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S Nikolaus

Publications and source records attributed to S Nikolaus.

33 records · Page 2Linked to original sources
PubMed2000

Anxiolytic-like effects in rats produced by ventral pallidal injection of both N- and C-terminal fragments of substance P.

Prior studies have shown that the neurokinin substance P (SP) has anxiolytic-like effects when administered into the nucleus basalis (NB) area of the rat ventral pallidum. The present work was performed to examine whether the anxiolytic effects of SP in the nucleus basalis can be assigned its amino (N)- or carboxy (C)-terminal moiety. Using the elevated plus-maze model of anxiety in combination with unilateral injection of N-terminal SP(1-7) or C-terminal SP(7-11) into the NB region, we found that the treatment with either SP-fragment increased the number of entries into and time spent on the open arms as well as excursions into the end of the open arms, indicative of an anxiolytic-like profile. Furthermore, the effective doses of SP(1-7) (0.67 ng) and SP(7-11) (0.45 ng) were equimolar to the dosage of the whole SP molecule (1 ng), which was effective to reduce anxiety. Thus, the results support earlier findings that ventral pallidal injection of SP has anxiolytic-like effects and provide new evidence that fragments of SP, representing the N- and C-terminal domain of the peptide can reduce fear-parameters at a concentration similar to that of the parent peptide.

Animals↗
PubMed2000

Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn's disease. Crohn's Disease IL-10 Cooperative Study Group.

BACKGROUND & AIMS: Interleukin (IL)-10 is a cytokine with potent anti-inflammatory properties. We investigated the safety and efficacy of different doses of human recombinant (rhu)IL-10 in patients with Crohn's disease (CD). METHODS: A prospective, multicenter, double-blind, placebo-controlled study was conducted in 329 therapy-refractory patients with CD. Clinical improvement was defined by a reduction of the Crohn's Disease Activity Index (CDAI) by 100 points or more and clinical remission by a decrease of the CDAI to <150 points. At selected centers, patients underwent ileocolonoscopies and activation of the nuclear factor-kappa B (NF-kappa B) system was assessed in biopsy specimens. RESULTS: Subcutaneous treatment with rhuIL-10 over 28 days induced a fully reversible, dose-dependent decrease in hemoglobin and thrombocyte counts but no clinically significant side effects. No differences in the induction of remission were observed between rhuIL-10 groups (1 microg, 18% [9.6-29.2]; 4 microg, 20% [11.3-32.2]; 8 microg, 20% [11.1-31.8]; 20 microg, 28% [18-40.7]; and placebo, 18% [9.6-29.6]). Clinical improvement was observed in 46% (33.7-59) in the 8-microg/kg rhuIL-10 group in comparison with 27% (17-39.6) in patients taking placebo. Responders to rhuIL-10 showed inhibition of NF-kappaB p65 activation in contrast to nonresponders. CONCLUSIONS: Up to 8 microg/kg of rhuIL-10 was well tolerated. A tendency toward clinical improvement but not remission was observed in the 8-microg/kg dose group. Further studies should delineate which subgroups of patients with CD benefit from rhuIL-10 therapy.

Adult↗
PubMed2000

Substance P and its role in neural mechanisms governing learning, anxiety and functional recovery.

The neurokinin Substance P (SP) is widely distributed in the central nervous system and has been extensively studied in various functional aspects. This review focuses on the behavioral relevance of SP. Here we show that SP can have memory-promoting, reinforcing and anxiolytic-like effects when administered systemically or into the nucleus basalis of the ventral pallidum. These effects seem to be mediated via the SP-preferring NK(1)receptor and differentially related to N- versus C-terminal fragments of the undecapeptide. Secondly, SP injection into the ventral pallidum can lead to increases of acetylcholine in frontal cortex and dopamine in nucleus accumbens, suggesting that the hypermnestic, positively reinforcing and anxiolytic effects observed upon basal forebrain injection of SP are mediated by activation of the nucleus accumbens-ventral pallidum circuitry. Furthermore, SP and certain SP-fragments may not only be considered to have beneficial behavioral effects in normal animals, but can also prevent lesion-induced functional deficits and improve the speed of recovery. This indicates that SP agonists might also have a neuroprotective capacity in parallel with recovery-promoting actions.

Animals↗
PubMed2000

Diffuse cortical reduction of neuronal activity in unipolar major depression: a retrospective analysis of 337 patients and 321 controls.

