This study investigated the role of kinins and their receptors in malignant brain tumors. As a fi... more This study investigated the role of kinins and their receptors in malignant brain tumors. As a first approach, GL-261 glioma cells were injected (2 × 10(5) cells in 2 μl/2 min) into the right striatum of adult C57/BL6 wild-type, kinin B1 and B2 receptor knockout (KOB1R and KOB2R) and B1 and B2 receptor double knockout mice (KOB1B2R). The animals received the selective B1R (SSR240612) and/or B2R (HOE-140) antagonists by intracerebroventricular (i.c.v.) route at 5, 10, and 15 days. The tumor size quantification, mitotic index, western blot analysis, quantitative autoradiography, immunofluorescence, and confocal microscopy were carried out in brain tumor samples, 20 days after tumor induction. Our results revealed an uncontrolled tumor growing in KOB1R or SSR240612-treated mice, which was blunted by B2R blockade with HOE-140, suggesting a crosstalk between B1R and B2R in tumor growing. Combined treatment with B1R and B2R antagonists normalized the upregulation of tumor B1R and decrease...
The mechanism by which kinin B1 receptor (B1R) contributes to type 1 diabetes is addressed by det... more 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 β-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 ...
Beneficial effects of argan oil on blood pressure, insulin resistance and oxidative stress in rat... more Beneficial effects of argan oil on blood pressure, insulin resistance and oxidative stress in rat Running head: Argan oil effects on insulin resistance and hypertension
The muscarinic and nicotinic transmissions in the primary visual cortex (V1) are involved in the ... more The muscarinic and nicotinic transmissions in the primary visual cortex (V1) are involved in the enhancement of specific visual stimuli as well as long-term modifications of the neuronal processing, in regards to perceptual learning. We investigated the involvement of the different cholinergic receptors subtypes underlying this long-term functional plasticity using RT-PCR and recording of visual evoked potentials (VEPs). Perceptual learning-like test was performed by exposing awaken rats to a visual stimulation (VS) - a sinusoidal grating (30°, 0.12cpd) - for 10min/day during 14days. This VS was provided alone or coupled to an electrical stimulation of the basal forebrain which sends cholinergic projections to V1 (HDB/VS) or paired with a cholinesterase inhibitor (donepezil, 1mg/kg injected 30min prior to visual exposure) to enhance cholinergic transmission in V1 (DONEP/VS). One week after the last training session, VEPs were recorded and the cortices encompassing V1 were collected to determine the expression level of mRNA of muscarinic (M1-5) and nicotinic (α/β) receptors sub-units by RT-PCR. VS coupled to pharmacological or electrical stimulation of the cholinergic system produced a significant enhancement of the cortical response, as shown by VEP recordings. Two weeks of VS treatment alone caused an increase of the expression of M3 and M5 mRNA suggesting an increase of their production and activity during long-term visual stimulation. In the HDB/VS group, α3 sub-unit was decreased suggesting its involvement in phasic cholinergic stimulation. The DONEP/VS treatment presented a decrease in the expression of M2, suggesting a down regulation of mRNA synthesis. This could indicate an increased cortico-cortical inhibition, as M2 receptors are located massively on the GABAergic neurons. Therefore, even with similar functional enhancement, the cholinergic receptors regulation differs between an electrical and a pharmacological treatment. These results are crucial for determining which receptors are the most involved in the pharmacological cholinergic stimulation to enhance visual perception. Meeting abstract presented at VSS 2015.
Using a rat lung slice model, this study compared the stress responses induced by cigarette whole... more Using a rat lung slice model, this study compared the stress responses induced by cigarette whole smoke (WS) to that induced by the vapor phase (VP) of the smoke. Following a 3-day exposure, lung slices exposed to 4, 10 and 20% WS retained 85, 42 and 16% relative survival respectively in comparison to the air-exposed ones. Consistently, histological observations revealed concentration-related alveolar damages in the lung slices. Expression of 5 stress-response genes was examined following a single 30 min exposure to 4% WS or VP. WS exposure resulted in 4, 11 and 50-fold induction of IL-1, kinin type I receptor (B 1 R) and CYP1A1 genes, respectively, while CYP1B1 and TNF-␣ genes expression was found only two times higher in comparison to VP group. Since cigarette WS consists of particulate and vapor phases, these results highlight the preferential or synergistic role of the particulate phase in the induction of IL-1, B 1 R and CYP1A1 genes and that VP did not have comparable effects on expression of these genes. However, both phases fairly contributed to the induction of CYP1B1 and TNF-␣ genes. VP was the fraction responsible for the toxic effect since WS did not produce further toxicity. The 4% whole smoke deposited about 7.1 g/cm 2 of total particulate matter (TPM) to the exposure chamber which may account for observed differential stress responses in the lung slices.
