| 61. |
- Christensen, Simon T., et al.
(författare)
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MEK1/2 inhibitor U0126, but not nimodipine, reduces upregulation of cerebrovascular contractile receptors after subarachnoid haemorrhage in rats
- 2019
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 14:4
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Tidskriftsartikel (refereegranskat)abstract
- Vascular pathophysiological changes after haemorrhagic stroke, such as phenotypic modulation of the cerebral arteries and cerebral vasospasms, are associated with delayed cerebral ischemia (DCI) and poor outcome. The only currently approved drug treatment shown to reduce the risk of DCI and improve neurologic outcome after aneurysmal subarachnoid haemorrhage (SAH) is nimodipine, a dihydropyridine L-type voltage-gated Ca 2+ channel blocker. MEK1/2 mediated transcriptional upregulation of contractile receptors, including endothelin-1 (ET-1) receptors, has previously been shown to be a factor in the pathology of SAH. The aim of the study was to compare intrathecal and subcutaneous treatment regimens of nimodipine and intrathecal treatment regimens of U0126, a MEK1/2 inhibitor, in a single injection experimental rat SAH model with post 48 h endpoints consisting of wire myography of cerebral arteries, flow cytometry of cerebral arterial tissue and behavioural evaluation. Following ET-1 concentration-response curves, U0126 exposed arteries had a significantly lower ET-1 max than vehicle arteries. Arteries from both the intrathecal- and subcutaneous nimodipine treated animals had significantly higher ET-1 max contractions than the U0126 arteries. Furthermore, Ca 2+ concentration response curves (precontracted with ET-1 and in the presence of nimodipine) showed that nimodipine treatment could result in larger nimodipine insensitive contractions compared to U0126. Flow cytometry showed decreased protein expression of the ET B receptor in U0126 treated cerebral vascular smooth muscle cells compared to vehicle. Only U0126 treatment lowered ET-1 max contractions and ET B receptor levels, as well as decreased the contractions involving nimodipine-insensitive Ca 2+ channels, when compared to both intrathecal and subcutaneous nimodipine treatment. This indicate that targeting gene expression might be a better strategy than blocking specific receptors or ion channels in future treatments of SAH.
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| 62. |
- Christensen, Simon T., et al.
(författare)
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Pre-clinical effects of highly potent MEK1/2 inhibitors on rat cerebral vasculature after organ culture and subarachnoid haemorrhage
- 2019
-
Ingår i: Clinical Science. - 0143-5221. ; 133:16, s. 1797-1811
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Tidskriftsartikel (refereegranskat)abstract
- Background: Aneurysmal subarachnoid haemorrhage (SAH) is a variant of haemorrhagic stroke with a striking 50% mortality rate. In addition to the initial insult, secondary delayed brain injury may occur days after the initial ischemic insult and is associated with vasospasms leading to delayed cerebral ischemia. We have previously shown that the MEK1/2 inhibitor U0126 improves neurological assessment after SAH in rats. Aim: The purpose of the present study was to analyse the impact of a broad selection of high potency MEK1/2 inhibitors in an organ culture model and use the IC50 values obtained from the organ culture to select highly potent inhibitors for pre-clinical in vivo studies. Results: Nine highly potent mitogen activated protein kinase kinase (MEK1/2) inhibitors were screened and the two most potent inhibitors from the organ culture screening, trametinib and PD0325901, were tested in an in vivo experimental rat SAH model with intrathecal injections. Subsequently, the successful inhibitor trametinib was administered intraperitoneally in a second in vivo study. In both regimens, trametinib treatment caused significant reductions in the endothelin-1 induced contractility after SAH, which is believed to be associated with endothelin B receptor up-regulation. Trametinib treated rats showed improved neurological scores, evaluated by the ability to traverse a rotating pole, after induced SAH. Conclusion: The PD0325901 treatment did not improve the neurological score after SAH, nor showed any beneficial therapeutic effect on the contractility, contrasting with the reduction in neurological deficits seen after trametinib treatment. These data show that trametinib might be a potential candidate for treatment of SAH.
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| 63. |
- Christiansen, Isabella Mai, et al.