Reduction of neuronal activity in frontocortical and limbic circuits is considered a characteristic of depression. We aimed to test this hypothesis by pooling all available data from experimental literature. All investigations were included comparing regional cerebral blood flow (rCBF) or glucose metabolism (rCMRGlc) between acutely depressed unipolar major depressive patients and healthy controls. For cortical and subcortical regions we computed the percentage difference between depressives (n = 337) and controls (n = 321). In patients with unipolar major depression rCBF and rCMRGlc were lowered in left (-4.4%, P = 0.022) and right frontal (-3.2%, P = 0.053), left (-1.7%, P = 0.061) and right temporal (-3.0%, P=0.003), left (-6.5%, P = 0.002), and right parietal (-8.8%, P=0.001), and left (-6.6%, P = 0.083) and right occipital cortex (-4.2%, P = 0.02). Moreover, there were reductions in left (-6.3%, P = 0.029) and right basal ganglia (-4.8%, P = 0.002), left (-3.4%, P = 0.114) and right thalamus (-3.1%, P = 0.036), and left limbic system (-2.2%, P = 0.127). Parameters were increased by 1.0% (P = 0.714) only in the right limbic system. There were no hemispheric asymmetries (P > 0.05). Moreover, there was no indication for an anterior-posterior gradient (P > 0.05), and thus no 'hypofrontality'. In contrast to the current view, the data indicate a diffuse cortical rather than regionalized reduction of neuronal activity in unipolar major depression.

Adult↗
PubMed1999

The neurokinin-1 receptor antagonist WIN51,708 attenuates the anxiolytic-like effects of ventralpallidal substance P injection.

We reported previously that the neurokinin substance P has anxiolytic-like effects when administered into the nucleus basalis of the rat ventral pallidum. The present study aimed to determine the possible involvement of the neurokinin-1 receptor in the anxiolytic action of intrabasalis substance P injection. Behavioral testing was performed in the rat elevated plus-maze model of anxiety. Microinjection of substance P (1 ng) into the nucleus basalis increased sojourn times on the open arms, excursions into the end of the open arms and scanning over the edge of an open arm, indicative of an anxiolytic-like profile. The non-peptide neurokinin-1 receptor antagonist WIN51,708, administered i.p. 20 min prior to intrabasalis substance P injection, antagonized the anxiolytic effects of the neurokinin in a dose-dependent manner. WIN51,708 at 10 mg/kg diminished, while at the higher dose of 20 mg/kg the antagonist completely blocked, the effect of substance P on anxiety-related behaviors. These findings suggest that the anxiolytic-like effects of substance P in the nucleus basalis are mediated through neurokinin-1 receptive sites.

Androstanes↗
PubMed1999

Reinforcing effects of neurokinin substance P in the ventral pallidum: mediation by the tachykinin NK1 receptor.

The neurokinin substance P has reinforcing effects when administered into the nucleus basalis of the rat's ventral pallidum and these effects are encoded by its carboxy-terminal amino acid sequence. The present study examined the effect of prior treatment with the tachykinin NK1 receptor antagonist WIN51,708 on the conditioned place preference produced by intrabasalis injection of substance P and its carboxy-terminal heptapeptide analog dimethyl-C7. Pretreatment with WIN51,708 (10 and 20 mg/kg, i.p.) dose-dependently reversed the place preference produced by intrabasalis substance P (0.74 pmol). The carboxy-terminal analog dimethyl-C7 (0.74 pmol) was also found to act as a reinforcer following injection into the nucleus basalis region, but unlike for substance P, the behavioral effects of dimethyl-C7 could not be completely antagonized by joint administration of the NK1 antagonist. When injected alone, WIN51,708 did not influence the preference behavior. These findings suggest that the reinforcing effects of substance P in the nucleus basalis region might be mediated via NK receptive sites. The failure of WIN51,708 to completely antagonize the behavioral effects of dimethyl-C7 is interesting in the light of evidence, indicating that the carboxy-terminal substance P analog shows higher affinity for the tachykinin NK3 than for the NK1 receptor subtype.

Androstanes↗
PubMed1999

Tumour necrosis factor alpha and interleukin 1beta in relapse of Crohn's disease.