An autoradiographic study was conducted to determine whether kinin receptors are altered in the r... more An autoradiographic study was conducted to determine whether kinin receptors are altered in the rat spinal cord in two experimental models of chronic hyperglycemia and insulin resistance. Sprague-Dawley rats were given 10% d-glucose in their drinking water alone or with insulin (9 mU/kg/min with osmotic pumps) for 4 weeks. Both groups and control rats were treated either with a normal chow diet or with an alpha-lipoic acid-supplemented diet as antioxidant therapy. After 4 weeks of treatment, glycemia, insulinemia, blood pressure, insulin resistance index, the production of superoxide anion in the aorta and the density of B2 receptor binding sites in the dorsal horn were significantly increased in the two models. These effects were prevented or attenuated by alpha-lipoic acid. In contrast, B2 receptor binding sites of most spinal cord laminae were increased in the glucose group only and were not affected by alpha-lipoic acid. Results show that chronic hyperglycemia associated with insulin resistance increases B1 and B2 receptor binding sites in the rat spinal cord through distinct mechanisms, including the oxidative stress for the B1 receptor.
Diabetes Mellitus leads to pain neuropathy and cardiovascular complications which remain resistan... more Diabetes Mellitus leads to pain neuropathy and cardiovascular complications which remain resistant to current therapies involving the control of glycaemia. This study aims at defining the contribution of kinin B 1 receptor (B 1 R) and the oxidative stress on sensory abnormalities and arterial hypertension in a rat model of insulin resistance. Rats were fed with 10% D-glucose for a chronic period of 12-14 weeks and the impact of a diet supplemented with a-lipoic acid, a potent antioxidant, was determined on tactile and cold allodynia, arterial hypertension and the expression of kinin B 1 R (real-time PCR and autoradiography) in several tissues. Acute effects of brain penetrant (LF22-0542) and peripherally acting (R-715) B 1 R antagonists were also assessed. Glucose-fed rats exhibited tactile and cold allodynia along with increases in systolic blood pressure between 4 and 12 weeks; these alterations were alleviated by a-lipoic acid. The latter regimen also decreased significantly increased plasma levels of insulin and glucose and insulin resistance (HOMA index) at 14 weeks. B 1 R mRNA was virtually absent in liver, aorta, lung, kidney and spinal cord isolated from control rats, yet B 1 R mRNA was markedly increased in all tissues in glucose-fed rats. Up-regulated B 1 R mRNA and B 1 R binding sites (spinal cord) were significantly reduced by a-lipoic acid in glucose-fed rats. LF22-0542 reduced tactile and cold allodynia (3 h) and reversed arterial hypertension (3-48 h) in glucose-fed rats. R-715 abolished tactile and cold allodynia but had not effect on blood pressure. Data suggest that the oxidative stress contributes to the induction and up-regulation of B 1 R in the model of insulin resistance induced by glucose feeding. The over expressed B 1 R contributes centrally to arterial hypertension and in the periphery to sensory abnormalities.
Kinin B1 and B2 receptor (R) gene expression (mRNA) is increased in the sensory system after peri... more Kinin B1 and B2 receptor (R) gene expression (mRNA) is increased in the sensory system after peripheral nerve injury. This study measured the densities of B1R and B2R binding sites in the spinal cord and dorsal root ganglia (DRG) by quantitative autoradiography, and evaluated the effects of two selective non-peptide antagonists at B1R (LF22-0542) and B2R (LF16-0687) on pain behavior after partial ligation of the left sciatic nerve. Increases of B1R binding sites were seen in superficial laminae of the ipsi- and contralateral spinal cord at 2 and 14 days while B2R binding sites were increased on the ipsilateral side at 2 days and on both sides at 14 days. In DRG, B1R and B2R binding sites were significantly increased at 2 days (ipsilateral) and 14 days on both sides. Whereas tactile allodynia started to develop progressively from 2 to 25 days post-ligation, the occurrence of cold allodynia and thermal hyperalgesia became significant from day 8 and day 14 post-ligation, respectively. At day 21 after sciatic nerve ligation, thermal hyperalgesia was blocked by LF22-0542 (10 mg/kg, s.c.) and LF16-0687 (3 mg/kg, s.c.), yet both antagonists had no effect on tactile and cold allodynia. Data highlight the implication of both kinin receptors in thermal hyperalgesia but not in tactile and cold allodynia associated with peripheral nerve injury. Hence LF22-0542 and LF16-0687 present therapeutic potential for the treatment of some aspects of neuropathic pain.
