Author: Gray, James ; Kaya, Ecem ; Palmer, Ashley M ; Kirkegaard, Thomas ; Fog, Cathrine K ; Fernández-Suárez, María E ; Falah, Maysa ; Platt, Frances M ; Smith, Claire ; Smith, David

BACKGROUNDNiemann-Pick disease type C (NPC) is a rare prematurely fatal lysosomal lipid storage disease with limited therapeutic options. The prominent neuropathological hallmarks include hypomyelination and cerebellar atrophy. We previously demonstrated the efficacy of recombinant human heat shock protein 70 (rhHSP70) in preclinical models of the disease. It reduced glycosphingolipid levels in the central nervous system (CNS), improving cerebellar myelination and improved behavioural phenotypes in Npc1^nih (Npc1^-/-) mice. Furthermore, treatment with arimoclomol, a well-characterised HSP amplifier, attenuated lysosomal storage in NPC patient fibroblasts and improved neurological symptoms in Npc1^-/- mice. Taken together, these findings prompted the investigation of the effects of HSP amplification on CNS myelination.METHODSWe administered bimoclomol daily or rhHSP70 6 times per week to Npc1^-/- (BALB/cNctr-Npc1^m1N/J, also named Npc1^nih) mice by intraperitoneal injection from P7 through P34 to investigate the impact on CNS myelination. The Src-kinase inhibitor saracatinib was administered with/without bimoclomol twice daily to explore the contribution of Fyn kinase to bimoclomol's effects.FINDINGSTreatment with either bimoclomol or rhHSP70 improved myelination and increased the numbers of mature oligodendrocytes (OLs) as well as the ratio of active-to-inactive forms of phosphorylated Fyn kinase in the cerebellum of Npc1^-/- mice. Additionally, treatment with bimoclomol preserved cerebellar weight, an effect that was abrogated when co-administered with saracatinib, an inhibitor of Fyn kinase. Bimoclomol-treated mice also exhibited increased numbers of immature OLs within the cortex.INTERPRETATIONThese data increase our understanding of the mechanisms by which HSP70 regulates myelination and provide further support for the clinical development of HSP-amplifying therapies in the treatment of NPC.FUNDINGFunding for this study was provided by Orphazyme A/S (Copenhagen, Denmark) and a Pathfinder Award from The Wellcome Trust.

01 Jan 2010·Italian journal of anatomy and embryology = Archivio italiano di anatomia ed embriologia

Stress proteins in experimental nephrotoxicity: a ten year experience.

Article

Author: Francesca Bonomini ; Luigi Fabrizio Rodella ; Alessandra Stacchiotti ; Gaia Favero ; Rita Rezzani ; C. Rossini

Heat shock proteins and glucose-regulated proteins represent an extraordinary mechanism of defense induced in the kidney by chemicals or drugs and essential to survive. Here we resume our experience on the presence and regulation of stress proteins into acute and chronic nephrotoxic models in rodents and in vitro. In acute renal damage, induced in rats by a single injection of inorganic mercury, stress proteins enhanced in a dose-dependent manner to recover cytoskeleton and mitochondria and maintain nuclear activity. When we pre-treated mercury injected-rats with antioxidant melatonin or with bimoclomol, a stress proteins-coinducer, stress proteins expression was modulated together with tubular recovery. Similar data were obtained in ischemia-reperfusion in rats treated with stannous chloride, that provided cytoprotection stimulating heme oxygenase induction. During nephrotoxicity induced by administration of cyclosporine A at therapeutic dosage for 1-2 months, stress protein overexpression well correlated with oxidative and cell death, but decreased if we counteracted renal damage using antioxidants. In aluminium intoxication through drinking water for 3-6 months, we detected a time-dependent stress response in the rat kidney that was organ specific and different from the liver. In vitro studies on rat tubular proximal cells exposed to heavy metals demonstrated that stress protein expression was related to peculiar mechanisms of action of each metal. In conclusion, experimental studies on the renal chaperones can greatly contribute to understand their role, and agents able to modulate the stress response might be considered promising therapeutic tools to reduce nephrotoxicity.

01 Oct 2006·Toxicology LettersQ2 · MEDICINE

Bimoclomol ameliorates mercuric chloride nephrotoxicity through recruitment of stress proteins

Q2 · MEDICINE

Article

Author: Elisa Borsani ; Luigi Fabrizio Rodella ; Rita Rezzani ; Francesca Ricci ; Antonio Lavazza ; Rossella Bianchi ; Alessandra Stacchiotti

Bimoclomol (BIM), is a stress proteins coinducer, that acts synergistically with a mild stressor to activate cytoprotective stress proteins. BIM has been successfully utilized in animal models for the treatment of various nervous, cardiac and cerebrovascular diseases. Mercuric chloride (HgCl(2)) induces acute renal failure in rats by a single dosage. The present in vivo study was conducted to assess the efficacy of BIM against acute HgCl(2) nephrotoxicity. At different times after BIM and/or HgCl(2) exposure we evaluated renal morphology and the localization/abundance of three stress proteins (HSP72, GRP75, HSP60) by electron microscopy, immunohistochemistry and Western blot analysis. BIM delivery to rats 6h before mercury, ameliorated damage to renal ultrastructure, with recovery of tubular and mitochondrial membranes 24h after mercury treatment. In rats pretreated with BIM prior to HgCl(2) exposure, HSP72 was significantly overexpressed in proximal tubules in a time-dependent manner. In contrast, the amounts of GRP75 and HSP60 after BIM pretreatment were comparable to the group treated with mercury alone, but these stress proteins had translocated to the nuclei at 14 and 24h, respectively. These novel findings suggest that BIM mitigates HgCl(2) nephrotoxicity in rats through the early recruitment of stress proteins in midcortical proximal tubules that are the main renal mercury-targets.

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