BACKGROUND: Concentrations of proinflammatory cytokines are increased in the intestinal mucosa of patients with active Crohn's disease. Experimental immunotherapeutic interventions with anticytokine agents in refractory Crohn's disease show that tumour necrosis factor alpha (TNF alpha) may be an important mediator of inflammation. We investigated the relation between production of TNF alpha and interleukin 1beta by mononuclear cells of the colonic lamina propria in patients with remitting Crohn's disease and the risk of relapse. METHODS: We followed up 137 patients with Crohn's disease in steroid-induced remission for 1 year. Secretion of proinflammatory cytokines (tumour necrosis factor alpha [TNF alpha] and interleukin 1beta) was assessed after short-term culture of human lamina propria mononuclear cells. FINDINGS: Increased secretion of TNF alpha and interleukin 1beta were predictive for acute relapses within the next year. Site and extent of disease, baseline demographics, and serum acute-phase proteins had little predictive value. INTERPRETATION: TNF alpha is important as a target molecule for immune interventions in Crohn's disease. The capacity to produce TNF alpha or interleukin 1beta may identify patients who would benefit from anti-inflammatory remission maintenance.

Biomarkers↗
PubMed1999

Pretreatment with fragments of substance-P or with cholecystokinin differentially affects recovery from sub-total nigrostriatal 6-hydroxydopamine lesion.

The neuropeptide substance P is known to have mnemogenic and reinforcing actions and can exert neurotrophic and regenerative effects in vitro as well as in vivo. Furthermore, our previous work in the rat showed that either pre- or post-lesion treatment with substance P can promote functional recovery in cases of partial nigrostriatal dopamine lesions. Other work has provided evidence that the effects of substance P might be differentially encoded by its C- and N-terminal fragments. The C-terminal fragment was found to be reinforcing, whereas the mnemogenic as well as neurotrophic properties have been ascribed to the N-terminal sequences. Given these relations, we asked here whether pre-lesion treatment with either a C- or an N-terminal fragment of substance P might differentially affect the behavioral and neurochemical outcome of nigrostriatal dopamine lesions. Therefore, either substance P1-7 or substance P5-11 (37 nmol/kg each) was administered intraperitoneally daily for eight consecutive days before unilateral 6-hydroxy-dopamine lesions of the substantia nigra. Control rats received pre-lesion treatment with vehicle. Furthermore, we investigated the effects of pre-treatment with Boc-cholecystokinin-4 (0.91 nmol/kg), as we had found an increase in dopamine metabolism in animals that were pre-treated with cholecystokinin-8 in a former study. In accordance with our previous work, drug treatment effects were observed when excluding animals with most severe dopamine lesions: In animals with partial lesions (residual neostriatal dopamine levels of more than 10%), lesion-dependent asymmetries in turning behavior were observed in animals that were pre-treated with vehicle-, substance P1-7, or Boc-cholecysto-kinin-4, whereas turning after pre-treatment with substance P5-11 was not significantly asymmetrical. Furthermore, the ipsi- and contra-lateral neostriatal dopamine levels did not differ significantly in this group. Moreover, pre-treatment with substance P5-11 affected dopamine metabolism in the neostriatum and in the ventral striatum, as indicated by increased ratios of dihydroxyphenyllic acid to dopamine. The data provide the first evidence that the promotive effects of substance-P treatment in the unilateral dopamine lesion model might be mediated by its C-terminal and might depend on actions on residual dopamine mechanisms.

Animals↗
PubMed1998

Increased secretion of pro-inflammatory cytokines by circulating polymorphonuclear neutrophils and regulation by interleukin 10 during intestinal inflammation.

BACKGROUND: Concentrations of pro-inflammatory cytokines are increased in the intestinal mucosa of patients with active inflammatory bowel disease (IBD). Polymorphonuclear neutrophil granulocytes (PMN) are the most abundant cell type in intestinal lesions in IBD. Interleukin 10 (IL-10) is an important contra-inflammatory cytokine which induces downregulation of pro-inflammatory cytokines. AIMS: To investigate whether PMN from patients with IBD or infectious colitis, respectively, secrete increased amounts of pro-inflammatory cytokines and can be regulated by IL-10. METHODS: Secretion (ELISA) as well as corresponding mRNA levels (semiquantitative RT-PCR) of pro-inflammatory cytokines (IL-1 beta, TNF-alpha) and of IL-1 receptor antagonist were assessed in peripheral PMN. RESULTS: PMN from patients with IBD are primed to secrete enhanced amounts of pro-inflammatory cytokines accompanied by detection of corresponding mRNAs in comparison with normal controls. This finding is not specific for IBD but rather reflects intestinal inflammation in general. IL-10 markedly inhibited proinflammatory cytokine secretion as well as corresponding mRNA concentrations. CONCLUSIONS: PMN are an important source of pro-inflammatory cytokines in patients with intestinal inflammation and can be downregulated by IL-10.

Adolescent↗
PubMed1998

Activation of nuclear factor kappa B inflammatory bowel disease.