Kinins are among the most potent autacoids involved in inflammatory, vascular and pain processes.... more Kinins are among the most potent autacoids involved in inflammatory, vascular and pain processes. These short-lived peptides, including bradykinin, kallidin and T-kinin, are generated during tissue injury and noxious stimulation. However, emerging evidence also suggests that kinins are stored in neuronal elements of the central nervous system (CNS) where they are thought to play a role as neuromediators in various cerebral functions, particularly in the control of nociceptive information. Kinins exert their biological effects through the activation of two transmembrane G-protein-coupled receptors, denoted bradykinin B(1) and B(2). Whereas the B(2) receptor is constitutive and activated by the parent molecules, the B(1) receptor is generally underexpressed in normal tissues and is activated by kinins deprived of the C-terminal Arg (des-Arg(9)-kinins). The induction and increased expression of B(1) receptor occur following tissue injury or after treatment with bacterial endotoxins or cytokines such as interleukin-1 beta and tumor necrosis factor-alpha. This review summarizes the most recent data from various animal models which convey support for a role of B(2) receptors in the acute phase of the inflammatory and pain response, and for a role of B(1) receptors in the chronic phase of the response. The B(1) receptor may exert a strategic role in inflammatory diseases with an immune component (diabetes, asthma, rheumatoid arthritis and multiple sclerosis). New information is provided regarding the role of sensory mechanisms subserving spinal hyperalgesia and intrapleural neutrophil migration that occur upon B(1) receptor activation in streptozotocin-treated rats, a model of insulin-dependent diabetes mellitus in which the B(1) receptor seems to be rapidly overexpressed. Although it is widely accepted that the blockade of kinin receptors with specific antagonists could be of benefit in the treatment of somatic and visceral inflammation and pain, recent molecular and functional evidence suggests that the activation of B(1) receptors with an agonist may afford a novel therapeutic approach in the CNS inflammatory demyelinating disorder encountered in multiple sclerosis by reducing immune cell infiltration (T-lymphocytes) into the brain. Hence, the B(1) receptor may exert either a protective or detrimental effect depending on the inflammatory disease. This dual function of the B(1) receptor deserves to be investigated further.
Kinins (bradykinin, kallidin and their active metabolites) are peptide autacoids with established... more Kinins (bradykinin, kallidin and their active metabolites) are peptide autacoids with established functions in cardiovascular homeostasis, contraction and relaxation of smooth muscles, inflammation and nociception. They are believed to play a role in disease states like asthma, allergies, rheumatoid arthritis, cancer, diabetes, endotoxic and pancreatic shock, and to contribute to the therapeutic effects of ACE inhibitors in cardiovascular diseases. Although kinins are also neuromediators in the central nervous system, their involvement in neurological diseases has not been intensively investigated thus far. This review analyzes the potential of central kinin receptors as therapeutic targets for neurological disorders. Initial data highlight potential roles for B 1 receptor antagonists as antiepileptic agents, and for B 2 receptor antagonists (and/or B 1 agonists) in the treatment of stroke. Functional B 1 receptors located on T-lymphocytes and on the blood brain-barrier are also putative targets for the management of multiple sclerosis. However, successful elucidation of the therapeutic value of these new pharmacological approaches will require refinement of our knowledge on the physiology and cellular localization of central kinin receptors.
Glucose-fed rat is a model of insulin resistance that displays sensory polyneuropathy and hyperte... more Glucose-fed rat is a model of insulin resistance that displays sensory polyneuropathy and hypertension. This study aimed at comparing the beneficial effects of N-Acetyl-L-Cysteine (NAC, antioxidant) and ramipril (angiotensin-1 converting enzyme inhibitor) on tactile and cold allodynia induced by chronic glucose feeding. Impact of these treatments was also assessed on hypertension, plasma glucose and insulin concentrations, insulin resistance and kinin B 1 receptor expression. Male Wistar rats (50-75 g) were given 10% D-glucose in their drinking water for 11 weeks or tap water (controls). Glucose-fed rats were treated either with NAC (1 g/kg/day, gavage), ramipril (1 mg/kg/day in drinking water) or no drug during the last 5 weeks. Glucose feeding for 6 weeks induced a significant increase in systolic blood pressure and hyperglycaemia which was accompanied by tactile and cold allodynia. At 11 weeks, plasma insulin, insulin resistance (HOMA index), kinin B 1 receptor mRNA in spinal cord and renal cortex and B 1 receptor binding sites in spinal cord were enhanced in glucose-fed rats. NAC and ramipril caused a progressive to complete inhibition of tactile and cold allodynia from 6 to 11 weeks. High systolic blood pressure, hyperinsulinemia, insulin resistance and kinin B 1 receptor expression were also normalized or attenuated in glucose-fed rats by either treatment. Results suggest that chronic treatment with an antioxidant or an ACE inhibitor provides similar beneficial effects on sensory polyneuropathy, hypertension and insulin resistance in glucose-fed rats. Both therapies were associated with a reduction of the expression of the pro-nociceptive kinin B 1 receptor.
