Abstract In a parallel study in 10 individual rats, three time series of plasma concentrations of ACTH, corticosterone (CORT), and interleukin-1β (IL-1β) were measured before (time 0) and at intervals between 15 and 480 min following intra-arterial (i.a.) infusions of 25μg/kg lipopolysaccharide (LPS). All LPS injections were given at 9 AM. The first time series was performed on naive rats (day 1). A sequence of six daily injections (days 3–8) of the same dose of LPS followed. The post-LPS time course of the plasma ACTH, CORT and IL-1β levels were studied on days 3 (second injection) and 8 (seventh injection). The first LPS injection induced a rapid (30 min) eightfold rise in plasma ACTH and CORT, culminating in concentrations 30 times the baseline at 60 min (ACTH) and 15 times baseline at 120 min (CORT). Both hormones receded back to the initial basal level at 480 min. On the other hand, IL-1β increased slowly to peak at 13 times baseline 120 min before declining to minimal seven- to ninefold basal levels, 480 min and even 48 h post-LPS. During the second phase of the experiment starting 48 h after the initial LPS priming sequence, the ACTH and CORT responses to daily recurrent LPS injections again differed from those of IL-1β. The post-LPS time courses of the ACTH and CORT reaction displayed a typical pattern of a progressive attenuation studied at days 3 and 8. The peak amplitudes at days 3 and 8 were reduced to 60 and 10%, respectively, for ACTH, and to 85 and 45% for CORT of those observed at the first LPS test. The duration of the response (both) was also shortened from 480 min (first LPS test) to 300 min at days 3 and 8. The post-LPS patterns of the IL-1β responses were characterized, first by basal levels seven to nine times higher than the initial baseline values (day 1), and by a rapid suppression of the post-LPS response, with only a slight (30%) increase at day 3 and no increase at day 8. Thus, after both acute and recurrent LPS administration, ACTH/CORT and IL-1β reacted differently to the endotoxin challenge. The two LPS reactive systems were not correlated. This is inconsistent with the often proposed role of increased plasma IL-1β release as an intermediary factor in the LPS-induced recruitment of the corticotropic axis in general infections.
Abstract Objective We asked whether blockade of voltage‐gated K + channel Kv1.1, whose altered axonal localization during myelin insult and remyelination may disturb nerve conduction, treats experimental autoimmune encephalomyelitis (EAE). Methods Electrophysiological, cell proliferation, cytokine secretion, immunohistochemical, clinical, brain magnetic resonance imaging, and spectroscopy studies assessed the effects of a selective blocker of Kv1.1, BgK‐F6A, on neurons and immune cells in vitro and on EAE‐induced neurological deficits and brain lesions in Lewis rats. Results BgK‐F6A increased the frequency of miniature excitatory postsynaptic currents in neurons and did not affect T‐cell activation. EAE was characterized by ventriculomegaly, decreased apparent diffusion coefficient, and decreased (phosphocreatine + β‐adenosine triphosphate)/inorganic phosphate ratio. Reduced apparent diffusion coefficient and impaired energy metabolism indicate astrocytic edema. Intracerebroventricularly BgK‐F6A–treated rats showed attenuated clinical EAE with unexpectedly reduced ventriculomegaly and preserved apparent diffusion coefficient values and (phosphocreatine + β‐adenosine triphosphate)/inorganic phosphate ratio. Thus, under BgK‐F6A treatment, brain damage was dramatically reduced and energy metabolism maintained. Interpretation Kv1.1 blockade may target neurons and astrocytes, and modulate neuronal activity and neural cell volume, which may partly account for the attenuation of the neurological deficits. We propose that Kv1.1 blockade has a broad therapeutic potential in neuroinflammatory diseases (multiple sclerosis, stroke, and trauma). Ann Neurol 2006
Abstract Light and electron microscopic immunocytochemistry was used to study the fine structural organization of the catecholaminergic and hypothalamic peptidergic innervation of the dorsal vagal complex of the medulla oblongata in the rat and guinea pig, the latter of which is known to lack central adrenergic neurons. In the rat, adrenergic fibers immunoreactive to phenylethanolamine‐N‐methyltransferase were concentrated in the dorsal motor nucleus of the vagus, where they established frequent symmetric synapses with dendrites and perikarya. On the other hand, the density of both oxytocin‐ and corticotropin‐immunoreactive fibers appeared far lower in this nucleus than in the dorsal regions of the nucleus of the tractus solitarius, where they formed asymmetric synapses with small dendrites. In tissue treated for the dual labeling of two neuronal antigens, oxytocin‐ or corticotropin‐reactive fibers were in close contact with adrenergic neurons in this dorsal medullary region. In the guinea pig, unlike the rat, the dorsal motor nucleus of the vagus contained large amounts of oxytocin‐ and corticotropin‐reactive fibers, which formed many symmetric synapses with perikarya and dendrites. Taken together, these data suggest that the control of vagal preganglionic neurons by hypothalamic peptidergic neurons involves a bisynaptic neuronal pathway including adrenergic medullary neurons in the rat, whereas it is direct in the guinea pig, which lacks this adrenergic relay.
