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Research Highlights from the Literature

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2003; Volume 13(2) from Clinical Autonomic Research                                           
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The vagal anti-inflammatory reflex
            Endotoxemia induces the release of TNF-α from macrophages, as part of an inflammatory process.  Acetylcholine and nicotine inhibit the release of TNF-α from macrophages in vitro, through activation of nicotinic receptors.  In animals, vagal nerve stimulation inhibits the increase in plasma TNF-α induced by endotoxemia in vivo (for review, see Tracey KJ.  Nature 2002;420:853).  It is proposed that acetylcholine diffuses from parasympathetic nerve terminals in reticuloendothelial organs, to inhibit inflammatory cells.  Wang et al. studied the receptor subtype that mediates these actions.  Nicotinic acetylcholine receptors are a family of ligand-gated pentameric ion channels.  In humans, 16 different subunits have been identified (α1-7, α9-10, β1-4, δ, ε, and γ), and pentameric receptors are formed by various combinations of these subunits.  It is known that the acetylcholine-sensitive TNF-α response is blocked by α-bungarotoxin, a peptide antagonist that binds to α1, α7, and α9.  Biding of α-bugarotoxin was present in human macrophages, and PCR confirmed the expression of α1, α7 and α10 in these cells.  Antisense oliogonucleotides specific for α7 blunted the anti-TNF-α effects of nicotine in macrophages in vitro.  As expected, vagal nerve stimulation blunted the increase in TNF-α induced by endotoxemia in normal mice, but this effect was blunted in α7-deficient mice.  These results suggest that the anti-inflammatory effects of neurally-mediated acetylcholine are mediated by nicotinic receptors containing the α7 subunit. 
    Wang H, Yu M, Ochani M et al. (2003) Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. 421:384-388.

 "Sometimes it just doesn’t pay to get out of bed”
    This is the conclusions Norman Kaplan reached in an editorial commenting the article by Kario et al., which showed that early morning hypertension was associated with strokes.  Over 500 elderly with hypertension were studied with ambulatory blood pressure monitoring.  Over an average follow up of 41 months there were 44 strokes.  Patients with the highest early morning blood pressure (within 2 hours of arising) had a higher prevalence of multiple silent infarcts at baseline MRI (57% versus 33%), and almost a three-fold higher stroke incidence during follow up (19% versus 7.3%).  It is believed that morning blood pressure surge is mediated by autonomic mechanisms, and these results are in agreement with the higher incidence of cardiovascular events reported early in the morning.
    Kario K, Pickering TG, Umeda Y et al. (2003) Morning Surge in Blood Pressure as a Predictor of Silent and Clinical Cerebrovascular Disease in Elderly Hypertensives: A Prospective Study. Circulation 107:1401-1406. 

Modulation of norepinephrine release
    Release of norepinephrine (NE) from sympathetic nerve terminals is modulated by a number of factors acting on presynaptic receptors.  To determine if presynaptic histamine H3 receptors (H3R) inhibit NE release Koyama et al. studied knock-out mice lacking H3R and found that these mice had 60% high basal NE release than wild type mice.  NE exocytosis induced by K+-induced depolarization was attenuated by adenosine and histamine agonists in wild type mice, but only by adenosine agonists in H3R (-/-) mice.  Ischemia-induced NE release was inhibited 50% by H3R activation in wild type mice, but not in H3R (-/-) mice.  Thus, histamine receptors modulate NE release at rest, and during physiological and pathological stimulation.
    It is generally believed that presynaptic angiotensin II receptors stimulate NE release from sympathetic terminals, although this remains controversial (e.g., see Lameris, et al. Hypertension 2002;40:491).  Dendorfer at al., found that infusion of angiotensin II increased renal sympathetic nerve traffic in pithed rats, even during ganglionic blockade, and increased plasma norepinephrine 27-fold.  These effects were blocked by an AT1 angiotensin receptor antagonist and by tetradotoxin.  These results suggest a direct effect of angiotensin II on autonomic ganglia, which can contribute to the pressor effects of angiotensin II through sympathetic activation.
    Koyama M, Seyedi N, Fung-Leung WP et al. (2003) Norepinephrine release from the ischemic heart is greatly enhanced in mice lacking histamine H3 receptors. Mol Pharmacol 63:378-382.
    Dendorfer A, Thornagel A, Raasch W et al. (2002) Angiotensin II induces catecholamine release by direct ganglionic excitation. Hypertension 40:348-354.