The paratrigeminal nucleus (Pa5), an input site for spinal, trigeminal, vagus and glossopharyngea... more The paratrigeminal nucleus (Pa5), an input site for spinal, trigeminal, vagus and glossopharyngeal afferents, is a recognized site for orofacial nociceptive sensory processing. It has efferent connections to brain structures associated with nociception and cardiorespiratory functions. This study aimed at determining the function of the Pa5 on the cardiovascular component of the somatosensory reflex (SSR) to sciatic nerve stimulation (SNS) in paralyzed and artificially-ventilated rats following Pa5 chemical lesions (ibotenic acid), synaptic transmission blockade (CoCl 2), local anaesthetics (lidocaine) or desensitization of primary afferent fibers (capsaicin). The pressor response to sciatic nerve stimulation at 0.6 mA and 20 Hz (14 ± 1 mm Hg) was strongly attenuated by contra-(−80%) or bilateral (−50%) paratrigeminal nucleus lesions. Ipsilateral Pa5 lesions only attenuated the response to 0.1 mA, 20 Hz SNS (− 55%). Cobalt chloride or lidocaine injected in the contralateral paratrigeminal nucleus also attenuated the SSR. In capsaicin-treated animals, the pressor responses to 0.1 mA were abolished, whereas the responses to SNS at 0.6 mA were increased from 65 to 100% depending on the stimulus frequency. The paratrigeminal nucleus receives both, excitatory and inhibitory components; the later apparently involving capsaicin-sensitive fiber inputs mostly to the ipsilateral site whereas the capsaicin insensitive excitatory components that respond to high or low frequency stimulation, respectively, target the contralateral and ipsilateral sites. Thus, the paratrigeminal nucleus mediates excitatory and inhibitory components of the somatosensory reflex, representing a primary synapse site in the brain for nociceptive inputs from the sciatic innervation field.
Canadian Journal of Physiology and Pharmacology, 1980
In order to develop a sensitive pharmacological preparation which would allow the measurement of ... more In order to develop a sensitive pharmacological preparation which would allow the measurement of the inhibitory effects of kinins and substance P (SP) in vascular smooth muscles, several large arteries of the dog were studied in vitro. The common carotid artery was found to be one of the most sensitive preparations to SP and kinins. When contracted with low concentrations of noradrenaline (between 3.0 × 10−8 and 3.0 × 10−7 M), this artery responds to SP (6.5 × 10−11 − 6.5 × 10−9 M) and bradykinin (BK) (8.1 × 10−11 − 9.1 × 10−8 M) with relaxations that are proportional to the concentrations of the two peptides. SP and BK appear to exert their relaxant effects through the activation of specific receptors as the exposure of the common carotid artery to concentrations of [Leu8]-angiotensin II, propranolol, methysergide, cimetidine, or atropine sufficient to inhibit the effects of the corresponding agonists do not affect the relaxing effect of SP and BK. [Leu8]-des-Arg9-BK (1.0 × 10−s M)...
In this paper we describe the release of hepoxilin A3 (HxA3) by intact pieces of the rat thoracic... more In this paper we describe the release of hepoxilin A3 (HxA3) by intact pieces of the rat thoracic aorta and its stimulation by exogenous arachidonic acid but not by the calcium ionophore A23187. Homogenates of the rat aorta metabolize HxA3 via two competing pathways; one involves hepoxilin epoxide hydrolase to form the trihydroxy metabolite, trioxilin A3 (TrXA3), and a second pathway involves conjugation of HxA3 with glutathione via glutathione S-transferase to form a glutathione conjugate, which we refer to as hepoxilin A3-C (HxA3-C), a name based upon the accepted nomenclature for the glutathione conjugate leukotriene C. The formation of HxA3-C was dependent on the presence of reduced glutathione in the incubation medium. HxA3-C formation was greatly enhanced in the presence of TCPO, an epoxide hydrolase inhibitor which blocks utilization of the substrate via hepoxilin epoxide hydrolase. Comparison of HxA3-C formation by several arteries and veins indicated that glutathione conjugation was more evident in veins than arteries. The aorta from spontaneously hypertensive rats was essentially similar in HxA3-C formation to aorta from local normotensive Wistar rats although the aorta from the normotensive Wistar Kyoto rats was much more active than aorta from either of the two other rat types. The biological activity of HxA3 and HxA3-C was investigated on isolated helicoidal strips of the rat aorta. While both compounds were inactive on their own, HxA3 and to a lesser extent HxA3-C potentiated the contractile response induced by norepinephrine. The present results provide evidence of the presence in rat aorta of a new pathway of arachidonic acid metabolism whose products may possess potential regulatory properties on vascular tissue.
The kallikrein-kinin system (KKS) contributes to vascular inflammation and neovascularization in ... more 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 ± ...
Saffron (Crocus sativus L.) is a medicinal plant, originally cultivated in the East and Middle Ea... more 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 a...
The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. T... more The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 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 athttp://onlinelibrary.wiley.com/doi/bph.15538. 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, cata...
δ‐opioid receptor (DOPr) agonists have analgesic efficacy in chronic pain models but development ... more 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 (...
