1: Front Biosci. 2007 Jan 1;12:1615-28.Links
Corticotropin-releasing hormone and the blood-brain-barrier.Theoharides TC, Konstantinidou AD.
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and Tufts-New England Medical Center, 136 Harrison Avenue, Boston, MA 02111, USA. firstname.lastname@example.org
Increased blood-brain-barrier (BBB) permeability precedes any clinical or pathologic signs and is critical in the pathogenesis of multiple sclerosis (MS) and brain metastases. CD4+ TH1 cells mediate demyelination in MS, but how they get sensitized and enter the brain to induce brain inflammation remains obscure. TH2 cytokines associated with allergic disorders have recently been implicated in MS, while genes upregulated in MS plaques include the mast cell-specific tryptase, the IgE receptor (Fc-epsilon-RI) and the histamine-1 receptor. Mast cell specific tryptase is elevated in the CSF of MS patients, induces microvascular leakage and stimulates protease-activated receptors (PAR), leading to widespread inflammation. BBB permeability, MS and brain metastases appear to worsen in response to acute stress that leads to the local release of corticotropin-releasing hormone (CRH), which activates brain mast cells to selectively release IL-6, IL-8 and vascular endothelial growth factor (VEGF). Acute stress increases BBB permeability that is dependent on CRH and mast cells. Acute stress shortens the time of onset of experimental alleric encephalomyelitis (EAE) that does not develop in W/W mast cell deficient or CRH -/- mice. Brain mast cell inhibition and CRHR antagonists offer novel therapeutic possibilities.
Is the blood brain barrier permeable owing to vasoconstriction in ms? This article suggests so:
1: Klin Oczna. 2007;109(7-9):317-20.Links
[Glaucoma neuropathy and neuropathy in multiple sclerosis--common elements of pathogenesis?][Article in Polish]
Jankowska-Lech I, Terelak-Borys B, Grabska-Liberek I, Palasik W.
Kliniki Okulistyki Centrum Medycznego Kształcenia Podyplomowego w Warszawie.
The optic neuropathy in multiple sclerosis and glaucoma neuropathy are very common ophthalmological diseases. Multiple sclerosis /MS/ is the chronic inflammatory central nervous system demyelinisation disease with an autoimmunological ethiology. The last investigation of multiple sclerosis indicate the molecular and cellular autoimmunisation aspects. Te role of vasoactive factors is underlines in its pathogenesis which also suggests the common elements of glaucoma and MS pathogenesis. The over expressed vasoconstrictive mechanisms in both diseases can conduct to optic nerve injury. The aim of this study is evaluation of the optic disc morphological changes in sclerosis multiplex patients /MS/ with or without neuritis optica in anamnesis in glaucoma "remodeling" aspects. MATERIAL AND METHODS: We present two patients with coexsist sclerosis multiplex and glaucoma neuropathy, which underwent retrobulbar neuritis. CONCLUSION: Coexistance of glaucoma neuropathy and multiple sclerosis neuropathy may indicate common elements of glaucoma and SM pathogenesis. The authors recommend precise morphological optic disc evaluation in multiple sclerosis patients because glaucoma neuropathy may appear.
PMID: 18260288 [PubMed - indexed for MEDLINE]
as does this article:
1: Eur Neurol. 2003;49(3):164-8. Links
Extraocular blood flow and endothelin-1 plasma levels in patients with multiple sclerosis.Pache M, Kaiser HJ, Akhalbedashvili N, Lienert C, Dubler B, Kappos L, Flammer J.
University Eye Clinic Basel, University Hospital Basel, Basel, Switzerland.
In order to evaluate whether plasma levels of the potent vasoconstrictor endothelin-1 (ET-1) are increased in patients with multiple sclerosis (MS) and whether these patients exhibit an ET-1-mediated vascular dysregulation, ET-1 plasma levels were measured in 30 patients with MS. Blood flow velocities in the ophthalmic artery, central retinal artery, central retinal vein, short lateral posterior ciliary artery, and short medial posterior ciliary artery were assessed in parallel. ET-1 plasma levels were significantly increased in MS patients when compared to sex- and age-matched healthy controls (2.0 +/- 0.4 pg/ml, range 1.1-2.8 vs. 1.5 +/- 0.2 pg/ml, range 0.9-2.0; p < 0.001). Moreover, the patients exhibited significant alterations of extraocular blood flow. The role of ET-1 in the inflammatory process remains to be clarified. Copyright 2003 S. Karger AG, Basel
as does this one:
1: Brain. 2002 Nov;125(Pt 11):2446-59. Links
TNF-alpha reduces cerebral blood volume and disrupts tissue homeostasis via an endothelin- and TNFR2-dependent pathway.Sibson NR, Blamire AM, Perry VH, Gauldie J, Styles P, Anthony DC.
