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- Bahrami, Fariba, et al.
(författare)
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Localization and comparative toxicity of methylsulfonyl-2,5-and 2,6-dichlorobenzene in the olfactory mucosa of mice
- 1999
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Ingår i: Toxicological Sciences. - 1096-6080 .- 1096-0929. ; 49:1, s. 116-123
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Tidskriftsartikel (refereegranskat)abstract
- Several methylsulfonyl (MeSO2) metabolites formed from chlorinated aromatic hydrocarbons have been identified in human milk, lung, and body fat, as well as in the tissues of Baltic grey seals and arctic polar bears. The tissue localization and nasal toxicity of two methylsulfonyl-substituted dichlorobenzenes (diCl-MeSO2-B), with the chlorine atoms in the 2,5-, and 2,6- positions, were investigated in female NMRI and C57B1 mice. Using tape-section autoradiography, animals dosed i.v. with 14C-labeled 2,5-, or 2,6-(diCl-MeSO2-B) showed a preferential uptake of radioactivity in the olfactory mucosa and the tracheobronchial epithelium. Histopathology showed that 2,6-(diCl-MeSO2- B) is a potent toxicant that induces necrosis in the olfactory mucosa following a single dose as low as 4 mg/kg (i.p. injection), whereas 2,5- (diCl-MeSO2-B) induced no signs of toxicity in the olfactory mucosa at doses as high as 130 mg/kg (i.p. injection). Necrosis of the Bowman's glands was the first sign of 2,6-(diCl-MeSO2-B)-induced toxicity followed by degeneration of the neuroepithelium, which implies that the Bowman's gland may be the primary site of toxicity and degeneration of the neuroepithelium may be a secondary effect. Administration of the parent compounds, 1,3-dichlorobenzene and 1,4-dichlorobenzene, or the chlorinated analog 1,2,3-trichlorobenzene (85, 85, and 105 mg/kg, respectively; i.p. injection), induced no signs of toxicity in the olfactory mucosa. These and previous results suggest that 2,6- positioned chlorine atoms and an electron withdrawing substituent in the primary position is an arrangement that predisposes for toxicity in the olfactory mucosa.
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- Bergstrom, U, et al.
(författare)
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Drug targeting to the brain: Transfer of picolinic acid along the olfactory pathways
- 2002
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Ingår i: Journal of Drug Targeting. - : Informa UK Limited. - 1061-186X .- 1029-2330. ; 10:6, s. 469-478
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Tidskriftsartikel (refereegranskat)abstract
- Picolinic acid (PA) protects against quinolinic acid- and kainic acid-induced neurotoxicity in the brain. To study the uptake of PA to the brain, we administered [H-3]PA via a unilateral nasal instillation or iv injection to mice. Autoradiography demonstrated a rapid uptake of radioactivity in the olfactory nerve layer and in the ipsilateral olfactory bulb (OB) following nasal instillation of [H-3]PA. After 4h, there was a high level of radioactivity in the central parts of the ipsilateral OB and olfactory peduncle. Moreover, iv injection of [H-3]PA demonstrated a selective uptake and retention of radioactivity in the OB. Gas chromatography-mass spectrometry (GC-MS) demonstrated the presence of PA and PA-glycine conjugate in the OB. In mice with reduced peripheral olfactory innervations there was a decreased uptake of [H-3]PA in the OB as compared to controls suggesting that an intact olfactory neuroepithelium, is a prerequisite for an uptake of PA to the OB. There is an increased interest in brain targeting of drugs with limited ability to pass the blood-brain barrier. The present results demonstrate that PA fulfils structural requirements for a transfer along the olfactory pathways to the brain.
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- Karlsson, O, et al.
(författare)
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Environmental neurotoxin interaction with proteins: Dose-dependent increase of free and protein-associated BMAA (β-N-methylamino-L-alanine) in neonatal rat brain
- 2015
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5, s. 15570-
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Tidskriftsartikel (refereegranskat)abstract
- β-Methylamino-L-alanine (BMAA) is implicated in the aetiology of neurodegenerative disorders. Neonatal exposure to BMAA induces cognitive impairments and progressive neurodegenerative changes including intracellular fibril formation in the hippocampus of adult rats. It is unclear why the neonatal hippocampus is especially vulnerable and the critical cellular perturbations preceding BMAA-induced toxicity remains to be elucidated. The aim of this study was to compare the level of free and protein-associated BMAA in neonatal rat brain and peripheral tissues after different exposures to BMAA. Ultra-high performance liquid chromatography-tandem mass spectrometry analysis revealed that BMAA passed the neonatal blood-brain barrier and was distributed to all studied brain areas. BMAA was also associated to proteins in the brain, especially in the hippocampus. The level in the brain was, however, considerably lower compared to the liver that is not a target organ for BMAA. In contrast to the liver there was a significantly increased level of protein-association of BMAA in the hippocampus and other brain areas following repeated administration suggesting that the degradation of BMAA-associated proteins may be lower in neonatal brain than in the liver. Additional evidence is needed in support of a role for protein misincorporation in the neonatal hippocampus for long-term effects of BMAA.
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