This study investigated the role of kinins and their receptors in malignant brain tumors. As a fi... more This study investigated the role of kinins and their receptors in malignant brain tumors. As a first approach, GL-261 glioma cells were injected (2 × 10(5) cells in 2 μl/2 min) into the right striatum of adult C57/BL6 wild-type, kinin B1 and B2 receptor knockout (KOB1R and KOB2R) and B1 and B2 receptor double knockout mice (KOB1B2R). The animals received the selective B1R (SSR240612) and/or B2R (HOE-140) antagonists by intracerebroventricular (i.c.v.) route at 5, 10, and 15 days. The tumor size quantification, mitotic index, western blot analysis, quantitative autoradiography, immunofluorescence, and confocal microscopy were carried out in brain tumor samples, 20 days after tumor induction. Our results revealed an uncontrolled tumor growing in KOB1R or SSR240612-treated mice, which was blunted by B2R blockade with HOE-140, suggesting a crosstalk between B1R and B2R in tumor growing. Combined treatment with B1R and B2R antagonists normalized the upregulation of tumor B1R and decrease...
The mechanism by which kinin B1 receptor (B1R) contributes to type 1 diabetes is addressed by det... more 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 β-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 ...
Beneficial effects of argan oil on blood pressure, insulin resistance and oxidative stress in rat... more Beneficial effects of argan oil on blood pressure, insulin resistance and oxidative stress in rat Running head: Argan oil effects on insulin resistance and hypertension
The muscarinic and nicotinic transmissions in the primary visual cortex (V1) are involved in the ... more The muscarinic and nicotinic transmissions in the primary visual cortex (V1) are involved in the enhancement of specific visual stimuli as well as long-term modifications of the neuronal processing, in regards to perceptual learning. We investigated the involvement of the different cholinergic receptors subtypes underlying this long-term functional plasticity using RT-PCR and recording of visual evoked potentials (VEPs). Perceptual learning-like test was performed by exposing awaken rats to a visual stimulation (VS) - a sinusoidal grating (30°, 0.12cpd) - for 10min/day during 14days. This VS was provided alone or coupled to an electrical stimulation of the basal forebrain which sends cholinergic projections to V1 (HDB/VS) or paired with a cholinesterase inhibitor (donepezil, 1mg/kg injected 30min prior to visual exposure) to enhance cholinergic transmission in V1 (DONEP/VS). One week after the last training session, VEPs were recorded and the cortices encompassing V1 were collected to determine the expression level of mRNA of muscarinic (M1-5) and nicotinic (α/β) receptors sub-units by RT-PCR. VS coupled to pharmacological or electrical stimulation of the cholinergic system produced a significant enhancement of the cortical response, as shown by VEP recordings. Two weeks of VS treatment alone caused an increase of the expression of M3 and M5 mRNA suggesting an increase of their production and activity during long-term visual stimulation. In the HDB/VS group, α3 sub-unit was decreased suggesting its involvement in phasic cholinergic stimulation. The DONEP/VS treatment presented a decrease in the expression of M2, suggesting a down regulation of mRNA synthesis. This could indicate an increased cortico-cortical inhibition, as M2 receptors are located massively on the GABAergic neurons. Therefore, even with similar functional enhancement, the cholinergic receptors regulation differs between an electrical and a pharmacological treatment. These results are crucial for determining which receptors are the most involved in the pharmacological cholinergic stimulation to enhance visual perception. Meeting abstract presented at VSS 2015.
Using a rat lung slice model, this study compared the stress responses induced by cigarette whole... more Using a rat lung slice model, this study compared the stress responses induced by cigarette whole smoke (WS) to that induced by the vapor phase (VP) of the smoke. Following a 3-day exposure, lung slices exposed to 4, 10 and 20% WS retained 85, 42 and 16% relative survival respectively in comparison to the air-exposed ones. Consistently, histological observations revealed concentration-related alveolar damages in the lung slices. Expression of 5 stress-response genes was examined following a single 30 min exposure to 4% WS or VP. WS exposure resulted in 4, 11 and 50-fold induction of IL-1, kinin type I receptor (B 1 R) and CYP1A1 genes, respectively, while CYP1B1 and TNF-␣ genes expression was found only two times higher in comparison to VP group. Since cigarette WS consists of particulate and vapor phases, these results highlight the preferential or synergistic role of the particulate phase in the induction of IL-1, B 1 R and CYP1A1 genes and that VP did not have comparable effects on expression of these genes. However, both phases fairly contributed to the induction of CYP1B1 and TNF-␣ genes. VP was the fraction responsible for the toxic effect since WS did not produce further toxicity. The 4% whole smoke deposited about 7.1 g/cm 2 of total particulate matter (TPM) to the exposure chamber which may account for observed differential stress responses in the lung slices.
