I'm hunting around for causes and solutions to tight junction failure. This is a report about the noradrenaline pathway:
1: Eur J Neurosci. 2006 Dec;24(12):3393-400. Links
Degeneration of noradrenergic fibres from the locus coeruleus causes tight-junction disorganisation in the rat brain.Kalinin S, Feinstein DL, Xu HL, Huesa G, Pelligrino DA, Galea E.
Department of Anaesthesiology, University of Illinois at Chicago, Illinois, USA.
Although functional studies demonstrate that noradrenaline controls the permeability of the blood-brain barrier, it has never been determined whether this neurotransmitter regulates the tight junction (TJ) assembly that confers the barrier property to brain microvessels. We thus tested in rats the effect of pharmacological depletion of noradrenaline with the noradrenergic toxin DSP4 (5 mg/kg) on the expression of the TJ proteins zonula occludens-1 (ZO1) and occludin. The effectiveness of the lesion was confirmed by tyrosine hydroxylase immunoreactivity, which showed noradrenergic fibre reduction accompanied by debris and swollen fibres in DSP4-treated brains. Noradrenergic fibre degeneration caused: (i) gliosis; (ii) disappearance of TJ proteins in vascular cell-to-cell contacts (49.9 and 38.3% reductions for occludin and ZO1, respectively); (iii) a 49.2% decrease in total ZO1 protein, measured by Western blot analysis, parallel to a 39.5% decrease in ZO1 mRNA, measured by real-time PCR; and (iv) a relative increase in the beta occludin isoform (62.9%), with no change in total occludin protein or mRNA. The expression of endothelial brain antigen, a marker of a functionally competent brain endothelium, was also reduced. We conclude that damage to the ascending fibres from the locus coeruleus caused TJ disruption and gliosis, a sign of inflammation. These results imply that the locus coeruleus degeneration reported in Alzheimer's and Parkinson's diseases may contribute to these disorders by causing blood-brain barrier dysfunction. Whether the vascular damage is the result of impaired noradrenergic transmission or secondary to the inflammatory reaction remains to be determined.
PMID: 17229089 [PubMed - indexed for MEDLINE]
Related ArticlesNoradrenergic depletion potentiates beta -amyloid-induced cortical inflammation: implications for Alzheimer's disease. [J Neurosci. 2002] Potentiation of parkinsonian symptoms by depletion of locus coeruleus noradrenaline in 6-hydroxydopamine-induced partial degeneration of substantia nigra in rats. [Eur J Neurosci. 2003] Severe alterations of endothelial and glial cells in the blood-brain barrier of dystrophic mdx mice. [Glia. 2003] ReviewThe blood-brain barrier/neurovascular unit in health and disease. [Pharmacol Rev. 2005] ReviewBlood-brain barrier breakdown in septic encephalopathy and brain tumours. [J Anat. 2002] » See Reviews... | » See All...
this looks at levels of noradrenaline and other neurotransmitters such as serotonin which appears low:
1: J Neurochem. 2008 Nov 12. [Epub ahead of print] Links
Relationship of CSF neurotransmitter metabolite levels to disease severity and disability in multiple sclerosis.Markianos M, Koutsis G, Evangelopoulos ME, Mandellos D, Karahalios G, Sfagos C.
Department of Neurology, Athens University Medical School, Eginition Hospital, Athens, Greece.
Axonal degeneration and brain tissue loss occur during disease progression in multiple sclerosis (MS) and are expected to influence neurotransmitter activities, with consequences on neurologic and psychiatric symptomatology. We searched for relationships of disease duration, disability, and severity of MS patients to CSF levels of the major metabolites of noradrenaline, dopamine, and serotonin, MHPG, methoxyhydroxyphenylglycol (MHPG), homovanillic acid, and 5-hydroxyindoleacetic acid (5-HIAA), respectively, in 39 patients with relapsing-remitting (RR) MS in remission, and 26 patients with progressive (PR) MS. Disability and Disease Severity were assessed by the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Severity Score (MSSS). Compared with the levels of 50 control subjects, MHPG levels were not different in either MS group, correlated negatively to duration of illness and number of relapses in the RRMS group, but not to EDSS score or to MSSS. Homovanillic acid levels were significantly lower only in the PRMS group, with a negative correlation to duration of illness, and a strong negative correlation to EDSS score, but not to MSSS. 5-HIAA was significantly lower in both RRMS and PRMS groups. In the RRMS group, 5-HIAA levels were negatively related to EDSS and to MSSS. Multiple regression analyses revealed a significant association of MHPG to duration of illness, and a strong negative association of 5-HIAA to MSSS rather than to EDSS. The strong negative correlation of MSSS to CSF 5-HIAA levels in RRMS group of patients indicates that deficits in central serotonergic activity are related to the rate of disability accumulation in RRMS, and could be linked to the reported reduction of disease activity by serotonergic drugs.