MRC Biochemical and Clinical Magnetic Resonance Unit, Department of Biochemistry, University of Oxford, UK. email@example.com
TNF-alpha expression is elevated in a variety of neuropathologies, including multiple sclerosis, cerebral malaria and HIV encephalitis. However, the consequences of such high cerebral TNF-alpha expression remain unresolved. Here, using MRI, we demonstrate that a focal intrastriatal injection of TNF-alpha causes a significant, acute reduction (15-30%) in cerebral blood volume (CBV), which is dependent on TNF-alpha-type 2 receptor (TNFR2) activation, and can be ameliorated by pre-treatment with a non-specific endothelin (ET) receptor antagonist. An acute breakdown of the blood-cerebrospinal fluid barrier (B-CSF-B) and a delayed breakdown of the blood-brain barrier (BBB) were also observed using contrast-enhanced MRI. Furthermore, a significant reduction in tissue water diffusion was apparent 24 h after intrastriatal injection of TNF-alpha injection, which may indicate compromise of tissue energy metabolism. Prolonged expression of endogenous TNF-alpha, achieved through the use of an adenoviral vector expressing TNF-alpha cDNA (Ad5TNF-alpha(m)), caused a sustained depression in CBV in accordance with the single TNF-alpha bolus data. These findings identify vasoconstriction, disrupted tissue homeostasis and damage to the BBBs as adverse effects of TNF-alpha within the brain, and suggest that antagonists of the endothelin and TNF-alpha type 2 receptors may be therapeutic in TNF-alpha-associated neuropathologies.
PMID: 12390971 [PubMed - indexed for MEDLINE]
And certainly this one:
1: J Neuroophthalmol. 2001 Mar;21(1):37-8. Links
Increased endothelin-1 plasma levels in patients with multiple sclerosis.Haufschild T, Shaw SG, Kesselring J, Flammer J.
University Eye Clinic, Basel, Switzerland.
OBJECTIVE: We tested the hypothesis that the plasma level of endothelin-1 (ET-1) is increased in patients with multiple sclerosis (MS). The peptide ET-1 is one of the most potent known vasoconstrictors. An increased level of endothelin could explain some of the vascular symptoms of these patients. MATERIALS AND METHODS: A specific radioimmunoassay was used to determine ET-1 plasma levels. Twenty patients with MS were compared to 20 age- and sex-pair-matched healthy subjects. RESULTS: The plasma ET-1 levels were, on average, 224% higher in the patients with MS than in the controls (p < 0.005). The mean ET-1 levels (mean +/- standard deviation [SD]) were 3.5 +/- 0.83 pg/mL (min 2.13, max 5.37 pg/mL) in patients with MS and 1.56 +/- 0.3 pg/mL (min 0.9, max 2.13 pg/mL) in healthy volunteers. Neither the different forms nor stages of MS had an influence on the results. The ET-1 level was also not correlated with the duration of the disease. CONCLUSIONS: The plasma ET-1 level is markedly and significantly increased in patients with MS. Neither the cause of such an increase nor the pathogenetic role is known.
PMID: 11315981 [PubMed - indexed for MEDLINE]
but this article suggests that vasodilation is the problem!
1: J Magn Reson Imaging. 2000 May;11(5):495-505. Links
Dynamic susceptibility contrast MR imaging of plaque development in multiple sclerosis: application of an extended blood-brain barrier leakage correction.Haselhorst R, Kappos L, Bilecen D, Scheffler K, Möri D, Radü EW, Seelig J.
Biocenter and MR Center of the University, CH-4056 Basel, Switzerland.
Since the pathogenesis of multiple sclerosis (MS) lesions is not yet fully understood, we investigated the potential of dynamic susceptibility contrast (DSC) magnetic resonance (MR) perfusion imaging for a better characterization of lesion pathology. Twenty-five MS patients were examined on a 1.5 T scanner. A single dose of gadolinium (Gd)-DOTA contrast agent was injected, and echoplanar images were acquired every 0.5 seconds for 1 minute. From the signal intensity-versus-time curves, the relative cerebral blood volume (rCBV) was evaluated for regions in plaques and in gray and white matter. The rCBV calculated for acute, Gd-enhancing plaques was corrected for the effects of blood-brain barrier leakage, using a new correction algorithm. Acute plaques had significantly higher blood volumes than normal-appearing white matter (P < = 0.01). Chronic plaques that appeared hypointense on T(1)-weighted images had lower rCBV than T(1)-isointense plaques (P < = 0.03). Our results indicate that the acute phase in MS is accompanied by vasodilation. In later stages of gliosis, the perfusion decreases with increasing axonal injury. Although the DSC technique is less sensitive than conventional MR imaging, the information provided is essentially different from that obtained with any other MR method.
