Biomedical subjects

M Schwaninger

Publications and source records attributed to M Schwaninger.

45 records · Page 3Linked to original sources

PubMed1993

The immunosuppressive drugs cyclosporin A and FK506 inhibit calcineurin phosphatase activity and gene transcription mediated through the cAMP-responsive element in a nonimmune cell line.

Cyclosporin A and the macrolide tacrolimus (FK506) are powerful immunosuppressive drugs that in T cells inhibit the calcium/calmodulin-dependent phosphatase calcineurin thereby preventing the activation of T-cell-specific transcription factors, such as NF-AT, involved in lymphokine gene expression. While this may explain, at least in part, the mechanism of cyclosporin A/FK506 immunosuppression, additional mechanisms have to be invoked in order to explain the pharmacological properties and toxic effects of these drugs, such as nephrotoxicity and neurotoxicity. We have studied the effects of cyclosporin A and FK506 on calcineurin phosphatase activity and gene transcription mediated by the cAMP-responsive element (CRE), a binding site of the ubiquitous transcription factor CREB. A reporter gene was placed under the transcriptional control of the CRE of the rat glucagon gene and transiently transfected into the glucagon-expressing cell line alpha TC2. Cyclosporin A and FK506 inhibited depolarization-induced gene transcription in a concentration-dependent manner (IC50 of about 1 nM and 30 nM for FK506 and cyclosporin A, respectively). Both cyclosporin A and FK506 inhibited calcineurin phosphatase activity at drug concentrations that inhibited gene transcription. The FK506 analogue rapamycin had no effect on calcineurin activity and gene transcription, but excess concentrations of rapamycin prevented the effects of FK506 on both calcineurin activity and gene transcription. These results support the notion that the interaction of drug-immunophilin complexes with calcineurin may be the molecular basis of cyclosporin A/FK506-induced inhibition of CREB/CRE-mediated gene transcription. The ability to interfere with CREB/CRE-mediated gene transcription represents a novel mechanism of cyclosporin A/FK506 action which may underlie pharmacological effects and toxic manifestations of these potent immunuosuppressive drugs.

Activating Transcription Factor 1↗

PubMed1993

[Gasperini syndrome--differential diagnosis of peripheral facial nerve paralysis. Neurologic and imaging findings].

The Gasperini syndrome is a cause of peripheral facial palsy: In the following case report, a 75-year-old woman is described who presented with a peripheral left facial palsy. On examination left beating nystagmus was found with contralateral loss of pain and temperature affecting the right side of the body but sparing the face. The signs and symptoms corresponded to the Gasperini syndrome caused by a lesion in the dorsal caudal pons in the region of the anterior inferior cerebellar artery. MR imaging confirmed a lesion in this site.

Aged↗

PubMed1992

Spinal canal metastases: a late complication of glioblastoma.

The case of a 41 year old woman with a cerebral glioblastoma is reported who developed paraplegia due to a pathologically confirmed spinal metastasis. This and 22 other case histories from the literature suggest that spinal seeding is a rather late complication of cerebral glioblastomas that can be diagnosed on clinical grounds with the help of myelography, CSF cytology and MR imaging.

Adult↗

PubMed1987

Effect of human growth hormone-releasing hormone on the release of dynorphin-like immunoreactivity, luteinizing hormone, and follicle-stimulating hormone from rat adenohypophysis in vitro.

