Upregulation of heat shock proteins rescues motoneurones from axotomy-induced cell death in neonatal rats.

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.

Molecular chaperones in the etiology and therapy of cancer.

Molecular chaperones are ubiquitous, well-conserved proteins that account for 2-5 % of all cellular proteins in most cells. The present review summarizes our current knowledge about their involvement in the etiology and therapy of cancer with special emphasis on the expression of chaperones in malignant cells, their role in folding of (proto)oncogene products, cell cycle regulation, cell differentiation and apoptosis, development of metastasis, and their participation in the recognition of malignant cells. We also overview the importance of chaperones in hyperthermia, drug resistance, and recent approaches in chaperone-immunotherapy.

Interference of the sulphonylurea antidiabeticum gliquidone with mitochondrial bioenergetics in the rat under in vitro conditions.

The hypoglycaemic sulphonylurea gliquidone and glibenclamide exerted a partial uncoupling effect on mitochondrial respiration of liver under in vitro conditions using various citrate cycle intermediates as substrates. Besides the uncoupling effect, gliquidone and glibenclamide caused a direct inhibition of ATP-as well as DNP-stimulated oxygen consumption. Both phenomena proved to be dose dependent. Respiratory control ratio decreased progressively with increasing concentrations of sulphonylureas mainly through the inhibition of ADP-stimulated respiration. Basal and DNP-stimulated ATP-ase activity of isolated mitochondria changed similarly to the respiratory parameters. Changes in membrane permeability of mitochondria and the inhibition of substrate uptake further support the assumption of structural and functional alteration of mitochondria by the hypoglycaemic compounds tested.

Interference of sulphonylurea antidiabetica with mitochondrial bioenergetics under in vivo conditions.

Sulphonylurea antidiabetica effectively inhibits the basal hepatic glucose production. Since it has been firmly established that lipophylic sulphonylurea drugs exerted an uncoupling effect on mitochondrial oxidative phosphorylation, a relationship between the reduction of hepatic gluconeogenesis and the insufficient energy supply due to sulphonylureas could be supposed. In this study we have investigated the effects of glibenclamide and gliquidone on mitochondrial bioenergetics in liver after peroral treatments of normal rats with different doses. The treatment of rats with 5 mg/kg glibenclamide or gliquidone daily for 14 days elicited only a marginal inhibition on mitochondrial oxidation capacity and remained without any effect on mitochondrial ATPase activity. Only the supermaximal dose 50 mg/kg for 14 day produced a significant damage in the mitochondrial functions. The basal respiration increased with 60-80 per cent, whereas the ADP- or DNP-stimulated oxygen consumption significantly decreased independently from the respiratory substrates investigated. Similar alterations were found in the mitochondrial ATPase activity after treatment with these drugs. No essential differences have been observed in the actions between glibenclamide and gliquidone. However, the lowest dose applied in this study is many times higher than the usual therapeutic dose. Consequently, glibenclamide and gliquidone do not interact with mitochondrial bioenergetic processes under therapeutic conditions. On the other hand, in different liver and kidney damages we have no sufficient knowledge whether these drugs can be accumulated in these organs and therefore their elevated concentration may interfere with the mitochondrial energy metabolism.