Irradiation of the head by 60Co opens the blood-brain barrier for drugs in rats

The passage of 6 model drugs; acetylsalicylic acid, chloramphenicol, ethimizol, carbisocaine, heptacaine, and diazepam, through the blood-brain barrier, was determined in unirradiated control rats and in animals 1, 3, and 7 days after irradiation of the head only with a dose of 25 Gy from a 60Co source. The brain uptake index (BUI), which compares the uptake of the test substance with that of 3H2O 5 s after their injection into the common carotid artery, was significantly increased in comparison with unirradiated controls 7 days after irradiation, for all substances tested except for ethimizol. For acetylsalicylic acid and chloramphenicol it was also significantly increased in the other time intervals. The less lipophilic substances showed a greater relative increase of BUI than the more lipophilic ones.     

Nitric oxide-dependent blood-brain barrier permeability alteration in the rat brain

The role of nitric oxide (NO), a well known vasodilator, in the regulation of blood-brain barrier (BBB) permeability is not clear. Therefore, the present study was planned to assess the role of NO-releasing compounds like sodium nitroprusside (SNP) and the active metabolite of molsidomine, SIN-1, as well as a precursor of NO, L-arginine, on this physiological barrier. The permeability was assessed by using several tracers. All three agents increased the permeability of BBB to the tracer. The increase in permeability caused by L-arginine was not blocked by N-nitro-L-arginine methyl ester (L-NAME). L-Arginine-treated brains did not show an elevation of nitrite content, thus ruling out the possibility of NO generation and its involvement in BBB permeability alteration. It is concluded that NO itself causes an increase in the permeability of BBB. However arginine-induced opening is not NO mediated.CDRI Communication Number: 5178.     

A relevant in vitro rat model for the evaluation of blood-brain barrier translocation of nanoparticles

Poly(MePEG₂₀₀₀cyanoacrylate-co-hexadecylcyanoacrylate) (PEG-PHDCA) nanoparticles have demonstrated their capacity to reach the rat central nervous system after intravenous injection. For insight into the transport of colloidal systems across the blood-brain barrier (BBB), we developed a relevant in vitro rat BBB model consisting of a coculture of rat brain endothelial cells (RBECs) and rat astrocytes. The RBECs used in our model displayed and retained structural characteristics of brain endothelial cells, such as expression of P-glycoprotein, occludin and ZO-1, and immunofluorescence studies showed the specific localization of occludin and ZO1. The high values of transendothelial electrical resistance and low permeability coefficients of marker molecules demonstrated the functionality of this model. The comparative passage of polyhexadecylcyanoacrylate and PEG-PHDCA nanoparticles through this model was investigated, showing a higher passage of PEGylated nanoparticles, presumably by endocytosis. This result was confirmed by confocal microscopy. Thanks to a good in vitro/in vivo correlation, this rat BBB model will help in understanding the mechanisms of nanoparticle translocation and in designing new types of colloidal carriers as brain delivery systems.Received 4 March 2005; accepted 14 April 2005     

电离辐射引发细胞凋亡的信号通路

电离辐射诱发细胞产生凋亡与细胞的辐射敏感性有关,而辐射的生物学效应则因其引发细胞凋亡的信号通路不同而有差异。辐射诱发凋亡作用过程至少包括SAPK／JNK信号通路及依赖于DNA损伤、依赖于胞质电离损伤和依赖于质膜损伤的四种信号通路。本文就辐射诱发细胞凋亡的信号传导途径进行简介。     

Sympathectomy enhances the substance P-mediated breakdown of the blood-aqueous barrier in response to infrared irradiation of the rabbit iris

Summary Rabbits were subjected to infrared irradiation of the iris 1 month after unilateral cervical sympathectomy. The resulting breakdown of the blood-aqueous barrier was greatly enhanced on the sympathectomized side. In contrast, the response to intravitreally injected substance P (SP) was the same in both eyes. The enhancement of the response to IR irradiation could be abolished by pretreatment with an SP antagonist, (D-Pro², D-Trp^7,9)-SP.This study was supported by grants from the Swedish MRC (04X-1007, 14X-2321), the Medical Faculty of Lund, Ferring Arzneimitel, Kiel (Federal Republic of Germany) and Ferring Pharmaceuticals, Malmö (Sweden).     

