Isoflurane induces endoplasmic reticulum stress and caspase activation through ryanodine receptors.

BACKGROUND: Isoflurane has been reported to induce caspase-3 activation, which may induce neurotoxicity and contribute to the pathogenesis of Alzheimer's disease. However, the underlying mechanism is largely unknown, especially whether or not isoflurane can induce ryanodine receptors (RyRs)-associated endoplasmic reticulum (ER) stress, leading to caspase-3 activation. We therefore assessed the effects of isoflurane on RyRs-associated ER stress. METHODS: We treated primary neurones from wild-type (C57BL/6J) mice with 1% and 2% isoflurane for 1, 3, or 6 h. We then measured levels of C/EBP homologous protein (CHOP) and caspase-12, two ER stress markers, using immunocytochemistry staining and western blotting analysis. Dantrolene (5 µM), the antagonist of RyRs, was used to investigate the role of RyRs in the isoflurane-induced ER stress and caspase-3 activation. RESULTS: Isoflurane 2% for 6 h treatment increased the levels of CHOP (876% vs 100%, P=0.00009) and caspase-12 (276% vs 100%, P=0.006), and induced caspase-3 activation in the neurones. The administration of 2% isoflurane for 3 h (shorter duration), however, only increased the levels of CHOP (309% vs 100%, P=0.003) and caspase-12 (266% vs 100%, P=0.001), without causing caspase-3 activation. The isoflurane-induced ER stress (CHOP: F=16.64, P=0.0022; caspase-12: F=6.13, P=0.0383) and caspase-3 activation (F=32.06, P=0.0005) were attenuated by the dantrolene treatment. CONCLUSIONS: These data imply that isoflurane might induce caspase-3 activation by causing ER stress through RyRs, and dantrolene could attenuate the isoflurane-induced ER stress and caspase-3 activation. Further investigations of the potential neurotoxicity of isoflurane are needed.

Histologic evaluation of response to implantation of polyvinilidine plates in dogs and rats.

The effect of implantation of polyvinilidine spinal plates was studied when placed on spinous processes of 11 mixed breed dogs and when placed within the thoracolumbar musculature of 12 male white rats. Specimens were also obtained from soft tissues adjacent to polyvinilidine plates 2 to 3 months after clinical surgery to repair spinal subluxations in three dogs. A similar pattern of dense, organized fibrous tissue interspersed with focal congregations of lymphocytes, plasma cells, and multinucleated giant cells was observed in the dog experiment, rat experiment, and in all clinical cases. Birefringent debris with polarization patterns identical to small slivers of polyvinilidine was associated with the observed reactions. It would appear that either a chemical or physical characteristic of the plates elicited this foreign body reaction. Grooving the inner surface of the plates, which is performed to increase the friction grip when applied to spinous processes, may make the surface texture of the plate more reactive or it may predispose the surface of the plate to minute fragmentation ("wear products").

Effect of application of polyvinilidine plates on the dorsal spinous processes of dogs.

Anecdotal comments in the literature suggest that spinous fracture many weeks after application of polyvinilidine plates to the dorsal spinous processes of dogs may be due to associated adverse vascular changes. This study was undertaken to evaluate that hypothesis. Large size Lubra plates were cut to the appropriate length and applied to the dorsal spines of vertebrae L3 and L4. Vertebrae L2 and L5 served as operated controls. Vertebrae L1 and L6 served as unoperated normals. Two dogs were euthanized 1 week postoperatively, and three dogs each at 4, 8, and 12 weeks. The effect of the plate on the dorsal spinous processes was evaluated using microangiography and correlated histology. There was no apparent change in vascular architecture associated with plate application, nor with surgery alone, at any time interval. There did appear to be a time dependent loss of bone associated with plate application, indicating a change in the relative balance of osteoblastic and osteoclastic activity, and altered bone turnover.