Kurt Heininger

Substance P and astrocytes: stimulation of the cyclooxygenase pathway of arachidonic acid metabolism.

Substance P (SP) may play an important role in the interactions between the nervous system and the immune system. Astrocytes carry receptors for SP on their surfaces. We examined whether ligand‐induced receptor activation would lead to the release of arachidonic acid metabolites. SP (10−10‐10−8 M) evokes the formation of prostaglandin E and thromboxane B2 in a dose‐dependent manner. Structure‐activity studies disclosed that the COOH‐terminal peptide sequence of SP is primarily responsible for this biological activity. The generation by astrocytes of arachidonate‐derived proinflammatory and immunoregulatory compounds in response to SP receptor activation may be relevant to immunoinflammatory responses within the central nervous system and emphasizes the concept of neuroimmunomodulation.— Hartung, H.‐P.; Heininger, K.; Schäfer, B.; Toyka, K. V. Substance P and astrocytes: stimulation of the cyclooxygenase pathway of arachidonic acid metabolism. FASEB J. 2: 48‐51; 1988.

Immune Mechanisms in Inflammatory Polyneuropathya

I t has been increasingly recognized that a small proportion of patients with the acute Guillain-Barrk syndrome (GBS) have a severe form of the disease with a poor prognosis. Clinical, pathologic, and electrophysiologic studies have demonstrated that axonal degeneration characterizes nerve pathology in these cases. Clinically, the disease reaches peak severity much earlier in these patients than in most other GBS patients, and they require ventilatory assistance more often. In some patients, conduction block occurred at distal sites, whereas in others there was electrophysiologic evidence of widespread muscle denervation. Thus, patients that fulfill all of the established diagnostic criteria for GBS may either-in the majority-have a demyelinating polyneuropathy with conduction slowing or block that is milder and yields better recovery, or have axonal damage with conduction failure, signaling severe disease with slower recovery (TABLE 1). It is unclear at present whether the axonal form is part of the spectrum of GBS

The mouse blood-brain barrier and blood-nerve barrier for IgG: a tracer study by use of the avidin-biotin system.

SummaryTo study the permeability of the blood-brain barrier (BBB) and the blood-nerve barrier (BNB) for immunoglobulin G (IgG) we adapted the avidin-biotin system for postembedding demonstration of the tracer IgG in the central and peripheral nervous system (CNS, PNS). Normal mouse and human IgG were biotinylated and injected daily into the intraperitoneal (i.p.) space of adult BDF1 mice. After 24 h, IgG was detected in blood vessels and in the interstitium of various organs, but staining was restricted to the dura mater in the CNS, to the spinal ganglia, and to the perineurium of peripheral nerves. After 4 days, IgG was also present in the endoneurial connective tissue of peripheral nerves, while the brain, spinal cord, and spinal roots remained free of IgG. Our results show a partial permeability of the normal mouse BNB for homologous and heterologous IgG.

A unifying hypothesis of Alzheimer's disease. III. Risk factors

Normal ageing and Alzheimers disease (AD) have many features in common and, in many respects, both conditions only differ by quantitative criteria. A variety of genetic, medical and environmental factors modulate the ageing‐related processes leading the brain into the devastation of AD. In accordance with the concept that AD is a metabolic disease, these risk factors deteriorate the homeostasis of the Ca2+–energy–redox triangle and disrupt the cerebral reserve capacity under metabolic stress. The major genetic risk factors (APP and presenilin mutations, Downs syndrome, apolipoprotein E4) are associated with a compromise of the homeostatic triangle. The pathophysiological processes leading to this vulnerability remain elusive at present, while mitochondrial mutations can be plausibly integrated into the metabolic scenario. The metabolic leitmotif is particularly evident with medical risk factors which are associated with an impaired cerebral perfusion, such as cerebrovascular diseases including stroke, cardiovascular diseases, hypo‐ and hypertension. Traumatic brain injury represents another example due to the persistent metabolic stress following the acute event. Thyroid diseases have detrimental sequela for cerebral metabolism as well. Furthermore, major depression and presumably chronic stress endanger susceptible brain areas mediated by a host of hormonal imbalances, particularly the HPA‐axis dysregulation. Sociocultural and lifestyle factors like education, physical activity, diet and smoking may also modulate the individual risk affecting both reserve capacity and vulnerability. The pathophysiological relevance of trace metals, including aluminum and iron, is highly controversial; at any rate, they may adversely affect cellular defences, antioxidant competence in particular. The relative contribution of these factors, however, is as individual as the pattern of the factors. In familial AD, the genetic factors clearly drive the sequence of events. A strong interaction of fat metabolism and apoE polymorphism is suggested by intercultural epidemiological findings. In cultures, less plagued by the ‘blessings’ of the ‘cafeteria diet–sedentary’ Western lifestyle, apoE4 appears to be not a risk factor for AD. This intriguing evidence suggests that, analogous to cardiovascular diseases, apoE4 requires a hyperlipidaemic lifestyle to manifest as AD risk factor. Overall, the etiology of AD is a key paradigm for a gene‐environment interaction. Copyright