I guess the only way to find out which herbs to take is to experiment. Horsechestnut seems to be vasoconstrictive:
1: Pharmacol Res. 2001 Sep;44(3):183-93. Links
Aescin: pharmacology, pharmacokinetics and therapeutic profile.Sirtori CR.
Department of Pharmacological Sciences, University of Milano, Via Balzaretti 9, 20133 Milano, Italy. firstname.lastname@example.org
Aescin, the major active principle from Aesculus hippocastanum (Hippocastanaceae) the horse chestnut tree, has shown satisfactory evidence for a clinically significant activity in chronic venous insufficiency (CVI), haemorrhoids and post-operative oedema. In one controlled trial aescin was shown to be as effective as compression therapy as an alternative to medical treatment for CVI. The therapeutic benefit is well supported by a number of experimental investigations in different animal models, indicative of clearcut anti-oedematous, anti-inflammatory and venotonic properties, mainly related to the molecular mechanism of the agent, allowing improved entry of ions into channels, thus raising venous tension in both in vitro and in vivo conditions. Other mechanisms, i.e. release of PGF(2) from veins, antagonism to 5-HT and histamine, reduced catabolism of tissue mucopolysaccharides, further underline the wide ranging mechanisms of the therapeutic activity of aescin. The excellent tolerability of aescin in the clinic indicates this treatment is of definite clinical benefit in patients with clinical conditions resulting in CVI, haemorrhoids or peripheral oedema formation. Copyright 2001 Academic Press.
1: Altern Med Rev. 2001 Apr;6(2):126-40. Links
Hemorrhoids and varicose veins: a review of treatment options.MacKay D.
Thorne Research, 4616 SE 30th, Portland, OR 97202, USA. email@example.com
Hemorrhoids and varicose veins are common conditions seen by general practitioners. Both conditions have several treatment modalities for the physician to choose from. Varicose veins are treated with mechanical compression stockings. There are several over-the-counter topical agents available for hemorrhoids. Conservative therapies for both conditions include diet, lifestyle changes, and hydrotherapy which require a high degree of patient compliance to be effective. When conservative hemorrhoid therapy is ineffective, many physicians may choose other non-surgical modalities: injection sclerotherapy, cryotherapy, manual dilation of the anus, infrared photocoagulation, bipolar diathermy, direct current electrocoagulation, or rubber band ligation. Injection sclerotherapy is the non-surgical treatment for primary varicose veins. Non-surgical modalities require physicians to be specially trained, own specialized equipment, and assume associated risks. If a non-surgical approach fails, the patient is often referred to a surgeon. The costly and uncomfortable nature of treatment options often lead a patient to postpone evaluation until aggressive intervention is necessary. Oral dietary supplementation is an attractive addition to the traditional treatment of hemorrhoids and varicose veins. The loss of vascular integrity is associated with the pathogenesis of both hemorrhoids and varicose veins. Several botanical extracts have been shown to improve microcirculation, capillary flow, and vascular tone, and to strengthen the connective tissue of the perivascular amorphous substrate. Oral supplementation with Aesculus hippocastanum, Ruscus aculeatus, Centella asiatica, Hamamelis virginiana, and bioflavonoids may prevent time-consuming, painful, and expensive complications of varicose veins and hemorrhoids.
PMID: 11302778 [PubMed - indexed for MEDLINE]
1: Acta Pharmacol Sin. 2004 Jul;25(7):869-75.Links
Effects of sodium beta-aescin on expression of adhesion molecules and migration of neutrophils after middle cerebral artery occlusion in rats.Hu XM, Zhang Y, Zeng FD.
Institute of Clinical Pharmacology, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, China.