Transport of the synthetic peptide DSIP through the blood-brain barrier in rabbit

Summary The synthetic delta sleep inducing peptide (DSIP) passes the blood-brain barrier, since i.v. injection in free moving rabbits (30 nmoles/kg) significantly increases the cortical delta activity and decreases the motor activity during 5 h.Acknowledgment. This work was supported by grants from the Swiss National Science Foundation (Nos 3.871-72, 3.525.75, 3.443.074, 3.780.076), Fonds für Lehre und Forschung der Universität Basel, Merck Sharp and Dohme (USA), Ciba-Stiftung Basel.     

Transport of the synthetic peptide DSIP through the blood-brain barrier in rabbit

The synthetic delta sleep inducing peptide (DSIP) passes the blood-brain barrier, since i.v. injection in free moving rabbits (30 nmoles/kg) significantly increases the cortical delta activity and decreases the motor activity during 5 h.     

Aspects of interastrocytic gap junctions in blood-brain barrier in the experimental penumbra area,revealed by transmission electron microscopy and freeze-fracture

Summary Interastrocytic gap junctions in the blood-brain barrier of the experimental penumbra area were studied in the cat caudate nucleus 1 h after ischemia. Transmission electron microscopy and freeze-fracture studies revealed only slight changes in gap junctions between astrocytes, indicating that these junctions are very resistant to hypoxia.Authors are grateful to M. Guerricabeitia and Ch. Bourdier for their technical and secretarial assistance.     

Aspects of interastrocytic gap junctions in blood-brain barrier in the experimental penumbra area, revealed by transmission electron microscopy and freeze-fracture

Interastrocytic gap junctions in the blood-brain barrier of the experimental penumbra area were studied in the cat caudate nucleus 1 h after ischemia. Transmission electron microscopy and freeze-fracture studies revealed only slight changes in gap junctions between astrocytes, indicating that these junctions are very resistant to hypoxia.     

Acute60Co-gamma irradiation of rats decreases the inhibitory effect of succinate on the lipid peroxidation of liver mitochondria

Summary Succinate inhibits NADPH-dependent lipid peroxidation of liver mitochondria. This effect of succinate decreased 12 h after whole-body⁶⁰Co-gamma irradiation, depending on the dose of irradiation.     

Decision-making at the surface of the intact or barrier disrupted skin: potential applications for vaccination or therapy

The skin is a highly accessible organ and constitutes an active immunological site. Both these properties make this surface an attractive route for what promises to be a cost-effective, simple, practical and needle-free delivery of vaccines and immunomodulators. Less obvious is the fact that the state of the skin barrier can influence quantitative and qualitative aspects of antigen-specific immune responses. The everyday decision-making at the skin epithelium concerns the choice between the induction of an immune response and the establishment of a state of non-responsiveness (tolerance). This decision is influenced by various factors such as the dose, the route (intact vs barrier-disrupted skin), the cytokine microenvironment and the nature of the antigenic stimulus. By increasing our understanding of how immune responses are regulated in the epidermis we can envisage the development of immunisation protocols aimed at eliciting a protective immune response or inducing tolerance, with direct applications to preventive or therapeutic vaccination, respectively.Received 29 November 2004; received after revision 2 February 2005; accepted 22 February 2005     

New bone induction by demineralized bone matrix in immunosuppressed rats

Subcutaneous implantation of demineralized bone matrix (DBM) initiates a sequence of developmental events which culminate in endochondral bone formation. To test the effects of T-cell deficiency on new bone formation, the morphology of DBM-induced bone was examined in rats thymectomized at three weeks of age and in thymectomized or nonthymectomized rats lethally irradiated and reconstituted with syngeneic bone marrow. At 24 days after implantation, bone induction in control rats was appropriate for their age, while thymectomized-irradiated-reconstituted rats and thymectomized rats had significantly more new bone and larger bone marrow space than the controls. In non-thymectomized, irradiated and reconstituted rats, bone induction occurred in only 25% of the animals, compared to 95% in other groups.     