Primary rat astroglial cultures can generate leukotriene B4

Astrocytes are important elements of cellular immune responses in the central nervous system. Eicosanoids exhibit immunomodulatory properties. We studied whether astroglial cells have the capacity to convert arachidonic acid via the lipoxygenase pathway to leukotriene B4 (LTB4). Calcium ionophore A23187 evoked a dose-related release of LTB4 into supernatants of primary culture rat astrocytes. This stimulatory effect was abrogated by the addition of the lipoxygenase inhibitors BW755c and nordihydroguaretic acid. Astrocyte production of the phlogistic and immunoregulatory mediator LTB4 may be one mechanism by which these cells influence immunity and inflammation in the central nervous system.

The aging feline kidney: a model mortality antagonist?

Traditional thinking views apparently non-programmed disruptions of aging, which medical science calls geriatric diseases, as separate from ‘less harmful’ morphological and physiological aging phenotypes that are more universally expected with passage of time (loss of skin elasticity, graying of hair coat, weight gain, increased sleep time, behavioral changes, etc). Late-life disease phenotypes, especially those involving chronic processes, frequently are complex and very energy-expensive. A non-programmed process of homeostatic disruption leading into a death trajectory seems inconsistent with energy intensive processes. That is, evolutionary mechanisms do not favor complex and prolonged energy investment in death. Taking a different view, the naturally occurring feline (Felis silvestris catus) renal model suggests that at least some diseases of late life represent only the point of failure in essentially survival-driven adaptive processes. In the feline renal model, individuals that succumbed to failure most frequently displayed progressive tubular deletion and peritubular interstitial fibrosis, but had longer mean life span than cats that died from other causes. Additionally, among cats that died from non-renal causes, those that had degrees of renal tubular deletion and peritubular interstitial fibrosis also had longer mean life span than those cats with no changes, even though causes of death differed minimally between these latter two groups. The data indicate that selective tubular deletion very frequently begins early in adult life, without a clear initiating phase or event. The observations support a hypothesis that this prolonged process may be intrinsic and protective prior to an ultimate point of failure. Moreover, given the genetic complexity and the interplay with associated risk factors, existing data also do not support the ideas that these changes are simple compensatory responses and that breed- or strain-based ‘default’ diseases are inevitable results of increasing individual longevity. Emerging molecular technology offers the future potential to further evaluate and refine these observations. At present, the existence of plastic and adaptive aging programming is suggested by these findings.

A Unifying Hypothesis of Alzheimer's Disease. II. Pathophysiological Processes

The age‐related loss of hormonal balance puts the homeostatic calcium–energy–antioxidant triangle under stress. The energetic compromise enhances β‐amyloid protein formation and tau protein hyperphosphorylation, both cellular stress responses, which may give rise to diffuse plaque and neurofibrillary tangle formation during normal ageing. Facilitated by a multitude of risk factors (discussed in part III of this series), the age‐related processes lead into the pathophysiological events of Alzheimers disease (AD). In AD, the hormonal imbalance is further aggravated with progressively detrimental sequelae for the calcium–energy–redox homeostasis and for both amyloid protein precursor and tau protein metabolism. The immune system as an integral component of the neuroendocrine immunological network is subject to the deteriorating endocrinological balance and displays a cellular and humoral acute phase‐type reaction. In an orchestrated action, an inflammatory response is mounted in which activated micro‐ and astro‐glia and their secreted inflammatory mediators and matrix constituents elicit the transformation of diffuse into neuritic plaques which, secondarily, may induce further tissue damage. Importantly, the AD brain is characterized by the microglial inability to clear the brain of the deposited material. The pathophysiological processes lead to functional and structural impairments of neuronal plasticity, a compromise of the neuronal network and, eventually, to cell death. Conspicuously, these alterations do not uniformly affect all brain regions but manifest with a temporal and topographical specificity vulnerable areas and nerve cell populations. Copyright