AIM: To investigate the effects of sodium beta-aescin on neutrophil migration and expression of adhesion molecules (ICAM-1 and E-selectin) after middle cerebral artery occlusion (MCAO) in rats. METHODS: Rats were pretreated with sodium beta-aescin for 7 d and then subjected to cerebral ischemia/reperfusion (I/R) injury induced by an MCAO. After a 2-h ischemia and a 24-h reperfusion, the infarct volume and neurological deficit were determined by the method of TTC staining and the Longa's score. The effect of sodium beta-aescin on the migration of neutrophils was evaluated by measuring the activity of myeloperoxidase (MPO) enzyme. The expressions of adhesion molecules were determined by immunohistochemistry and Western blot. RESULTS: Sodium beta-aescin significantly reduced the cerebral infarct volume and ameliorated the neurological deficit (P<0.05 or P<0.01). The MPO activity and the expressions of ICAM-1 and E-selectin in the vehicle-treated rats were increased significantly (P<0.01) after cerebral I/R. After treatment with sodium beta-aescin, the enzymatic activity of MPO and the expressions of these adhesion molecules were significantly reduced compared with the vehicle-treated group (P<0.05 or P<0.01). CONCLUSION: Sodium beta-aescin can attenuate brain injury, down-regulate the protein expressions of ICAM-1 and E-selectin, and reduce the migration of neutrophils after cerebral I/R.
I'm going to look into ICAM-1 later
1: Vascul Pharmacol. 2007 Jul;47(1):68-73. Epub 2007 Apr 21. Links
Endothelium protectant and contractile effects of the antivaricose principle escin in rat aorta.Carrasco OF, Vidrio H.
Department of Pharmacology School of Medicine, Universidad Nacional Autónoma de México, Apartado Postal 70297, 04510 Mexico, D.F. Mexico.
The triterpene saponin escin is the active component of the extract of seeds of Aesculus hippocastanum used in the treatment of chronic venous insufficiency. Escin is also used experimentally to increase membrane permeability in isolated cells. Since endothelial dysfunction is postulated to be involved in venous insufficiency, the possible endothelium-protectant effect of escin was explored in rat aortic rings, a model widely used to study such effects with cardiovascular agents. Escin enhanced endothelium-dependent relaxation induced by acetylcholine when such relaxation had been reduced by exposure to the superoxide ion generator pyrogallol. This effect was attributed to enhanced nitric oxide production by endothelial nitric oxide synthase, a calcium-dependent enzyme, activated by the increased endothelial cell permeability to calcium induced by escin. Another effect of escin thought to contribute to its therapeutic activity is its ability to produce venous contraction. The compound was found to induce concentration-related contraction also in rat aortic rings. This response was partially inhibited by removal of the endothelium or by preincubation with indomethacin, and was completely abolished by incubation in a calcium-free perfusion fluid. Contraction was considered to be due mainly to the aforementioned effect on calcium permeability, with some mediation by release of endothelial vasoconstrictor prostanoids. It was concluded that, in rat aorta, escin possesses an endothelium-protectant action and a direct contractile effect. The former could contribute to its beneficial effect in the treatment of venous insufficiency, while the latter could constitute a limiting side effect.
PMID: 17512261 [PubMed - indexed for MEDLINE
1: Planta Med. 2007 Mar;73(3):285-8. Epub 2007 Feb 19.Links
Aescin protection of human vascular endothelial cells exposed to cobalt chloride mimicked hypoxia and inflammatory stimuli.Montopoli M, Froldi G, Comelli MC, Prosdocimi M, Caparrotta L.
Department of Pharmacology and Anaestesiology, University of Padova, Padova, Italy.
Human vascular endothelial cells (HUVECs) were exposed to CoCl2 as an in vitro model of hypoxia. Expression of VCAM-1 (vascular cell adhesion molecule), reduction of PECAM-1 (platelet endothelial cell adhesion molecule) and cytoskeletal changes without alterations in cell viability were observed. HUVECs were also exposed to Escherichia coli lipopolysaccaride (LPS) as an in vitro model of inflammation: significant IL-6 release was measured. Pre-treatment of HUVECs with aescin prevented, in a concentration-dependent fashion (0.1-1 microM), the action of CoCl2 on VCAM-1 and PECAM-1, also preserving endothelial cell morphology. Furthermore, aescin pre-treatment reduced IL-6 release from LPS-activated vascular endothelium.
PMID: 17310430 [PubMed - indexed for MEDLINE]
and butterbur appears to be vasodilatory:
1: Eur J Pharmacol. 2008 Sep 28;593(1-3):79-86. Epub 2008 Jul 10. Links
S-petasin and butterbur lactones dilate vessels through blockage of voltage gated calcium channels and block DNA synthesis.Sheykhzade M, Smajilovic S, Issa A, Haunso S, Christensen SB, Tfelt-Hansen J.
Department of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark.