BACKGROUND: Expression of pro-inflammatory cytokines is increased in the intestinal lamina propria of patients with inflammatory bowel disease (IBD). Nuclear factor kappa B (NF kappa B) controls transcription of inflammation genes. On activation, NF kappa B is rapidly released from its cytoplasmic inhibitor (I kappa B), transmigrates into the nucleus, and binds to DNA response elements in gene promoter regions. AIMS: To investigate whether increased activation of NF kappa B is important in IBD and may be down-regulated by anti-inflammatory treatment. METHODS: Activation of NF kappa B was determined by western blot assessment and electrophoretic mobility shift assay in nuclear extracts of colonic biopsy samples as well as lamina propria mononuclear cells. RESULTS: Nuclear levels of NF kappa B p65 are increased in lamina propria biopsy specimens from patients with Crohn's disease in comparison with patients with ulcerative colitis and controls. Increased activation of NF kappa B was detected in lamina propria mononuclear cells from patients with active IBD. Corticosteroids strongly inhibit intestinal NF kappa B activation in IBD in vivo and in vitro by stabilising the cytosolic inhibitor I kappa B alpha against activation induced degradation. CONCLUSIONS: In both IBDs, but particularly Crohn's disease, increased activation of NF kappa B may be involved in the regulation of the inflammatory response. Inhibition of NF kappa B activation may represent a mechanism by which steroids exert an anti-inflammatory effect in IBD.

Adolescent↗
PubMed1997

Pretreatment with neurokinin substance P but not with cholecystokinin-8S can alleviate functional deficits of partial nigrostriatal 6-hydroxydopamine lesion.

The neuropeptide substance P (SP) has been implicated in the control of various neuro-behavioral functions including reinforcement and learning processes. It also exerts neurotrophic and regenerating effects in vitro and in vivo. A previous study indicated a potential therapeutic effect of SP in rats with partial 6-hydroxydopamine lesions of the nigrostriatal dopamine system when SP was administered after the lesion. The purpose of the present study was to determine whether prelesion treatment with SP would also interact with the effects of unilateral 6-hydroxydopamine lesion of the substantia nigra. Thus, SP (50 micrograms/kg) was administered i.p. on 8 consecutive days prior to unilateral lesion of the substantia nigra. Furthermore, we investigated the effects of prelesion treatment with cholecystokinin-8S (CCK; 1 microgram/kg), another neuropeptide, which is closely related to dopaminergic neurons, and which also can have neurotrophic and neuroprotective functions. Our results show that animals with partial neostriatal dopamine depletions (residual dopamine levels of more than 10%) did not show turning asymmetries when pretreated with SP, whereas animals pretreated with vehicle exhibited an initial ipsiversive asymmetry from which they recovered. In contrast, behavioral asymmetries were most pronounced in animals which had been pretreated with CCK. These peptide treatments did not affect the degree of neostriatal dopamine depletion; however, dihydroxyphenylacetic acid/dopamine ratios were enhanced in the neurostriatum of animals with partial dopamine damage after SP- and CCK-pretreatment, and in the ventral striatum of SP-pretreated animals. These data provide evidence that prelesion treatment with SP, but not with CCK, can alleviate functional deficits induced by a partial nigro-striatal dopamine lesion. This effect may be related to enhanced ventral striatal dopamine activity and/or to the peptide's known effects on learning, motivation, and emotion.

Animals↗
PubMed1996

Recombinant erythropoietin for the treatment of anemia in inflammatory bowel disease.