PMID: 19014375 [PubMed - as supplied by publisher
interestingly serotonin regulates the endothelium from wikipedia:
Endothelial cell function and Serotonin
5-hydroxytryptamine evokes endothelial nitric oxide synthase activation and stimulates phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures.
this article states that noradrenaline downregulates cytokines in the brain:
1: Neurochem Int. 2002 Nov;41(5):357-65. Links
Noradrenergic regulation of inflammatory gene expression in brain.Feinstein DL, Heneka MT, Gavrilyuk V, Dello Russo C, Weinberg G, Galea E.
Department of Anesthesiology, University of Illinois, Chicago, IL, USA. email@example.com
It is now well accepted that inflammatory events contribute to the pathogenesis of numerous neurological disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease, and AID's dementia. Whereas inflammation in the periphery is subject to rapid down regulation by increases in anti-inflammatory molecules and the presence of scavenging soluble cytokine receptors, the presence of an intact blood-brain barrier may limit a similar autoregulation from occurring in brain. Mechanisms intrinsic to the brain may provide additional immunomodulatory functions, and whose dysregulation could contribute to increased inflammation in disease. The findings that noradrenaline (NA) reduces cytokine expression in microglial, astroglial, and brain endothelial cells in vitro,
and that modification of the noradrenergic signaling system occurs in some brain diseases having an inflammatory component, suggests that NA could act as an endogenous immunomodulator in brain. Furthermore, accumulating studies indicate that modification of the noradrenergic signaling system occurs in some neurodiseases. In this article, we will briefly review the evidence that NA can modulate inflammatory gene expression in vitro, summarize data supporting a similar immunomodulatory role in brain, and present recent data implicating a role for NA in attenuating the cortical inflammatory response to beta amyloid protein.
PMID: 12176079 [PubMed - indexed for MEDLINE]
Related ArticlesReviewIntrinsic regulation of brain inflammatory responses. [Cell Mol Neurobiol. 2003] Repeated administration of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) modulates neuroinflammation and amyloid plaque load in mice bearing amyloid precursor protein and presenilin-1 mutant transgenes. [J Neuroinflammation. 2007] Noradrenaline deficiency in brain increases beta-amyloid plaque burden in an animal model of Alzheimer's disease. [Neurobiol Aging. 2007] ReviewStructural pathways for macromolecular and cellular transport across the blood-brain barrier during inflammatory conditions. Review. [Histol Histopathol. 2004] Noradrenergic depletion increases inflammatory responses in brain: effects on IkappaB and HSP70 expression. [J Neurochem. 2003] » See Reviews... | » See All...
It seems to me that we should maybe boost our noradrenaline levels, perhaps with its precursor tyrosine. Likewise a boost to serotonin with its precursors tryptophan or 5htp. I've tried the latter and noticed no difference but now I've got the salvia maybe things will come together. Hope springs eternal!
So here is shown that noradrenaline (norepinephrine is same thing) is low in Ms patients.
1: Mult Scler. 2001 Oct;7(5):327-34. Links
Mult Scler. 2003 Mar;9(2):216; author reply 215.
Autonomic dysfunction in multiple sclerosis is related to disease activity and progression of disability.Flachenecker P, Reiners K, Krauser M, Wolf A, Toyka KV.
Department of Neurology, Julius-Maximilians-Universität Würzburg, Germany.