(författare)
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Dual action of the cannabinoid receptor 1 ligand arachidonyl-2′-chloroethylamide on calcitonin gene-related peptide release
- 2022
-
Ingår i: Journal of Headache and Pain. - : Springer Science and Business Media LLC. - 1129-2369 .- 1129-2377. ; 23
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Tidskriftsartikel (refereegranskat)abstract
- Background: Based on the current understanding of the role of neuropeptide signalling in migraine, we explored the therapeutic potential of a specific cannabinoid agonist. The aim of the present study was to examine the effect of the synthetic endocannabinoid (eCB) analogue, arachidonyl-2′-chloroethylamide (ACEA), on calcitonin gene-related peptide (CGRP) release in the dura and trigeminal ganglion (TG), as cannabinoids are known to activate Gi/o-coupled cannabinoid receptors type 1 (CB1), resulting in neuronal inhibition. Methods: The experiments were performed using the hemi-skull model and dissected TGs from male Sprague-Dawley rats. CGRP release was induced by either 60 mM K+ (for depolarization-induced stimulation) or 100 nM capsaicin (for transient receptor potential vanilloid 1 (TRPV1) -induced stimulation) and measured using an enzyme-linked immunosorbent assay. The analysis of CGRP release data was combined with immunohistochemistry in order to study the cellular localization of CB1, cannabinoid receptor type 2 (CB2), CGRP and receptor activity modifying protein 1 (RAMP1), a subunit of the functional CGRP receptor, in the TG. Results: CB1 was predominantly expressed in neuronal somas in which colocalization with CGRP was observed. Furthermore, CB1 exhibited colocalization with RAMP1 in neuronal Aδ-fibres but was not clearly expressed in the CGRP-immunoreactive C-fibres. CB2 was mainly expressed in satellite glial cells and did not show substantial colocalization with either CGRP or RAMP1. Without stimulation, 140 nM ACEA per se caused a significant increase in CGRP release in the dura but not TG, compared to vehicle. Furthermore, 140 nM ACEA did not significantly modify neither K+- nor capsaicin-induced CGRP release. However, when the TRPV1 blocker AMG9810 (1 mM) was coapplied with ACEA, K+-induced CGRP release was significantly attenuated in the TG and dura. Conclusions: Results from the present study indicate that ACEA per se does not exhibit antimigraine potential due to its dual agonistic properties, resulting in activation of both CB1 and TRPV1, and thereby inhibition and stimulation of CGRP release, respectively.
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| 64. |
- Csati, Anett, et al.
(författare)
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Calcitonin gene-related peptide and its receptor components in the human sphenopalatine ganglion - Interaction with the sensory system.
- 2012
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Ingår i: Brain Research. - : Elsevier BV. - 1872-6240 .- 0006-8993. ; 1435, s. 29-39
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Tidskriftsartikel (refereegranskat)abstract
- Clinical studies have suggested a link between the sensory trigeminal system and the parasympathetic ganglia. Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide which plays an important role in vasodilatation and pain transmission in craniocervical structures. The present study was designed to examine if CGRP and CGRP receptor components are present in the human sphenopalatine ganglion (SPG) in order to reveal an interaction between the sensory and parasympathetic systems. Indirect immunofluorescence technique was used for immunohistochemical demonstration of CGRP, the calcitonin receptor-like receptor (CLR) and the receptor activity modifying protein 1 (RAMP1) in human and rat SPG. Cryostat sections were examined and images were obtained using a light- and epifluorescence microscope coupled to a camera to visualize co-labeling by superimposing the digital images. In addition, Western blot technique was used to demonstrate the existence of CGRP receptor components in rat SPG. CGRP immunoreactive fibers were frequently found intraganglionic in the SPG in the vicinity of neurons. CLR immunoreactivity was observed in satellite glial cells (SGCs) as well as in nerve fibers, but not in neurons. RAMP1 immunoreactivity was localized in many neurons and SGCs. Thus, the two CGRP receptor components together were found in the SGCs. In addition, Western blot revealed the presence of RAMP1 and CLR in rat SPG. Our results suggest a possible sensory influence in the parasympathetic cranial ganglia. The sensory CGRP-containing fibers probably originate in the trigeminal ganglion, project to the SPG and act on CGRP receptors on SGCs.
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| 65. |
- Csati, A, et al.
(författare)
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Distribution of vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide, nitric oxide synthase, and their receptors in human and rat sphenopalatine ganglion.