BACKGROUND: Some patients with inflammatory bowel disease have anemia that is refractory to treatment with iron and vitamins. We examined whether administering iron and recombinant erythropoietin could raise hemoglobin levels in such patients. METHODS: Thirty-four patients with inflammatory bowel disease (15 with ulcerative colitis and 19 with Crohn's disease) and anemia refractory to iron therapy (hemoglobin concentrations below 10.0 g per deciliter [6.2 mmol per liter]) were randomly assigned in a prospective, double-blind, 12-week trial to receive either oral iron (100 mg per day) and subcutaneous erythropoietin (150 U per kilogram of body weight twice per week) (n=17) or oral iron and placebo (n=17). The primary measure of efficacy was an increase in hemoglobin levels of more than 1.0 g per deciliter (0.62 mmol per liter). Additional analyses were performed with other patients with inflammatory bowel disease. RESULTS: The severity of anemia was related to clinical disease activity as well as to in vitro monocyte secretion of interleukin-1 beta, a proinflammatory cytokine. Serum erythropoietin concentrations were increased in 52 randomly selected outpatients with inflammatory bowel disease and anemia, but the concentrations were inadequate in relation to the degree of anemia. Twelve weeks of therapy with recombinant erythropoietin and oral iron increased mean (+/-SE) hemoglobin concentrations from 8.81+/-0.27 g per deciliter (5.47+/-0.17 micromol per liter) to 10.52+/-0.41 g per deciliter (6.5+/-0.25 micromol per liter), whereas hemoglobin concentrations in the placebo group decreased from 8.69+/-0.11 g per deciliter (5.4+/-0.068 micromol per liter) to 7.84+/- 0.33 g per deciliter (4.9+/-0.2 mmol per liter) (P<0.001). After 12 weeks, hemoglobin levels had increased by more than 1.0 g per deciliter in 82 percent of the patients in the erythropoietin group, as compared with 24 percent of those in the placebo group (P=0.002). There were five treatment failures in the placebo group and two in the erythropoietin group (P=0.18); treatment failure was defined as a decrease in hemoglobin levels of more than 2.0 g per deciliter (1.24 micromol per liter) to a value below 8.0 g per deciliter (4.96 micromol per liter) or any decrease to less than 6.5 g per deciliter (4.03 micromol per liter). CONCLUSIONS: In patients with inflammatory bowel disease and anemia refractory to treatment with iron and vitamins, treatment with oral iron and recombinant erythropoietin can raise hemoglobin levels.

Adolescent↗
PubMed1994

Chronic administration of neurokinin SP improves maze performance in aged Rattus norvegicus.

Deficits in associative functions seen with senescence may be based, at least in part, on a decreased availability of trophic factors in the CNS. A reduced concentration of neurokinins, including undecapeptide substance P (SP), also accompanies aging. Thus, given the change in SP metabolism and the known mnemogenic as well as neurotrophic/neuroprotective effects of the peptide, it seems possible that age-related deficits in associative processes could be influenced by treatment with exogenous SP. In the present study, 30-month-old Wistar rats were injected daily with SP (50 or 250 micrograms/kg, intraperitoneally) starting 1 week before they were tested on the Morris water maze task and on motor coordination tests. Control groups included vehicle-injected old and adult (3-month-old) rats. Over the days of maze testing, application of the substances was performed 5 h after testing daily for 15 days and after the last drug delivery, maze testing was continued for 4 more days. The main finding of this study is that chronic administration of both dosages of SP (50 and 250 micrograms/kg) improved the maze performance of the old rats. This facilitatory effect of SP on performance was also evident after the drug treatment had been terminated in the course of maze testing. Furthermore, chronic application of SP in a dose range of 50-250 micrograms/kg was found to reduce age-related deficits in motor capacities.

Aging↗
PubMedDate not supplied

Immunopharmacology of 5-aminosalicylic acid and of glucocorticoids in the therapy of inflammatory bowel disease.

Glucocorticoids as well as 5-aminosalicylic acid have been used successfully in different formulations during the past 40 years for the treatment of both acute and chronic inflammation in inflammatory bowel disease. The mechanism by which the drugs exert their actions are only partially known. Recent studies of the immunoregulation in the lamina propria provide evidence that numerous therapeutic mechanisms contribute to the efficacy of these drugs including the inhibition of arachidonic acid metabolism, a decrease in radical formation by oxygen radical scavenging, an inhibition of both in vivo and in vitro activation of peripheral and intestinal lymphocytes. Moreover direct immunoregulatory effects exerted by the drug may be important in influencing the complex balance of pro-inflammatory mechanisms during active intestinal inflammation. Such effects are the inhibition of both peripheral and intestinal B lymphocyte immunoglobulin secretion as well as the inhibition of pro-inflammatory cytokine production and their binding to receptors. Some of these immunoregulatory effects appear to be mediated by an inhibition of the activation of the nuclear factor kappa B transcription factor family by steroids and (less potent) aminosalicylic acid. Activation of nuclear factor kappa B appears to be pivotal for the sustained upregulation of inflammation molecule expression in many inflammatory diseases. It seems, therefore, most likely that the enormous therapeutic potency of steroids, as well as the anti-inflammatory properties of 5-aminosalicylic acid, are not achieved by a single action of the drug. The complex orchestration of numerous inhibitory interactions with pro-inflammatory principles will add to the therapeutic potential of steroids and of 5-aminosalicylic acid in the treatment of both acute and chronic intestinal inflammation.

Anti-Inflammatory Agents, Non-Steroidal↗