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1.
Cell Death Dis ; 5: e1236, 2014 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-24853414

RESUMEN

Retinitis pigmentosa (RP) is a group of inherited diseases that cause blindness due to the progressive death of rod and cone photoreceptors in the retina. There are currently no effective treatments for RP. Inherited mutations in rhodopsin, the light-sensing protein of rod photoreceptor cells, are the most common cause of autosomal-dominant RP. The majority of mutations in rhodopsin, including the common P23H substitution, lead to protein misfolding, which is a feature in many neurodegenerative disorders. Previous studies have shown that upregulating molecular chaperone expression can delay disease progression in models of neurodegeneration. Here, we have explored the potential of the heat-shock protein co-inducer arimoclomol to ameliorate rhodopsin RP. In a cell model of P23H rod opsin RP, arimoclomol reduced P23H rod opsin aggregation and improved viability of mutant rhodopsin-expressing cells. In P23H rhodopsin transgenic rat models, pharmacological potentiation of the stress response with arimoclomol improved electroretinogram responses and prolonged photoreceptor survival, as assessed by measuring outer nuclear layer thickness in the retina. Furthermore, treated animal retinae showed improved photoreceptor outer segment structure and reduced rhodopsin aggregation compared with vehicle-treated controls. The heat-shock response (HSR) was activated in P23H retinae, and this was enhanced with arimoclomol treatment. Furthermore, the unfolded protein response (UPR), which is induced in P23H transgenic rats, was also enhanced in the retinae of arimoclomol-treated animals, suggesting that arimoclomol can potentiate the UPR as well as the HSR. These data suggest that pharmacological enhancement of cellular stress responses may be a potential treatment for rhodopsin RP and that arimoclomol could benefit diseases where ER stress is a factor.


Asunto(s)
Respuesta al Choque Térmico/efectos de los fármacos , Hidroxilaminas/farmacología , Células Fotorreceptoras de Vertebrados/efectos de los fármacos , Degeneración Retiniana/prevención & control , Retinitis Pigmentosa/prevención & control , Rodopsina/deficiencia , Rodopsina/metabolismo , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citoprotección , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Electrorretinografía , Humanos , Mutación , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/patología , Ratas , Ratas Sprague-Dawley , Ratas Transgénicas , Degeneración Retiniana/genética , Degeneración Retiniana/metabolismo , Degeneración Retiniana/patología , Degeneración Retiniana/fisiopatología , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/metabolismo , Retinitis Pigmentosa/patología , Retinitis Pigmentosa/fisiopatología , Rodopsina/genética , Factores de Tiempo , Transfección , Respuesta de Proteína Desplegada/efectos de los fármacos , Visión Ocular/efectos de los fármacos
2.
Biochem Soc Trans ; 33(Pt 4): 551-2, 2005 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16042542

RESUMEN

Neurodegenerative diseases are characterized by a number of common hallmarks, such as the presence of intracellular aggregates and activation of the apoptotic cell-death pathway. Intracellular chaperones, responsible for protein integrity and structural repair, may play a crucial role in the progression of a disease. In this paper, we aim to summarize our understanding of the role and potential of a particular family of chaperones, the heat-shock proteins, in neurodegeneration, by focusing our discussion on models of motoneuron death.


Asunto(s)
Proteínas de Choque Térmico/fisiología , Chaperonas Moleculares/fisiología , Enfermedad de la Neurona Motora/terapia , Neuronas Motoras/patología , Progresión de la Enfermedad , Humanos , Enfermedades del Sistema Nervioso Periférico/patología
3.
Exp Neurol ; 184(2): 636-47, 2003 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-14769355

RESUMEN

In this study, we examined the effect BRX-220, a co-inducer of heat shock proteins, in injury-induced peripheral neuropathy. Following sciatic nerve injury in adult rats and treatment with BRX-220, the following features of the sensory system were studied: (a) expression of calcitonin gene-related peptide (CGRP); (b) binding of isolectin B4 (IB4) in dorsal root ganglia (DRG) and spinal cord; (c) stimulation-evoked release of substance P (SP) in an in vitro spinal cord preparation and (d) nociceptive responses of partially denervated rats. BRX-220 partially reverses axotomy-induced changes in the sensory system. In vehicle-treated rats there is a decrease in IB4 binding and CGRP expression in injured neurones, while in BRX-220-treated rats these markers were better preserved. Thus, 7.0 +/- 0.6% of injured DRG neurones bound IB4 in vehicle-treated rats compared to 14.4 +/- 0.9% in BRX-220-treated animals. Similarly, 4.5 +/- 0.5% of DRG neurones expressed CGRP in the vehicle-treated group, whereas 9.0 +/- 0.3% were positive in the BRX-220-treated group. BRX-220 also partially restored SP release from spinal cord sections to electrical stimulation of primary sensory neurones. Behavioural tests carried out on partially denervated animals showed that BRX-220 treatment did not prevent the emergence of mechanical or thermal hyperalgesia. However, oral treatment for 4 weeks lead to reduced pain-related behaviour suggesting either slowly developing analgesic actions or enhancement of recovery processes. Thus, the morphological improvement seen in sensory neurone markers was accompanied by restored functional activity. Therefore, treatment with BRX-220 promotes restoration of morphological and functional properties in the sensory system following peripheral nerve injury.