- 2012
-
Ingår i: Neuroscience. - : Elsevier BV. - 1873-7544 .- 0306-4522. ; 202, s. 158-168
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Tidskriftsartikel (refereegranskat)abstract
- Cranial parasympathetic outflow is mediated through the sphenopalatine ganglion (SPG). The present study was performed to examine the expression of the parasympathetic signaling transmitters and their receptors in human and rat SPG. Indirect immunofluorescence technique was used for the demonstration of vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating peptide (PACAP), nitric oxide synthase (NOS), glutamine synthetase (GS), glial fibrillary acidic protein (GFAP), VIP and PACAP common receptors (VPAC1, VPAC2), and PACAP receptor (PAC1). In addition, double labeling was carried out to reveal the co-localization of neurotransmitters. VIP-immunoreactive (-ir) neurons as well as fibers were frequently found in human SPG. Many, homogenously stained NOS-ir cells were found, but no positive fibers. In addition, PACAP-ir was observed in some of the neurons and in fibers. Co-localization was found between VIP and NOS. In rat VIP-, NOS-, and PACAP-ir were found in many neurons and fibers. Co-localization of PACAP and NOS was observed in neurons. PACAP and GS double staining revealed that the PACAP-ir was localized in/close to the cell membrane, but not in the satellite glial cells. PAC1 and VPAC1 immunoreactivity was found in the satellite glial cells of both human and rat. Western blot revealed protein expression of PAC1, VPAC1, and VPAC2 in rat SPG. The trigeminal-autonomic reflex may be active in migraine attacks. We hypothesized that VIP, PACAP, NOS, PAC1, VPAC1, and VPAC2 play a role in the activation of parasympathetic cranial outflow during migraine attacks.
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| 66. |
- Csáti, A, et al.
(författare)
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Kynurenic acid modulates experimentally induced inflammation in the trigeminal ganglion.
- 2015
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Ingår i: Journal of Headache and Pain. - : Springer Science and Business Media LLC. - 1129-2369 .- 1129-2377. ; 16:99
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Tidskriftsartikel (refereegranskat)abstract
- The trigeminal ganglion (TG) plays a central role in cranial pain. Administration of complete Freund's adjuvant (CFA) into the temporomandibular joint (TMJ) elicits activation of TG. Kynurenic acid (KYNA) is an endogenous excitatory amino acid receptor blocker, which may have an anti-inflammatory effect. We hypothesize that KYNA may reduce CFA-induced activation within the TG.
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| 67. |
- Deen, Marie, et al.
(författare)
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Blocking CGRP in migraine patients – a review of pros and cons
- 2017
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Ingår i: Journal of Headache and Pain. - : Springer Science and Business Media LLC. - 1129-2369 .- 1129-2377. ; 18, s. 1-9
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Forskningsöversikt (refereegranskat)abstract
- Migraine is the most prevalent neurological disorder worldwide and it has immense socioeconomic impact. Currently, preventative treatment options for migraine include drugs developed for diseases other than migraine such as hypertension, depression and epilepsy. During the last decade, however, blocking calcitonin gene-related peptide (CGRP) has emerged as a possible mechanism for prevention of migraine attacks. CGRP has been shown to be released during migraine attacks and it may play a causative role in induction of migraine attacks. Here, we review the pros and cons of blocking CGRP in migraine patients. To date, two different classes of drugs blocking CGRP have been developed: small molecule CGRP receptor antagonists (gepants), and monoclonal antibodies, targeting either CGRP or the CGRP receptor. Several trials have been conducted to test the efficacy and safety of these drugs. In general, a superior efficacy compared to placebo has been shown, especially with regards to the antibodies. In addition, the efficacy is in line with other currently used prophylactic treatments. The drugs have also been well tolerated, except for some of the gepants, which induced a transient increase in transaminases. Thus, blocking CGRP in migraine patients is seemingly both efficient and well tolerated. However, CGRP and its receptor are abundantly present in both the vasculature, and in the peripheral and central nervous system, and are involved in several physiological processes. Therefore, blocking CGRP may pose a risk in subjects with comorbidities such as cardiovascular diseases. In addition, long-term effects are still unknown. Evidence from animal studies suggests that blocking CGRP may induce constipation, affect the homeostatic functions of the pituitary hormones or attenuate wound healing. However, these effects have so far not been reported in human studies. In conclusion, this review suggests that, based on current knowledge, the pros of blocking CGRP in migraine patients exceeds the cons.
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| 68. |
- Dimitrijevic, Ivan, et al.
(författare)
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Increased angiotensin II type 1 receptor expression in temporal arteries from patients with giant cell arteritis.