 Cardiac sympathetic activity in congestive heart failure and autonomic disorders
    Congestive heart failure is associated with sympathetic activation, initially as a compensatory mechanism, but detrimental in the long term.  Aggarwal et al. performed a proof-of-concept study in 10 patients with moderate-severe congestive heart failure to examine potential beneficial effects of intravenous clonidine on regional sympathetic activity.  Clonidine preferentially reduced cardiac and renal NE spillover (by 50 and 40%, respectively), compared to global NE spillover (22% reduction).  In addition to the beneficial effects of antiadrenergic therapy in the heart, the renal sympatholytic effect may counter the salt and water retention that is a hallmark of congestive heart failure.  Central sympatholitics should be further investigated for the treatment of this condition.
    Goldstein et al. used similar methodology to examine cardiac NE spillover in patients with postural tachycardia syndrome (POTS) and with neurocardiogenic syncope (NCS).  Cardiac NE spillover was higher in POTS (by about 68%) and lower in NCS (by about 40%) compared to healthy controls. Despite differences in NE spillover, both patient groups had normal cardiac extraction of NE, normal cardiac production of the intraneuronal NE metabolite dihydroxyphenylalanine, and normal myocardial 6-[18F]fluorodopamine-derived radioactivity, suggesting normal function of NE transporter and NE synthesis, and normal density of myocardial sympathetic innervation.
    Aggarwal A, Esler MD, Morris MJ et al. (2003) Regional Sympathetic Effects of Low-Dose Clonidine in Heart Failure. Hypertension 41:553-557.
    Goldstein DS, Holmes C, Frank SM et al. (2002) Cardiac sympathetic dysautonomia in chronic orthostatic intolerance syndromes. Circulation 106:2358-2365.

Parkinson’s Disease, unusual causes and future treatments
    Whereas only a small percentage of Parkinson disorders is monogenic, such disorders can improve our understanding of general pathophysiological mechanisms.  Bonifati et al. described two consanguineous families from genetically isolated communities in the Netherlands and Italy suffering from autosomal recessive early-onset Parkinsonism.  Homozygosity mapping localized the responsible gene, labeled PARK7, on chromosome 1p36.  Systematic PCR screening of this region revealed mutations of the Dj-1 gene leading to loss of function.  This gene encodes a ubiquitous highly-conserved protein of unknown function, but thought to be involved in the oxidative stress response.  We will need to wait for more studies to understand the role of this protein in neurodegenerative disorders. 
    Brain transplantation of dopamine-producing cells is theoretically appealing for the treatment of Parkinson’s disease.  This approach, however, has several limitations.  Transplants increase dopamine levels locally, but this effect is usually transient and there is little restorative action on nigrostriatal pathways.  The source of transplanted cells and the need of immunosuppression are also limiting factors.  Toledo-Aral et al. studied the possible use of carotid body cells as a source of transplants in a rat model of Parkinson’s disease.  Hemiparkinsonian rats were grafted intrastriatally with carotid body cell aggregates.  The motor syndrome improved in transplanted rats, apparently as a result of the trophic actions of these grafts on the remaining ipsilateral substantia nigra neurons, rather than of the release of dopamine.  Remarkably, grafts survived throughout the life of the animals.  Improved survival of the grafts was attributed to adult carotid body cells expressing high levels of glia cell line-derived neurotrophic factor.  Carotid body glomus cells, although highly dopaminergic, are protected from dopamine-mediated oxidative damage because they lack high-affinity dopamine transporters.  Thus, carotid body cells have theoretical advantages as a source of grafts to restore nigrostriatal function.
    Bonifati V, Rizzu P, van Baren MJ et al. (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. 299:256-259.;
    Toledo-Aral JJ, Mendez-Ferrer S, Pardal R et al. (2003) Trophic restoration of the nigrostriatal dopaminergic pathway in long-term carotid body-grafted parkinsonian rats. J Neurosci 23:141-148.

Cardiac denervation in Parkinson’s disease
    Several imaging studies have now documented a high prevalence of decreased uptake of catechols in the heart of patients with Parkinson’s disease, suggesting decreased sympathetic innervation.  Even among patients without orthostatic hypotension, about half have diffusely decreased innervation.  Li et al. studied 9 such patients with repeat fluorodopamine scans taken on average two years apart.  They found that fluorodopamine cardiac uptake decreased by about 30% in the second scan, compared to the initial one.  This findings suggest progressive cardiac denervation in Parkinson’s disease, even in patients with no initial evidence of orthostatic hypotension.
    Li ST, Dendi R, Holmes C et al. (2002) Progressive loss of cardiac sympathetic innervation in Parkinson's disease. Ann Neurol 52:220-223.