Asunto(s)
Hidroxilaminas/farmacología , Neuronas Aferentes/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Dolor/fisiopatología , Nervio Ciático/fisiología , Animales , Axotomía , Western Blotting , Péptido Relacionado con Gen de Calcitonina/biosíntesis , Estimulación Eléctrica , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/fisiología , Proteínas HSP70 de Choque Térmico/efectos de los fármacos , Lectinas/metabolismo , Masculino , Neuronas Aferentes/fisiología , Técnicas de Cultivo de Órganos , Dolor/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Médula Espinal/efectos de los fármacos , Médula Espinal/fisiología , Nervios Espinales/fisiología , Sustancia P/biosíntesis , Sustancia P/efectos de los fármacos
4.
Exp Neurol ; 176(1): 87-97, 2002 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-12093085

RESUMEN

Heat shock proteins (hsps) are induced in a variety of cells following periods of stress, where they promote cell survival. In this study, we examined the effect of upregulating hsp expression by treatment with BRX-220, a co-inducer of hsps, on the survival of injured motoneurones. Following sciatic nerve crush at birth, rat pups were treated daily with BRX-220. The expression of hsp70 and hsp90, motoneurone survival, and muscle function was examined at various intervals later and the number of functional motor units was assessed by in vivo isometric tension recordings. Fourteen days after injury, significantly more motoneurones survived in the BRX-220-treated group (39 +/- 2.8%) compared to the saline-treated group (21 +/- 1.7%). Moreover, in the BRX-220-treated group no further loss of motoneurones occurred, so that at 10 weeks 42 +/- 2.1% of motoneurones survived compared to 15 +/- 0.6% in the untreated group. There were also more functional motor units in the hindlimb muscles of BRX-220-treated animals. In addition, treatment with BRX-220 resulted in a significant increase in the expression of hsp70 and hsp90 in glia and neurones. Thus, treatment with BRX-220, a co-inducer of hsps, protects motoneurones from axotomy-induced cell death.


Asunto(s)
Proteínas de Choque Térmico/metabolismo , Hidroxilaminas/farmacología , Neuronas Motoras/metabolismo , Fármacos Neuroprotectores/farmacología , Regulación hacia Arriba/fisiología , Animales , Animales Recién Nacidos , Axotomía , Western Blotting , Recuento de Células , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Supervivencia Celular/efectos de los fármacos , Esquema de Medicación , Evaluación Preclínica de Medicamentos , Femenino , Proteínas HSP70 de Choque Térmico/biosíntesis , Proteínas HSP90 de Choque Térmico/biosíntesis , Inmunohistoquímica , Contracción Isométrica/efectos de los fármacos , Masculino , Neuronas Motoras/citología , Neuronas Motoras/efectos de los fármacos , Contracción Muscular/efectos de los fármacos , Compresión Nerviosa , Ratas , Ratas Sprague-Dawley , Regulación hacia Arriba/efectos de los fármacos
5.
Neurochem Int ; 38(5): 453-61, 2001 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11222926

RESUMEN

Phagocytosis and prostaglandin E(2) production were investigated in purified cultures of perinatal rat forebrain astrocytes. Light and electron microscopic data indicated that astrocytes respond to bacterial endotoxin, lipopolysaccharide (LPS) by increased phagocytosis and by activating the cyclooxygenase enzyme-pathway. LPS-inducible phagocytosis of astrocytes was demonstrated by electron microscopic studies on colloidal gold uptake and by photometric determination of fluorescent bead ingestion. The internalisation of fragments of the plasma membrane was shown by histochemical detection of membrane-bound ecto-ATPase activity within intracellular vesicles. Activation of the cyclooxygenase pathway, a characteristic reaction of immune cells under inflammatory conditions, was also detected in astroglial cells upon treatment with LPS. The increased prostaglandin E(2) (PGE(2)) production by astrocytes in response to LPS was reduced by the non-steroid anti-inflammatory drug, indomethacin. Our data indicate that astrocytes display some tissue-protective reactions in response to inflammation inducing factors, even in the absence of peripheral immune cells or central microglia. The role of inducible astrocytic phagocytosis in a non-immune protection-pathway is discussed.


Asunto(s)
Astrocitos/efectos de los fármacos , Fagocitosis , Prostaglandina-Endoperóxido Sintasas/metabolismo , Animales , Astrocitos/enzimología , Astrocitos/inmunología , Células Cultivadas , Activación Enzimática , Prosencéfalo/citología , Prosencéfalo/efectos de los fármacos , Prosencéfalo/enzimología , Ratas
6.
J Mol Spectrosc ; 192(2): 386-393, 1998 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-9831505

RESUMEN

The intracavity laser spectroscopy (ILS) technique has been shown to be a very sensitive method for observing absorption spectra. By considering quantitative results (line-strengths and pressure broadening coefficients) obtained using the ILS method with a dye laser, the technique has been shown to provide quantitative information that is in excellent agreement with the values afforded by use of more traditional methods for acquiring absorption spectra. A similar investigation has been conducted for an ILS system based on a Ti:sapphire laser. Presented here are quantitative results for water vapor transitions occurring around 795 nm. Line intensities are determined as a function of water vapor pressure and effective path length (i.e., generation time). The line-strengths are compared with values determined by R. A. Toth [J. Mol. Spectrosc. 166, 176-183 (1994)] who used a multipass cell and the Fourier transform spectrometer at the Kitt Peak National Observatory. The good agreement between the results demonstrates that quantitatively accurate data can be obtained using the ILS technique with a Ti:sapphire laser. Copyright 1998 Academic Press.

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