Ciclosporin A prevents P2 T cell line-mediated experimental autoimmune neuritis (AT-EAN) in rat

Adoptive transfer experimental autoimmune neuritis (AT-EAN) produced in Lewis rats by injection of P2-reactive T lymphocyte line cells offers the unique possibility to study the exclusive contribution of cell-mediated immune responses to the pathogenesis of autoimmune disease of the peripheral nervous system (PNS). It further lends itself to the evaluation of novel therapeutic approaches that may bear relevance to the human acute Guillain-Barré syndrome. The effects of the immunosuppressive agent ciclosporin A on the clinical, electrophysiological and morphological expression of AT-EAN were examined. We found that ciclosporin A suppressed development of the disease. In view of the known actions of ciclosporin A on T cells, these results indicate the requirement of activation and clonal proliferation of T lymphocytes to produce myelin damage in autoimmune diseases of the PNS.

A UNIFYING HYPOTHESIS OF ALZHEIMER'S DISEASE. I. AGEING SETS THE STAGE

In a series of five papers, evidence from neurobiology, endocrinology and immunology is integrated into a holistic, coherent hypothesis accommodating genetic, medical and environmental risk factors into a cascade of pathophysiological events that leads to the clinical manifestation of Alzheimers disease (AD). The perturbation of the calcium‐energy‐oxidative stress triangle emerges as pathophysiological leitmotif of ageing and AD. Cellular Ca2+ homeostasis and energy metabolism are closely interdependent. Ca2+ ions regulate the activity of a variety of rate‐limiting enzymes of the tricarboxylic acid cycle and respiratory chain. Under physiological circumstances, the supply of energy according to demand is regulated by Ca2+ cycling across mitochondrial membranes. In certain pathological conditions, Ca2+ uncouples electron transfer and oxidative phosphorylation and increases the mitochondrial production of oxygen radicals which in tandem with Ca2+ precipitate the breakdown of mitochondrial function and structure. As most important risk factor, ageing sets the stage for the development of AD. The delicate regulation of the neuroendocrine network which physiologically modulates the Ca2+‐energy‐redox homeostasis, deteriorates in ageing, compromising the hormonal balance between neurotrophic/protective and neuroaggressive factors. Thus, levels and/or signal transduction pathways of neurotrophic‐factors such as neuropeptide Y, neurotrophins, DHEA/DHEAS, gonadal hormones, melatonin, insulin, insulin‐like growth factors, somatostatin, thyroid hormones, and substance P decay, paralleled by the compromise of the hypothalmic‐pituitary‐adrenal (HPA)‐axis feedback inhibition leading to a hyperresponsiveness to stress and a loss of diurnal rhythm of secretion of neuroaggressive glucocorticoids. Both add up to disrupt Ca2+ and energy homeostasis, put the nerve cells under metabolic and oxidative stress and lead to a compromise of neuronal excitability, signal transduction processes and neuronal plasticity. Subject to the same endocrinological dysregulation, the ageing immune system exhibits a primitive response pattern with impairment of specific cellular and activation of unspecific humoral and microglial immune responses. Thus, the ageing‐related concerted perturbation of the homeostatic control in the neuroendocrino‐immunological network creates phenomena which in many aspects are qualitatively similar to changes in AD and lay the foundations for the development of the disease. Copyright

Substance P Stimulates Release of Arachidonic Acid Cyclooxygenation Products from Primary Culture Rat Astrocytes

There is growing evidence that the neuropeptide substance P (SP), through stimulation of leukocytes, is involved in inflammatory responses. The recent demonstration that SP specifically binds to and activates both T lymphocytes and macrophages further suggests a role of this undecapeptide in immunoregu1ation.’-’ Astrocytes, which constitute key cellular components of immunoinflammatory responses within the central nervous system, express SP receptors on their s ~ r f a c e . ~ We examined the possible effects of SP on arachidonic acid metabolism in astrocytes.