Cette thematique vise a etudier les effets du stress post-traumatique et la depression sur les capacites adaptatives de l’organisme ainsi que sur les interactions entre les systemes immunitaires (SI) et neuroendocrinien (SNE). Les resultats montrent que, chez les sujets reconnus depressifs, l’augmentation de la cortisolemie est correlee simultanement a une immunosuppression (humorale et cellulaire) et a une baisse remarquable de la testosteronemie. En revanche, les sujets ayant subit un PTSD presentent une cortisolemie remarquablement faible avec une baisse de l’immunite (humorale et cellulaire) et egalement une chute de la testosteronemie. Les variations de la reponse immunitaire semblent etre liees au sexe; on constate une immunosuppression chez les femmes deprimees par rapport aux hommes alors que ces derniers presentent une chute de la reponse immunitaire lorsqu’ils subissent un PTSD. Le SNE, via les axes corticotrope et gonadotrope, est capable de moduler la fonction immunitaire par la voie cognitive ou par des signaux venant du SI
The possible correlation between the circadian and episodic release of corticotropin-releasing hormone 41 (CRH41) in male rats was explored in a comparative study, including the measurement at 0700 hr and 1700 hr of (1) the quantitative parameters of the episodic release pattern of CRH41 into the push-pull-cannulated median eminence (ME); (2) CRH41 content measured by radioimmunoassay in the hypothalamus, and immunocytochemically in the ME; and (3) plasma adrenocorticotropic hormone (ACTH). The data showed that in early evening, the 3.4-fold rise in plasma ACTH coincided with a doubling of CRH41 content in the hypothalamus and in the ME, and of the CRH41 release from the perfused ME. The immunocytochemical data further indicated that the ME area labeled with CRH41 immunoreactivity, rather than the labeling intensity of CRH41-stained neurons, increased in the evening, which may point to an evening recruitment of additional CRH41-producing neurons as the origin of the evening increment in CRH41 and ACTH releases. Finally, the computerized analysis of the CRH41-releasing pattern with three different algorithms (Pulsar, Ultra, and the Santen and Bardin algorithm) showed for the first time that the evening rise in CRH41 output was associated with correlative increases of three parameters of the episodic pattern—peak amplitude (+ 55% to + 80%), peak duration (+ 20%), and mean absolute peak values (+ 73%)-while the pulse frequency remained at the baseline level of 3 cycles · hr -1 . The data suggest the occurrence of a connection between the circadian pacemaker and the machinery generating the episodic release of CRH41.
To explore the interaction between the hypothalamic-pituitary-adrenocortical axis and the immune system under stress conditions, we used an experimental rat model for chronic tail-restraint devise earlier for ground studies in space physiology. The system was used in two positions: (1) the orthostatic restraint position (OR) and (2) the antiorthostatic position (AOR) after the rat hind limbs had been raised by a head-down tilt. After 7 days of either restraints sequential blood samples were taken via an indwelling aortic cannula, before and at various time intervals between 15 and 300 min after an intravascular infusion of 25 µg/kg lipopolysaccharide (LPS). The plasma titers of adrenocorticotropin (ACTH), corticosterone (CORT) and interleukin-1β (IL-1β) were assayed. Under basal conditions, both OR and AOR restraints induced a 5-fold increase in IL-1β with no significant changes in ACTH and CORT levels. A robust increase in all three variables was observed after LPS injection. However, the IL-1β response to LPS was significantly higher in both restrained groups than in controls. Both the amplitude and the percentage of individually restrained rats displaying elevated IL-1β levels were increased up to 5 h. In contrast, the ACTH and CORT post-LPS responses were normal in the OR group. They were unusually dissociated in the AOR rats, which displayed depressed ACTH levels associated with slightly increased CORT levels. Our results suggest that immune-neuroendocrine responses to chronic restraint stress may differ from those generally observed in acute stress.