- 2009
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Ingår i: Ophthalmology. - : Elsevier BV. - 1549-4713 .- 0161-6420. ; 116:5, s. 990-996
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Currently, giant cell arteritis (GCA) is primarily treated with corticosteroids or immunomodulating agents, but there is interest in identifying other noncorticosteroid alternatives. Similarities exist in the injury pathways between GCA and atherosclerosis. Angiotensin II is a vasoactive peptide involved in vessel inflammation during atherosclerosis, and angiotensin II receptor inhibitors are effective in preventing atherosclerosis. The present study was performed to elucidate the role of angiotensin type 1 (AT(1)) and type 2 (AT(2)) receptors in GCA. DESIGN: Experimental retrospective immunohistochemical study of temporal arteries using archival formalin-fixed, paraffin-embedded tissue. PARTICIPANTS: Ten patients with GCA and 10 control patients, who were clinically suspected of having GCA but were diagnosed as not having GCA, were included. METHODS: Immunohistochemistry, using anti-AT(1) and anti-AT(2) antibodies, was performed on formalin-fixed and paraffin-embedded temporal arteries. MAIN OUTCOME MEASURES: AT(1) and AT(2) receptor immunostaining intensity was quantified. RESULTS: Hematoxylin-eosin-stained sections of temporal arteries from patients with GCA showed intimal hyperplasia, internal elastic lamina degeneration, and band-shaped infiltrates of inflammatory cells, including lymphocytes, histocytes, and multinucleated giant cells. AT(1) receptor staining was primarily observed in the medial layer of the temporal arteries and was higher in the patients with GCA than in the control patients. This was a result of increased AT(1) receptor immunostaining of both vascular smooth muscle cells and infiltrating inflammatory cells. Only faint immunostaining was seen for AT(2) receptors, primarily in the endothelial cells, and to a lesser extent on the smooth muscle cells. Immunostaining with antibodies for the AT(2) receptor was similar in the patients with GCA and in controls. CONCLUSIONS: These results suggest that AT(1) receptors play a role in the development of GCA. Inhibition of the angiotensin system may thus provide a noncorticosteroid alternative for the treatment of GCA. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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| 69. |
- Dimitrijevic, Ivan, et al.
(författare)
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Increased endothelin 1 type B receptors in nasal lesions of patients with granulomatosis with polyangiitis.
- 2013
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Ingår i: American Journal of Rhinology & Allergy. - : SAGE Publications. - 1945-8924 .- 1945-8932. ; 27:6, s. 444-450
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Tidskriftsartikel (refereegranskat)abstract
- Endothelin 1 (ET-1) is a locally produced vasoactive peptide with proinflammatory capabilities. Systemic levels of ET-1 seem elevated in granulomatosis with polyangiitis (GPA). The aim of this study was to examine the involvement of the endothelin system in patients with GPA using nasal mucosal biopsies.
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| 70. |
- Dimitrijevic, Ivan, et al.
(författare)
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Increased expression of endothelin ETB and angiotensin AT(1) receptors in peripheral resistance arteries of patients with suspected acute coronary syndrome
- 2009
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Ingår i: Heart and Vessels. - : Springer Science and Business Media LLC. - 1615-2573 .- 0910-8327. ; 24:6, s. 393-398
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Tidskriftsartikel (refereegranskat)abstract
- Patients who experience chest pain, in which ischemic heart disease has been ruled out, still have an increased risk of future ischemic cardiac events and premature death, possibly due to subclinical endothelial dysfunction. A feature of endothelial dysfunction is an increased expression of arterial vasoconstrictor endothelin (ET) and angiotensin (AT) receptors. Our aim was to investigate if the arterial expressions of these receptors are changed in patients with suspected but ruled out acute coronary syndrome (ACS). Small subcutaneous arteries (diameter of 100 A mu m) were surgically removed in an abdominal biopsy from 12 patients suspicious of ACS (susp ACS), admitted to the medical telemetry unit for chest pain. The vessels were analyzed for their receptor protein expression by quantitative immunohistochemistry using specific antibodies directed against ETA, ETB, AT(1), and AT(2) receptors. The control group (controls) consisted of eight healthy volunteers matched for age and sex with no previous cardiac illness or medication. The susp ACS group had an increased expression of ETB (by 94%) and AT(1) (by 34%) receptors in the smooth muscle cells of resistance arteries as compared to the control group. There were no significant differences in AT(2) and ETA receptor expression between the groups. The results indicate that the expression of arterial smooth muscle ETB and AT(1) receptors are increased in patients with suspected but ruled out ACS. These receptor changes could be important in the regulation of coronary tone and in the development of atherosclerosis, and may be related to increased cardiovascular risk.
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