An autoradiographic study was conducted to determine whether kinin receptors are altered in the r... more An autoradiographic study was conducted to determine whether kinin receptors are altered in the rat spinal cord in two experimental models of chronic hyperglycemia and insulin resistance. Sprague-Dawley rats were given 10% d-glucose in their drinking water alone or with insulin (9 mU/kg/min with osmotic pumps) for 4 weeks. Both groups and control rats were treated either with a normal chow diet or with an alpha-lipoic acid-supplemented diet as antioxidant therapy. After 4 weeks of treatment, glycemia, insulinemia, blood pressure, insulin resistance index, the production of superoxide anion in the aorta and the density of B2 receptor binding sites in the dorsal horn were significantly increased in the two models. These effects were prevented or attenuated by alpha-lipoic acid. In contrast, B2 receptor binding sites of most spinal cord laminae were increased in the glucose group only and were not affected by alpha-lipoic acid. Results show that chronic hyperglycemia associated with insulin resistance increases B1 and B2 receptor binding sites in the rat spinal cord through distinct mechanisms, including the oxidative stress for the B1 receptor.
Diabetes Mellitus leads to pain neuropathy and cardiovascular complications which remain resistan... more Diabetes Mellitus leads to pain neuropathy and cardiovascular complications which remain resistant to current therapies involving the control of glycaemia. This study aims at defining the contribution of kinin B 1 receptor (B 1 R) and the oxidative stress on sensory abnormalities and arterial hypertension in a rat model of insulin resistance. Rats were fed with 10% D-glucose for a chronic period of 12-14 weeks and the impact of a diet supplemented with a-lipoic acid, a potent antioxidant, was determined on tactile and cold allodynia, arterial hypertension and the expression of kinin B 1 R (real-time PCR and autoradiography) in several tissues. Acute effects of brain penetrant (LF22-0542) and peripherally acting (R-715) B 1 R antagonists were also assessed. Glucose-fed rats exhibited tactile and cold allodynia along with increases in systolic blood pressure between 4 and 12 weeks; these alterations were alleviated by a-lipoic acid. The latter regimen also decreased significantly increased plasma levels of insulin and glucose and insulin resistance (HOMA index) at 14 weeks. B 1 R mRNA was virtually absent in liver, aorta, lung, kidney and spinal cord isolated from control rats, yet B 1 R mRNA was markedly increased in all tissues in glucose-fed rats. Up-regulated B 1 R mRNA and B 1 R binding sites (spinal cord) were significantly reduced by a-lipoic acid in glucose-fed rats. LF22-0542 reduced tactile and cold allodynia (3 h) and reversed arterial hypertension (3-48 h) in glucose-fed rats. R-715 abolished tactile and cold allodynia but had not effect on blood pressure. Data suggest that the oxidative stress contributes to the induction and up-regulation of B 1 R in the model of insulin resistance induced by glucose feeding. The over expressed B 1 R contributes centrally to arterial hypertension and in the periphery to sensory abnormalities.
Kinin B1 and B2 receptor (R) gene expression (mRNA) is increased in the sensory system after peri... more Kinin B1 and B2 receptor (R) gene expression (mRNA) is increased in the sensory system after peripheral nerve injury. This study measured the densities of B1R and B2R binding sites in the spinal cord and dorsal root ganglia (DRG) by quantitative autoradiography, and evaluated the effects of two selective non-peptide antagonists at B1R (LF22-0542) and B2R (LF16-0687) on pain behavior after partial ligation of the left sciatic nerve. Increases of B1R binding sites were seen in superficial laminae of the ipsi- and contralateral spinal cord at 2 and 14 days while B2R binding sites were increased on the ipsilateral side at 2 days and on both sides at 14 days. In DRG, B1R and B2R binding sites were significantly increased at 2 days (ipsilateral) and 14 days on both sides. Whereas tactile allodynia started to develop progressively from 2 to 25 days post-ligation, the occurrence of cold allodynia and thermal hyperalgesia became significant from day 8 and day 14 post-ligation, respectively. At day 21 after sciatic nerve ligation, thermal hyperalgesia was blocked by LF22-0542 (10 mg/kg, s.c.) and LF16-0687 (3 mg/kg, s.c.), yet both antagonists had no effect on tactile and cold allodynia. Data highlight the implication of both kinin receptors in thermal hyperalgesia but not in tactile and cold allodynia associated with peripheral nerve injury. Hence LF22-0542 and LF16-0687 present therapeutic potential for the treatment of some aspects of neuropathic pain.
