or mRNA expression of the following target genes in the aorta (by Western blot and real-time quantitative polymerase chain reaction): B1R, endothelial nitric oxide synthase, inducible nitric oxide synthase, macrophage CD68, macrophage/monocyte CD11b, interleukin (IL) -1ß, tumor necrosis factor-α, IL-6, macrophage migration inhibitory factor, intercellular adhesion molecule-1, and E-selectin (endothelial adhesion molecule). Data showed increased expression of all these markers in the aorta of glucose-fed rats except endothelial nitric oxide synthase and tumor necrosis factor-α, which were not affected. SSR240612 reversed hyperglycemia, hyperinsulinemia, insulin resistance, and the upregulation of B1R, inducible nitric oxide synthase, macrophage CD68, and CD11b, IL-1ß, inter-cellular adhesion molecule-1, macrophage migration inhibitory factor, and E-selectin in glucose-fed rats, yet it had no significant effect on IL-6 and in control rats. CONCLUSIONS: Kinin B1R antagonism reversed the upregulation of its own receptor and several pro-inflammatory markers in the aorta of glucose-fed rats. These data provide the first evidence that B1R may contribute to the low-grade vascular inflammation in insulin resistance, an early event in the development of type-2 diabetes.

Saffron (Crocus sativus L.): A Source of Nutrients for Health and for the Treatment of Neuropsychiatric and Age-Related Diseases.

Saffron (Crocus sativus L.) is a medicinal plant, originally cultivated in the East and Middle East, and later in some Mediterranean countries. Saffron is obtained from the stigmas of the plant. Currently, the use of saffron is undergoing a revival. The medicinal virtues of saffron, its culinary use and its high added value have led to the clarification of its phytochemical profile and its biological and therapeutic characteristics. Saffron is rich in carotenoids and terpenes. The major products of saffron are crocins and crocetin (carotenoids) deriving from zeaxanthin, pirocrocin and safranal, which give it its taste and aroma, respectively. Saffron and its major compounds have powerful antioxidant and anti-inflammatory properties in vitro and in vivo. Anti-tumor properties have also been described. The goal of this review is to present the beneficial effects of saffron and its main constituent molecules on neuropsychiatric diseases (depression, anxiety and schizophrenia) as well as on the most frequent age-related diseases (cardiovascular, ocular and neurodegenerative diseases, as well as sarcopenia). Overall, the phytochemical profile of saffron confers many beneficial virtues on human health and, in particular, on the prevention of age-related diseases, which is a major asset reinforcing the interest for this medicinal plant.

Modulation of retinal blood flow by kinin B1 receptor in Streptozotocin-diabetic rats.

The vasoactive kinin B1 receptor (B1R) is overexpressed in the retina of diabetic rats in response to hyperglycemia and oxidative stress. The aim of the present study was to determine whether B1R could contribute to the early retinal blood flow changes occurring in diabetes. Male Wistar rats were rendered diabetic with a single i.p. injection of Streptozotocin (STZ) and studied 4 days or 6 weeks after diabetes induction. The presence of B1R in the retina was confirmed by Western blot. The impact of oral administration of the B1R selective antagonist SSR240612 (10mg/kg) was measured on alteration of retinal perfusion in awake diabetic rats by quantitative autoradiography. Data showed that B1R was upregulated in the STZ-diabetic retina at 4 days and 6 weeks. Retinal blood flow was not altered in 4-day diabetic rats compared with age-matched controls but was significantly decreased following SSR240612 treatment. In 6-week diabetic rats, retinal blood flow was markedly reduced compared to control rats and SSR240612 did not further decrease the blood flow. These results suggest that B1R is upregulated in STZ-diabetic retina and has a protective compensatory role on retinal microcirculation at 4 days but not at 6 weeks following diabetes induction.

Impact of α-lipoic acid on liver peroxisome proliferator-activated receptor-α, vascular remodeling, and oxidative stress in insulin-resistant rats.