The effect of GH-releasing hormone (GHRH) on the release of the endogenous opioid dynorphin from rat adenohypophysis was investigated in vitro. Rat anterior pituitary quarters were incubated in vitro, and hormone release into the incubation medium was measured by RIAs. Human pancreatic GHRH [hpGHRH-(1-44)] as well as human Leu27,Gly45-GHRH [GHRH-(1-45)] enhanced the secretion of dynorphin A1-13-like immunoreactivity (Dyn A1-13-IR) in a concentration-dependent manner. The concentrations of hpGHRH-(1-44) that stimulated the release of Dyn A1-13-IR were about 100-fold higher than those that enhanced GH secretion. GH release induced by hpGHRH-(1-44) was blocked by somatostatin (IC50, approximately 10 nM) without affecting hpGHRH-(1-44)-induced release of Dyn A1-13-IR. GH release was elicited by prostaglandin E2, while Dyn A1-13-IR secretion remained unchanged. At concentrations that enhanced Dyn A1-13-IR release, hpGHRH-(1-44) also elicited LH and FSH secretion. The LHRH antagonist D-pGlu1, D-Phe2,D-Trp3,6-LHRH blocked the secretion of Dyn A1-13-IR, LH, and FSH induced by hpGHRH-(1-44), whereas the LHRH antagonist did not influence the simultaneous GH release elicited by hpGHRH-(1-44). A possible direct effect of GHRH on the LHRH receptor was examined in radioligand binding studies using iodinated D-Ala6, des-Gly10-LHRH ethylamide (LHRH-A). The binding of [125I]iodo-LHRH-A to rat anterior pituitary membranes was completely displaced by hpGHRH-(1-44) and GHRH-(1-45). The deduced apparent dissociation constants were about 3 orders of magnitude higher than that of LHRH-A, but were close to those concentrations that enhanced Dyn A1-13-IR release. We conclude that GHRH-induced release of Dyn A1-13-IR is unrelated to GH release. High concentrations of GHRH may interact directly with LHRH receptors on gonadotrophs and thereby enhance the release of LH, FSH, and Dyn A1-13-IR.

Animals↗

PubMed1987

Release of dynorphin-like immunoreactivity from rat adenohypophysis in vitro during inhibition of anterior pituitary hormone secretion from individual cell types.

LHRH has previously been found to be the only known hypothalamic releasing factor which can specifically stimulate the release of the opioid dynorphin and other proenkephalin B-derived peptides from the rat adenohypophysis in vitro. In the present study the mechanisms that regulate dynorphin release were further characterized. It was examined whether or not dynorphin release from the adenohypophysis in vitro is altered during inhibition of the secretion of various anterior pituitary hormones. Rat anterior pituitary quarters were incubated in vitro and hormone release into the incubation medium was measured by RIAs. Somatostatin, dopamine, T3, dexamethasone, and 5 alpha-dihydrotestosterone were used to inhibit the secretion of GH, PRL, TSH, ACTH/beta-endorphin, or LH/FSH, respectively. GH, PRL, or beta-endorphin release was inhibited without affecting the simultaneous release of dynorphin A-(1-13)-like immunoreactivity (Dyn A1-13-IR). Concentrations of T3, somatostatin, or dopamine which were effective in suppressing the evoked and/or basal release of TSH, GH, or PRL, respectively, produced no effect on Dyn A1-13-IR release caused by high potassium concentration (40 mM) or LHRH (500 pM). The LHRH-induced release of LH and FSH was inhibited by the glucocorticoid dexamethasone or the androgen 5 alpha-dihydrotestosterone. Under these conditions, Dyn A1-13-IR release was also reduced. However, whereas LH release was completely blocked by 5 alpha-dihydrotestosterone, FSH and Dyn A1-13-IR release was reduced only by 50%. The release of FSH and Dyn A1-13-IR in vitro from anterior pituitary glands taken from rats, castrated 3 weeks before, was enhanced to a similar extent (about 2.5-fold); the simultaneous enhancement of LH release was significantly (P less than 0.005) greater (about 5-fold). We conclude that the mechanisms which regulate the release and/or biosynthesis of dynorphin and other proenkephalin B-derived peptides of the adenohypophysis are similar to those of the gonadotropins but different from those of any other anterior pituitary hormone, and may be more closely related with FSH release than LH release. These data support the view that dynorphin of the normal rat adenohypophysis may be localized in at least a subpopulation of gonadotrophs.

Adrenalectomy↗

PubMed1986

Top concentrations of dynorphin-like immunoreactivity in fractions of rat anterior pituitary cells enriched in gonadotrophs.

A possible relationship between anterior pituitary cells containing luteinizing hormone (LH) and those containing the endogenous opioid dynorphin and other proenkephalin B-derived peptides was examined. Gonadotroph-enriched and gonadotroph-depleted cell fractions were prepared from cell suspensions of adult female rat anterior pituitary glands by centrifugal elutriation. Fractions with high or low concentrations of LH contained also high or low concentrations of dynorphin-like immunoreactivity. A positive correlation was found between the content in the eluted cell fractions of LH and dynorphin-like immunoreactivity with a correlation coefficient and a slope of the regression line close to one. Therefore, LH-containing and dynorphin-containing cells of the rat adenohypophysis exhibit almost the same characteristics under the conditions of centrifugal elutriation. This is consistent with the suggestion that dynorphin and other proenkephalin B-derived peptides may be colocalized with LH and/or follicle-stimulating hormone in at least some of the gonadotrophs of the rat anterior pituitary gland.