Kinins are among the most potent autacoids involved in inflammatory, vascular and pain processes.... more Kinins are among the most potent autacoids involved in inflammatory, vascular and pain processes. These short-lived peptides, including bradykinin, kallidin and T-kinin, are generated during tissue injury and noxious stimulation. However, emerging evidence also suggests that kinins are stored in neuronal elements of the central nervous system (CNS) where they are thought to play a role as neuromediators in various cerebral functions, particularly in the control of nociceptive information. Kinins exert their biological effects through the activation of two transmembrane G-protein-coupled receptors, denoted bradykinin B(1) and B(2). Whereas the B(2) receptor is constitutive and activated by the parent molecules, the B(1) receptor is generally underexpressed in normal tissues and is activated by kinins deprived of the C-terminal Arg (des-Arg(9)-kinins). The induction and increased expression of B(1) receptor occur following tissue injury or after treatment with bacterial endotoxins or cytokines such as interleukin-1 beta and tumor necrosis factor-alpha. This review summarizes the most recent data from various animal models which convey support for a role of B(2) receptors in the acute phase of the inflammatory and pain response, and for a role of B(1) receptors in the chronic phase of the response. The B(1) receptor may exert a strategic role in inflammatory diseases with an immune component (diabetes, asthma, rheumatoid arthritis and multiple sclerosis). New information is provided regarding the role of sensory mechanisms subserving spinal hyperalgesia and intrapleural neutrophil migration that occur upon B(1) receptor activation in streptozotocin-treated rats, a model of insulin-dependent diabetes mellitus in which the B(1) receptor seems to be rapidly overexpressed. Although it is widely accepted that the blockade of kinin receptors with specific antagonists could be of benefit in the treatment of somatic and visceral inflammation and pain, recent molecular and functional evidence suggests that the activation of B(1) receptors with an agonist may afford a novel therapeutic approach in the CNS inflammatory demyelinating disorder encountered in multiple sclerosis by reducing immune cell infiltration (T-lymphocytes) into the brain. Hence, the B(1) receptor may exert either a protective or detrimental effect depending on the inflammatory disease. This dual function of the B(1) receptor deserves to be investigated further.
Kinins (bradykinin, kallidin and their active metabolites) are peptide autacoids with established... more Kinins (bradykinin, kallidin and their active metabolites) are peptide autacoids with established functions in cardiovascular homeostasis, contraction and relaxation of smooth muscles, inflammation and nociception. They are believed to play a role in disease states like asthma, allergies, rheumatoid arthritis, cancer, diabetes, endotoxic and pancreatic shock, and to contribute to the therapeutic effects of ACE inhibitors in cardiovascular diseases. Although kinins are also neuromediators in the central nervous system, their involvement in neurological diseases has not been intensively investigated thus far. This review analyzes the potential of central kinin receptors as therapeutic targets for neurological disorders. Initial data highlight potential roles for B 1 receptor antagonists as antiepileptic agents, and for B 2 receptor antagonists (and/or B 1 agonists) in the treatment of stroke. Functional B 1 receptors located on T-lymphocytes and on the blood brain-barrier are also putative targets for the management of multiple sclerosis. However, successful elucidation of the therapeutic value of these new pharmacological approaches will require refinement of our knowledge on the physiology and cellular localization of central kinin receptors.
Glucose-fed rat is a model of insulin resistance that displays sensory polyneuropathy and hyperte... more Glucose-fed rat is a model of insulin resistance that displays sensory polyneuropathy and hypertension. This study aimed at comparing the beneficial effects of N-Acetyl-L-Cysteine (NAC, antioxidant) and ramipril (angiotensin-1 converting enzyme inhibitor) on tactile and cold allodynia induced by chronic glucose feeding. Impact of these treatments was also assessed on hypertension, plasma glucose and insulin concentrations, insulin resistance and kinin B 1 receptor expression. Male Wistar rats (50-75 g) were given 10% D-glucose in their drinking water for 11 weeks or tap water (controls). Glucose-fed rats were treated either with NAC (1 g/kg/day, gavage), ramipril (1 mg/kg/day in drinking water) or no drug during the last 5 weeks. Glucose feeding for 6 weeks induced a significant increase in systolic blood pressure and hyperglycaemia which was accompanied by tactile and cold allodynia. At 11 weeks, plasma insulin, insulin resistance (HOMA index), kinin B 1 receptor mRNA in spinal cord and renal cortex and B 1 receptor binding sites in spinal cord were enhanced in glucose-fed rats. NAC and ramipril caused a progressive to complete inhibition of tactile and cold allodynia from 6 to 11 weeks. High systolic blood pressure, hyperinsulinemia, insulin resistance and kinin B 1 receptor expression were also normalized or attenuated in glucose-fed rats by either treatment. Results suggest that chronic treatment with an antioxidant or an ACE inhibitor provides similar beneficial effects on sensory polyneuropathy, hypertension and insulin resistance in glucose-fed rats. Both therapies were associated with a reduction of the expression of the pro-nociceptive kinin B 1 receptor.