This study sought to determine the impact of α-lipoic acid (LA) on superoxide anion (O(2)(•-)) production and peroxisome proliferator-activated receptor-α (PPARα) expression in liver tissue, plasma free fatty acids (FFA), and aortic remodeling in a rat model of insulin resistance. Sprague-Dawley rats (50-75 g) were given either tap water or a drinking solution containing 10% D-glucose for 14 weeks, combined with a diet with or without LA supplement. O(2)(•-) production was measured by lucigenin chemiluminescence, and PPAR-α expression by Western blotting. Cross-sectional area (CSA) of the aortic media and lumen and number of smooth muscle cells (SMC) were determined histologically. Glucose increased systolic blood pressure (SBP), plasma levels of glucose and insulin, and insulin resistance (HOMA index). All of these effects were attenuated by LA. Whereas glucose had no effect on liver PPAR-α protein level, it decreased plasma FFA. LA decreased the aortic and liver O(2)(•-) production, body weight, and plasma FFA levels in control and glucose-treated rats. Liver PPAR-α protein levels were increased by LA, and negatively correlated with plasma FFA. Medial CSA was reduced in all glucose-treated rats, and positively correlated with plasma FFA but not with SBP or aortic O(2)(•-) production. Glucose also reduced aortic lumen area, so that the media-to-lumen ratio remained unchanged. The ability of LA to lower plasma FFA appears to be mediated, in part, by increased hepatic PPAR-α expression, which may positively affect insulin resistance. Glucose-fed rats may serve as a unique model of aortic atrophic remodeling in hypertension and early metabolic syndrome.

In Vivo Anti-Diabetic Activity of the Ethanolic Crude Extract of Sorbus decora C.K.Schneid. (Rosacea): A Medicinal Plant Used by Canadian James Bay Cree Nations to Treat Symptoms Related to Diabetes.

A number of potential anti-diabetic plants were identified through an ethnobotanical survey of the traditional pharmacopeia of the Cree of Eeyou Istchee (CEI-Northeastern Canada) used against symptoms of diabetes and their biological activity assessed by in vitro bioassays. Among these, Sorbus decora C.K.Schneid. (Rosacea) ranked highly and increased the transport of glucose in skeletal muscle cells in culture. The present study thus aimed at confirming the antidiabetic potential of S. decora in in vivo models of insulin resistance and diabetes, notably the streptozotocin Type 1 diabetic rat (STZ), the genetic KK-A(y) Type 2 diabetic mouse and the rat rendered insulin resistant with 10% glucose water consumption for 6 weeks. Sorbus decora ethanolic crude extract (SDEE) was administered orally (200 mg kg(-1)) and compared to metformin (150 or 500 mg kg(-1)). The intragastric (i.g.) gavage of SDEE transiently decreased glycemia in STZ rats in a bi-phasic manner but the effect was cumulative over several days. In KK-A(y) mice, SDEE incorporated in food (0.12%) decreased glycemia by 15% within 1 week as compared to vehicle controls. In pre-diabetic insulin-resistant rats, SDEE fed daily by i.g. gavage for 2 weeks significantly decreased the slight hyperglycemia and hyperinsulinemia, without affecting sugar water intake. Using the HOMA insulin resistance parameter, the effect of SDEE was equivalent to that of metformin. In conclusion, the ethanolic crude extract of S. decora demonstrates both anti-hyperglycemic and insulin-sensitizing activity in vivo, thereby confirming anti-diabetic potential and validating CEI traditional medicine.

Kinins and Their Receptors as Potential Therapeutic Targets in Retinal Pathologies.

The kallikrein-kinin system (KKS) contributes to retinal inflammation and neovascularization, notably in diabetic retinopathy (DR) and neovascular age-related macular degeneration (AMD). Bradykinin type 1 (B1R) and type 2 (B2R) receptors are G-protein-coupled receptors that sense and mediate the effects of kinins. While B2R is constitutively expressed and regulates a plethora of physiological processes, B1R is almost undetectable under physiological conditions and contributes to pathological inflammation. Several KKS components (kininogens, tissue and plasma kallikreins, and kinin receptors) are overexpressed in human and animal models of retinal diseases, and their inhibition, particularly B1R, reduces inflammation and pathological neovascularization. In this review, we provide an overview of the KKS with emphasis on kinin receptors in the healthy retina and their detrimental roles in DR and AMD. We highlight the crosstalk between the KKS and the renin-angiotensin system (RAS), which is known to be detrimental in ocular pathologies. Targeting the KKS, particularly the B1R, is a promising therapy in retinal diseases, and B1R may represent an effector of the detrimental effects of RAS (Ang II-AT1R).