BACKGROUND: Autonomic dysfunction is frequently observed in patients with multiple sclerosis (MS) but the evolution over time and the relationship to clinical characteristics are not yet established. OBJECTIVES: We investigated the correlation of disease activity and progression of disability with composite scores of cardiovascular autonomic dysfunction and serum levels of catecholamines in a cross-sectional study of patients with clinically active and clinically stable MS. In a longitudinal study of clinically active MS patients, we performed cardiovascular reflex tests for up to 2 years. METHODS: Twenty-six patients with clinically active relapsing-remitting MS, age 33.0 +/- 7.3 years, and nine patients with clinically stable MS, age 41.3 +/- 10.9 were studied. Twenty-four healthy volunteers served as controls. Standard autonomic tests were repeated at 3, 6, 12, 18 and 24 months in 18 of the 26 active patients participating in a placebo-controlled trial with interferon-beta-1a. Parasympathetic dysfunction was assessed by heart rate response to the Valsalva manoeuvre, deep breathing and active change of posture, while sympathetic dysfunction was analysed by blood pressure response to active change of posture and to sustained handgrip, and by measuring levels of norepinephrine and epinephrine in serum obtained in the supine position. RESULTS: In the cross-sectional study, the number of patients with at least one abnormal sympathetic test was higher in the 'active' patient group (39%) than in healthy controls (8%, P< 0.02) or 'stable' patients (0%, P< 0.04), while no difference was seen in the parasympathetic score. Median catecholamine levels were significantly lower in 'active' MS patients than in those with stable disease (norepinephrine, 204 ng/l (interquartile range 158-310 ng/l) vs 363 ng/l (269-507 ng/l), P<0.02 and epinephrine, 23 ng/l (16-28 ng/l) vs 32 ng/l (24-107 ng/l), P<0.04). In the subgroup of patients studied longitudinally, parasympathetic but not sympathetic dysfunction increased slightly during the follow-up period, with a significant correlation to the increase in clinical disability (r=0.7, P<0.002). No difference was seen for any of the autonomic scores between patients treated with interferon-beta (n=12) and those receiving placebo (n=6). During acute exacerbations, only parasympathetic dysfunction tended to increase in parallel with a deterioration in the EDSS. CONCLUSIONS: Parasympathetic dysfunction was closely related to the progression of disability in patients with MS. In contrast, sympathetic dysfunction was associated to the clinical activity of MS. This is in line with previous observations suggesting that the autonomic nervous system may be intimately linked with the disordered immune regulation in MS.
PMID: 11724449 [PubMed - indexed for MEDLINElink
and in the 3rd term norepinephrine is higher along with vitamin d and cortisol:
1: J Clin Endocrinol Metab. 2001 Oct;86(10):4933-8. Links
IL-12, TNF-alpha, and hormonal changes during late pregnancy and early postpartum: implications for autoimmune disease activity during these times.Elenkov IJ, Wilder RL, Bakalov VK, Link AA, Dimitrov MA, Fisher S, Crane M, Kanik KS, Chrousos GP.
Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA. firstname.lastname@example.org
Clinical observations indicate that some autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, frequently remit during pregnancy but exacerbate, or have their onset, in the postpartum period. The immune basis for these phenomena is poorly understood. Recently, excessive production of IL-12 and TNF-alpha was causally linked to rheumatoid arthritis and multiple sclerosis. We studied 18 women with normal pregnancies in their third trimester and during the early postpartum period. We report that during the third trimester pregnancy, ex vivo monocytic IL-12 production was about 3-fold and TNF-alpha production was approximately 40% lower than postpartum values. At the same time, urinary cortisol and norepinephrine excretion and serum levels of 1,25-dihydroxyvitamin were 2- to 3-fold higher than postpartum values. As shown previously, these hormones can directly suppress IL-12 and TNF-alpha production by monocytes/macrophages in vitro. We suggest that a cortisol-, norepinephrine-, and 1,25-dihydroxyvitamin-induced inhibition and subsequent rebound of IL-12 and TNF-alpha production may represent a major mechanism by which pregnancy and postpartum alter the course of or susceptibility to various autoimmune disorders.