The paratrigeminal nucleus (Pa5), an input site for spinal, trigeminal, vagus and glossopharyngea... more The paratrigeminal nucleus (Pa5), an input site for spinal, trigeminal, vagus and glossopharyngeal afferents, is a recognized site for orofacial nociceptive sensory processing. It has efferent connections to brain structures associated with nociception and cardiorespiratory functions. This study aimed at determining the function of the Pa5 on the cardiovascular component of the somatosensory reflex (SSR) to sciatic nerve stimulation (SNS) in paralyzed and artificially-ventilated rats following Pa5 chemical lesions (ibotenic acid), synaptic transmission blockade (CoCl 2), local anaesthetics (lidocaine) or desensitization of primary afferent fibers (capsaicin). The pressor response to sciatic nerve stimulation at 0.6 mA and 20 Hz (14 ± 1 mm Hg) was strongly attenuated by contra-(−80%) or bilateral (−50%) paratrigeminal nucleus lesions. Ipsilateral Pa5 lesions only attenuated the response to 0.1 mA, 20 Hz SNS (− 55%). Cobalt chloride or lidocaine injected in the contralateral paratrigeminal nucleus also attenuated the SSR. In capsaicin-treated animals, the pressor responses to 0.1 mA were abolished, whereas the responses to SNS at 0.6 mA were increased from 65 to 100% depending on the stimulus frequency. The paratrigeminal nucleus receives both, excitatory and inhibitory components; the later apparently involving capsaicin-sensitive fiber inputs mostly to the ipsilateral site whereas the capsaicin insensitive excitatory components that respond to high or low frequency stimulation, respectively, target the contralateral and ipsilateral sites. Thus, the paratrigeminal nucleus mediates excitatory and inhibitory components of the somatosensory reflex, representing a primary synapse site in the brain for nociceptive inputs from the sciatic innervation field.
Canadian Journal of Physiology and Pharmacology, 1980
In order to develop a sensitive pharmacological preparation which would allow the measurement of ... more In order to develop a sensitive pharmacological preparation which would allow the measurement of the inhibitory effects of kinins and substance P (SP) in vascular smooth muscles, several large arteries of the dog were studied in vitro. The common carotid artery was found to be one of the most sensitive preparations to SP and kinins. When contracted with low concentrations of noradrenaline (between 3.0 × 10−8 and 3.0 × 10−7 M), this artery responds to SP (6.5 × 10−11 − 6.5 × 10−9 M) and bradykinin (BK) (8.1 × 10−11 − 9.1 × 10−8 M) with relaxations that are proportional to the concentrations of the two peptides. SP and BK appear to exert their relaxant effects through the activation of specific receptors as the exposure of the common carotid artery to concentrations of [Leu8]-angiotensin II, propranolol, methysergide, cimetidine, or atropine sufficient to inhibit the effects of the corresponding agonists do not affect the relaxing effect of SP and BK. [Leu8]-des-Arg9-BK (1.0 × 10−s M)...
In this paper we describe the release of hepoxilin A3 (HxA3) by intact pieces of the rat thoracic... more In this paper we describe the release of hepoxilin A3 (HxA3) by intact pieces of the rat thoracic aorta and its stimulation by exogenous arachidonic acid but not by the calcium ionophore A23187. Homogenates of the rat aorta metabolize HxA3 via two competing pathways; one involves hepoxilin epoxide hydrolase to form the trihydroxy metabolite, trioxilin A3 (TrXA3), and a second pathway involves conjugation of HxA3 with glutathione via glutathione S-transferase to form a glutathione conjugate, which we refer to as hepoxilin A3-C (HxA3-C), a name based upon the accepted nomenclature for the glutathione conjugate leukotriene C. The formation of HxA3-C was dependent on the presence of reduced glutathione in the incubation medium. HxA3-C formation was greatly enhanced in the presence of TCPO, an epoxide hydrolase inhibitor which blocks utilization of the substrate via hepoxilin epoxide hydrolase. Comparison of HxA3-C formation by several arteries and veins indicated that glutathione conjugation was more evident in veins than arteries. The aorta from spontaneously hypertensive rats was essentially similar in HxA3-C formation to aorta from local normotensive Wistar rats although the aorta from the normotensive Wistar Kyoto rats was much more active than aorta from either of the two other rat types. The biological activity of HxA3 and HxA3-C was investigated on isolated helicoidal strips of the rat aorta. While both compounds were inactive on their own, HxA3 and to a lesser extent HxA3-C potentiated the contractile response induced by norepinephrine. The present results provide evidence of the presence in rat aorta of a new pathway of arachidonic acid metabolism whose products may possess potential regulatory properties on vascular tissue.
The kallikrein-kinin system (KKS) contributes to vascular inflammation and neovascularization in ... more 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 ± ...
Saffron (Crocus sativus L.) is a medicinal plant, originally cultivated in the East and Middle Ea... more 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 a...
The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. T... more The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 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 athttp://onlinelibrary.wiley.com/doi/bph.15538. 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, cata...
δ‐opioid receptor (DOPr) agonists have analgesic efficacy in chronic pain models but development ... more 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 (...
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