Animals↗

PubMed1985

Release of dynorphin-like immunoreactivity from rat anterior pituitary gland in vitro.

Rat anterior pituitary quarters were incubated in vitro and the release of dynorphin A1-13-like immunoreactivity (Dyn A1-13-IR) into the incubation medium was studied. An elevation of the potassium concentration of the incubation medium to 40 mmol/l increased the release of Dyn A1-13-IR in a calcium-dependent manner. Addition of luteinizing hormone-releasing hormone (LHRH) stimulated the release of Dyn A1-13-IR in a dose-dependent manner. The LHRH-induced release of Dyn A1-13-IR was almost completely prevented by omission of calcium ions from the incubation medium or by addition of the LHRH-antagonist D-pGlu1,D-Phe2,D-Trp3,6-LHRH. This is the first demonstration that dynorphin-like immunoreactivity can be released from the rat adenohypophysis through calcium-dependent mechanisms by both high potassium concentration and receptor-mediated stimulation.

Animals↗

PubMed1985

Corelease of dynorphin-like immunoreactivity, luteinizing hormone, and follicle-stimulating hormone from rat adenohypophysis in vitro.

Rat anterior pituitary quarters or acutely dispersed rat anterior pituitary cells were incubated in vitro, and the release of dynorphin A1-13-like immunoreactivity (Dyn A1-13-IR) into the incubation medium was studied. Addition of LHRH led to a concentration-dependent enhancement of the release of Dyn A1-13-IR with a maximum secretory rate which was about 4-fold higher than basal secretion. Dyn A1-13-IR was released by LHRH concomitantly with LH and FSH, and the concentration-response relationships as well as the time course were virtually identical. Gel filtration and HPLC revealed a single peak of Dyn A1-13-IR, with an apparent mol wt of about 6000. In addition to Dyn A1-13-IR, alpha-neo-endorphin-like immunoreactivity was released by LHRH. The LHRH-stimulated release of Dyn A1-13-IR was mimicked by the LHRH analog D-Ala6,des-Gly10-LHRH ethylamide and blocked in a competitive manner by the LHRH antagonist D-pGlu1,D-Phe2,D-Trp3,6-LHRH. Addition of TRH (5 microM), rat corticotropin-releasing factor (100 nM), arginine vasopressin (1 microM), or synthetic human pancreatic GH-releasing hormone (10 nM) produced no effect on Dyn A1-13-IR release. An extract of the rat medial basal hypothalamus stimulated the release of Dyn A1-13-IR and beta-endorphin-like immunoreactivity, and the former, but not the latter, effect was blocked by the LHRH antagonist D-pGlu1,D-Phe2,D-Trp3,6-LHRH. These results demonstrate that dynorphin-like material and other proenkephalin B-derived peptides are released concomitantly with LH and FSH from rat adenohypophysis in vitro upon activation of LHRH receptors. This may indicate that proenkephalin B-derived peptides coexist with LH and/or FSH in at least some gonadotrophs of the normal rat anterior pituitary gland.

Animals↗

PubMedDate not supplied

Hypothermia induced by atypical neuroleptics.

Hypothermia is a potentially life-threatening emergency. This article examines the case of a 34-year-old, mentally retarded man who experienced three episodes of hypothermia during recurrent exposure to pipamperone. After the pipamperone dose was largely reduced, no further hypothermic episodes occurred. Nine other cases of hypothermia with neuroleptic treatment were reported to the German Federal Institute of Drugs and Medical Devices from 1988 to 1997. A review of the cases revealed that nine of ten patients were treated with drugs that are potent antagonists of 5-HT2 receptors. In conjunction with experimental data, this suggests that antipsychotics with a strong 5-HT2 antagonistic component might be associated with hypothermia. Most of the newly developed "atypical" neuroleptic drugs belong to this group. Therefore, special attention for hypothermia is warranted during the use of "atypical" neuroleptics.

Adult↗