Eremophilanlactones isolated from roots of Petasites hybridus (L.) G.M. et Sch. (Asteraceae) and S-petasin have vasodilatory effects with pD(2) -log (EC(50)) values of 6.01+/-0.08, 5.24+/-0.10, 4.74+/-0.13, and 5.43+/-0.06 for S-petasin, the (Z)-3-methylthioacrylic ester of 2beta-hydroxy-8betaH-7(11)-eremophilene-12,8-olide, the angelic ester of 2beta-hydroxy-8alphaH-7(11)-eremophilene-12,8-olide, and the angelic ester of 2beta-hydroxy-8betaH-7(11)-eremophilene-12,8-olide, respectively, in the mesenteric arteries. The pD(2) values were somewhat lower for all compounds in aortic segments. The vasodilation was caused by a blockage of the voltage gated calcium channels. S-petasin, (Z)-3-methylthioacrylic ester of 2beta-hydroxy-8betaH-7(11)-eremophilene-12,8-olide, and the angelic ester of 2beta-hydroxy-8alphaH-7(11)-eremophilene-12,8-olide displayed similar potencies in inhibiting DNA synthesis in cardiomyocytes and vascular smooth muscle cells.
PMID: 18655785 [PubMed - in process]
and berberine seems vasodilatory and overcomes the transient vasoconstriction of coffee:
1: Eur J Pharmacol. 2000 Jul 7;399(2-3):187-96. Links
Vasorelaxant and antiproliferative effects of berberine.Ko WH, Yao XQ, Lau CW, Law WI, Chen ZY, Kwok W, Ho K, Huang Y.
Department of Physiology, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong, People's Republic of China.
The present study was intended to examine the relaxant effects of berberine in rat isolated mesenteric arteries. Berberine produced a rightward shift of the concentration-response curve to phenylephrine and significantly reduced the maximal contractile response to phenylephrine. Berberine (10(-7)-3x10(-5) M) also relaxed the phenylephrine- and 9,11-dideoxy-11alpha, 9alpha-epoxy-methanoprostaglandin F(2alpha)-precontracted arteries with respective IC(50) values of 1.48+/-0.16x10(-6) and 2.23+/-0. 22x10(-6) M. Removal of a functional endothelium significantly attenuated the berberine-induced relaxation (IC(50): 4.73+/-0. 32x10(-6) M) without affecting the maximum relaxant response. Pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME) or methylene blue reduced the relaxant effect of berberine, and L-arginine (10(-3) M) partially antagonized the effect of L-NAME. In contrast, pretreatment with 10(-6) M glibenclamide or 10(-5) M indomethacin had no effect. Berberine (10(-5) M) reduced over by 50% the transient contraction induced by caffeine or phenylephrine in endothelium-denuded rings bathed in Ca(2+)-free Krebs solution. Pretreatment with putative K(+) channel blockers, such as tetrapentylammonium ions (1-3x10(-6) M), 4-aminopyridine (10(-3) M), or Ba(2+) (3x10(-4) M), significantly attenuated the berberine-induced relaxation in endothelium-denuded arteries. In contrast, tetraethylammonium ions (3x10(-3) M), charybdotoxin (10(-7) M) or glibenclamide (10(-6) M) were without effect. Berberine reduced the high-K(+)-induced sustained contraction and the relaxant response to berberine was greater in rings with endothelium (IC(50): 4.41+/-0.47x10(-6) M) than in those without endothelium (IC(50): 8.73+/-0.74x10(-6) M). However, berberine (10(-6)-10(-4) M) did not affect the high-K(+)-induced increase of intracellular [Ca(2+)] in cultured aortic smooth muscle cells. Berberine did not affect active phorbol ester-induced contraction in Ca(2+)-free Krebs solution. In addition, berberine inhibited proliferation of cultured rat aortic smooth muscle cells with an IC(50) of 2.3+/-0.43x10(-5) M. These findings suggest that berberine could act at both endothelium and the underlying vascular smooth muscle to induce relaxation. Nitric oxide from endothelium may account primarily for the berberine-induced endothelium-dependent relaxation, while activation of tetrapentylammonium-, 4-aminopyridine- and Ba(2+)-sensitive K(+) channels, inhibition of intracellular Ca(2+) release from caffeine-sensitive pools, or a direct relaxant effect, is likely responsible for the berberine-induced endothelium-independent relaxation. Mechanisms related to either Ca(2+) influx or protein kinase C activation may not be involved. Both vasorelaxant and antiproliferative effects may contribute to a long-term benefit of berberine in the vascular system.
PMID: 10884519 [PubMed - indexed for MEDLINE
My hunch is that people with MS generally have vasoconstriction but during relapse the endothelial suffers from a sort of burst dam effect. I'm going to start with the vasodilators.
3 years antibiotics, 06/09 bilateral jug stents at C1, 05/11 ballooning of both jug valves, 07/12 stenting of renal vein, azygos & jug valve ballooning,