Suppression of the immune response by drugs interfering with the metabolism of serotonin

Summary The work was based on the assumption that neurohumoral control of the immune response, particularly in stressed animals, involves central serotoninergic mechanisms. Rats immunized with sheep erythrocytes were stressed by repeated restraints and/or treated with a precursor of serotonin (5-hydroxytryptophan, 5-HTP) or with an inhibitor of serotonin synthesis (parachlorophenylalanine, PCPA). As expected, repeated stresses reduced the plaque-forming cell (PFC) response. Treatment with 5-HTP also reduced the PFC response, and potentiated the immunosuppressive effect of stress. This was accompanied by increased metabolism of serotonin in the brain, as indicated by increased concentration of its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in cerebral tissue. Treatment with PCPA also suppressed the PFC response, but this suppression was accompanied by decreased levels of brain serotonin and of 5-HIAA. Plasma corticosterone levels were elevated in rats treated with PCPA. It seems that putative central effects of PCPA on serotoninergic regulation of the immune response were outweighed by its effects on corticosterone secretion and/or on lymphoid cells.     

Role of dystrophin and utrophin for assembly and function of the dystrophin glycoprotein complex in non-muscle tissue

The dystrophin glycoprotein complex (DGC) is a multimeric protein assembly associated with either the X-linked cytoskeletal protein dystrophin or its autosomal homologue utrophin. In striated muscle cells, the DGC links the extracellular matrix to the actin cytoskeleton and mediates three major functions: structural stability of the plasma membrane, ion homeostasis, and transmembrane signaling. Mutations affecting the DGC underlie major forms of congenital muscle dystrophies. The DGC is prominent also in the central and peripheral nervous system and in tissues with a secretory function or which form barriers between functional compartments, such as the blood-brain barrier, choroid plexus, or kidney. A considerable molecular heterogeneity arises from cell-specific expression of its constituent proteins, notably short C-terminal isoforms of dystrophin. Experimentally, the generation of mice carrying targeted gene deletions affecting the DGC has clarified the interdependence of DGC proteins for assembly of the complex and revealed its importance for brain development and regulation of the ’milieu intérieur. Here, we focus on recent studies of the DGC in brain, blood-brain barrier and choroid plexus, retina, and kidney and discuss the role of dystrophin isoforms and utrophin for assembly of the complex in these tissues. Received 4 October 2005; received after revision 14 March 2006; accepted 5 April 2006     

Wound-induced alterations in survival of60Co irradiated mice: importance of wound timing

Summary Wounding mice shortly before or shortly after lethal⁶⁰Co irradiation enhances survival. Survival of wounded-irradiated mice may be due to enhanced hematopoietic recovery as measured by endogenous spleen colony (E-CFU-s) formation.Supported by the Armed Forces Radiobiology Research Institute, Defense Nuclear Agency, under research Work Unit 00129. Views presented in this paper are those of the authors; no endorsement by the Defense Nuclear Agency has been given or should be inferred.Research was conducted according to the principles enunciated in the Guide for the Care and Use of Laboratory Animals' prepared by the Institute of Laboratory Research, National Research Council.     

Possible role of growth hormone in the stimulation of the thymus of rats following irradiation of the head

Zusammenfassung Die Röntgenbestrahlung des Kopfes junger Ratten verursacht eine vermehrte DNS-Synthese im Thymus, was mit der Freisetzung von Wachstumshormon-ähnlichen Substanzen in Zusammenhang gebracht wird.

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Acknowledgment. This project was supported in part by a grant from the Israel Cancer Association.     

The effects of X-irradiation,applied in infancy to the head region,on the reproductive system of female rats

Résumé Les rats femelles de 8 jours, dont la tête a été irradiée à une dose atteignant 800 R croissent et se reproduisent normalement. L'ouverture du vagin s'affectue au même moment que chez des témoins. Quelques'un des corporea lutea des femelles gravides irradiées dépassent la taille et le poids maximum.