PMID: 11600565 [PubMed - indexed for MEDLINE]
Related ArticlesDoes differential neuroendocrine control of cytokine production govern the expression of autoimmune diseases in pregnancy and the postpartum period? [Mol Med Today. 1997] ReviewHormonal regulation of tumor necrosis factor-alpha, interleukin-12 and interleukin-10 production by activated macrophages. A disease-modifying mechanism in rheumatoid arthritis and systemic lupus erythematosus? [Ann N Y Acad Sci. 1999] The effect of estradiol, but not progesterone, on the production of cytokines in stimulated whole blood, is concentration-dependent. [Neuro Endocrinol Lett. 2003] Stress-induced versus preovulatory and pregnancy hormonal levels in modulating cytokine production following whole blood stimulation. [Neuroimmunomodulation. 2005] ReviewHormones, pregnancy, and autoimmune diseases. [Ann N Y Acad Sci. 1998] » See Reviews... | » See All...
time for some berberine?
1: Eur J Pharmacol. 2008 Jul 28;589(1-3):163-72. Epub 2008 Jun 3. Links
On the mechanism of antidepressant-like action of berberine chloride.Kulkarni SK, Dhir A.
Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. email@example.com
Berberine, an alkaloid isolated from Berberis aristata Linn. has been used in the Indian system of medicines as a stomachic, bitter tonic, antiamoebic and also in the treatment of oriental sores. Evidences have demonstrated that berberine possesses central nervous system activities, particularly the ability to inhibit monoamine oxidase-A, an enzyme involved in the degradation of norepinephrine and serotonin (5-HT). With this background, the present study was carried out to elucidate the antidepressant-like effect of berberine chloride in different behavioural paradigms of despair. Berberine (5, 10, 20 mg/kg, i.p.) inhibited the immobility period in mice in both forced swim and tail-suspension test, however, the effect was not dose-dependent. Berberine (5 and 10 mg/kg, i.p.) also reversed the reserpine-induced behavioral despair. Berberine (5 mg/kg, i.p.) enhanced the anti-immobility effect of subeffective doses of various typical but not atypical antidepressant drugs in forced swim test. Berberine (5 mg/kg, i.p.) following its acute administration in mice resulted in increased levels of norepinephrine (31%), serotonin (47%) and dopamine (31%) in the whole brain. Chronic administration of berberine (5 mg/kg, i.p.) for 15 days significantly increased the levels of norepinephrine (29%), serotonin (19%) as well as dopamine (52%) but at higher dose (10 mg/kg, i.p.), there was no change in the norepinephrine (12%) levels but a significant increase in the serotonin (53%) and dopamine (31%) levels was found. The antidepressant-like effect of berberine (5 mg/kg, i.p.) in forced swim test was prevented by pretreatment with l-arginine (750 mg/kg, i.p.) or sildenafil (5 mg/kg, i.p.). On the contrary, pretreatment of mice with 7-nitroindazole (7-NI) (25 mg/kg, i.p.) or methylene blue (10 mg/kg, i.p.) potentiated the effect of berberine (2 mg/kg, i.p.) in the forced swim test. Pretreatment of mice with (+)-pentazocine (2.5 mg/kg, i.p.), a high-affinity sigma1 receptor agonist, produced synergism with subeffective dose of berberine (2 mg/kg, i.p.). Pretreatment with various sigma receptor antagonists viz. progesterone (10 mg/kg, s.c.), rimcazole (5 mg/kg, i.p.) and N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047; 1 mg/kg, i.p.) reversed the anti-immobility effects of berberine (5 mg/kg, i.p.). Berberine at lower dose did not affect the locomotor activity and barbiturate-induced sleep time. It produced mild hypothermic action in rats and displayed analgesic effect in mice. Taken together, theses findings demonstrate that berberine exerted antidepressant-like effect in various behavioural paradigms of despair possibly by modulating brain biogenic amines (norepinephrine, serotonin and dopamine). Further, nitric oxide pathway and/or sigma receptors are involved in mediating its antidepressant-like activity in mouse forced swim test.
PMID: 18585703 [PubMed - indexed for MEDLINE]
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,