Mammalian cardiomyocytes may withstand prolonged periods of ischaemia, only to die on reperfusion. We review data that implicate mitochondrial dysfunction as a basis for reperfusion induced cell injury, and present some new evidence that suggests that such a mechanism operates in intact cardiomyocytes. The mitochondrial dysfunction is the consequence of the opening of high conductance pores in the inner mitochondrial membrane, which uncouple mitochondrial oxidative phosphorylation, promoting ATP hydrolysis. The conditions required to open the pores correlate closely to conditions that prevail upon reperfusion of the ischaemic heart: a high [Ca2+]i and Pi, low [ATP], and oxidative stress. Pore opening is suppressed by physiological concentrations of ATP. Pore opening may be prevented by cyclosporin A. Studies in isolated myocytes show that mitochondria become uncoupled after reoxygenation, and that this is associated with the hypercontracture that signals cell death. Cyclosporin A reduces the proportion of hypercontracted myocytes in populations of cells rendered anoxic.

Temporal lobe epilepsy remains one of the most widespread seizure disorders in man, the etiology of which is controversial. Using new rat models of temporal lobe epilepsy that are either prone or resistant to develop complex partial seizures, we provide evidence that this seizure susceptibility may arise from arrested development of the GABAA receptor system. In seizure-prone (Fast kindling) and seizure-resistant (Slow kindling) rat models, both the mRNA and protein levels of the major alpha subunit expressed in adult brain (alpha1), as well as those highly expressed during development (alpha2, alpha3, and alpha5), were differentially expressed in both models compared with normal controls. We found that alpha1 subunit mRNA expression in the Fast kindling strain was approximately half the abundance of control rats, whereas in the Slow kindling strain, it was approximately 70% greater than that of controls. However, Fast rats overexpressed the alpha2, alpha3, and alpha5 ("embryonic") subunits, having a density 50-70% greater than controls depending on brain area, whereas the converse was true of Slow rats. Using subunit-specific antibodies to alpha1 and alpha5 subunits, quantitative immunoblots and immunocytochemistry revealed a concordance with the mRNA levels. alpha1 protein expression was approximately 50% less than controls in the Fast strain, whereas it was 200% greater in the Slow strain. In contrast, alpha5 subunit protein expression was greater in the Fast strain than either the control or Slow strain. These data suggest that a major predispositional factor in the development of temporal lobe epilepsy could be a failure to complete the normal switch from the GABAA receptor alpha subunits highly expressed during development (alpha2, alpha3, and alpha5) to those highly expressed in adulthood (alpha1).

The progression toward end-stage Alzheimer's disease (AD) in the aging brain is driven by accumulating amyloid-beta (Abeta)(1-42) oligomers that is accompanied by the downregulation of the Trk A neurotrophin receptor and by either upregulation or at least maintenance of the p75 neurotrophin receptor (p75(NTR)), which can be stimulated by the accumulating Abeta(1-42) peptides. Here we show that Abeta(1-42) and its active fragment Abeta(25-35), but not Abeta(42-1), can at least double the level of p75(NTR) receptors in the membranes of model SH-SY5Y human neuroblastoma cells. We also show that p75(NTR) is upregulated in the hippocampi of two strains of AD transgenic mice. Specifically, the level of the p75(NTR) receptor in the hippocampal membranes from 12-15 month old AD-triple transgenic mice (3xTg-AD) harboring PS1 (M146V), AbetaPP (Swe), and tau (P301L) was nearly twice that in hippocampal membranes from age-matched wild-type mice. Similarly, the level of p75 (NTR) receptor in 7 month-old B6.Cg-Tg AD mice harboring PSEN1dE9 and AbetaPP (Swe) was also increased above the level in the corresponding wild-type mice. This increase correlated with the age-dependent rise in Abeta(1-42) levels in the AD mice. Thus, it appears that it could be the accumulating Abeta(1-42) that increases or at least prevents the downregulation of p75 (NTR) receptors in key parts of AD brains. It is possible that when the Abeta (1-42) accumulation reaches a critical level in the brain on the way to late-onset AD, the Abeta (1-42) induced p75 (NTR) receptor signaling starts a vicious cycle that accelerates AD development because of the activated receptors' recently shown ability to stimulate Abeta(1-42) production.

No abstract