Inhibition of calpain prevents NMDA-induced cell death and beta-amyloid-induced synaptic dysfunction in hippocampal slice cultures.

BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is a multifactorial, neurodegenerative disease, which is in part caused by an impairment of synaptic function, probably mediated by oligomeric forms of amyloid-beta (Abeta). While the Abeta pathology mainly affects the physiology of neurotransmission, neuronal decline is caused by excitotoxic cell death, which is mediated by the NMDA receptor. A comprehensive therapeutic approach should address both Abeta-induced synaptic deficits, as well as NMDA receptor-mediated neurodegeneration, via one molecular target. This study was designed to test whether calpain could be involved in both pathological pathways, which would offer a promising avenue for new treatments. EXPERIMENTAL APPROACH: Application of the specific, water-soluble calpain inhibitor A-705253 was used to inhibit calpain in hippocampal slice cultures. We examined whether inhibition of calpain would prevent Abeta-induced deficits in neurotransmission in CA1, as well as NMDA-induced neuronal cell death. KEY RESULTS: A-705253 dose-dependently prevented excitotoxicity-induced neurodegeneration at low nanomolar concentrations, determined by propidium iodide histochemistry. Inhibition of the NMDA receptor similarly protected from neuronal damage. Caspase staining indicated that calpain inhibition was protective by reducing apoptosis. Electrophysiological analysis revealed that inhibition of calpain by A-705253 also fully prevented Abeta oligomer-induced deficits in neurotransmission. The protective effect of calpain was compared to the clinically available NMDA receptor antagonist memantine, which was also effective in this model. CONCLUSIONS AND IMPLICATIONS: We suggest that inhibition of calpain exhibits a promising strategy to address several aspects of the pathology of AD that may go beyond the available therapeutic intervention by memantine.

Comparison of severe life stress in depressed mothers and non-mothers: do children matter?

Given the high rates of maladjustment among children of depressed mothers, parenting is likely to cause significant life stress in this population, potentially worsening the course of mothers' depression. The present study is a comparison of severe life stress in 38 mothers and 62 non-mothers receiving treatment for recurrent major depression. Life stress was assessed using the Life Events and Difficulties Schedule [Brown and Harris, 1978a]. We hypothesized that mothers would evidence a greater number of severe life events and marked difficulties both in the year prior to the onset of their depressive index episode and in the time period following the onset of their current depressive episode. Prior to depression onset, mothers reported a significantly greater number of entrapping difficulties, but not marked difficulties, severe events, entrapping events, or humiliating events. However, following the onset of depression, mothers experienced a significantly greater number of severe events, entrapping events, marked difficulties, and entrapping difficulties, but not humiliating events. Mothers' elevated levels of stress were attributable to child-related stress, predominantly related to children's psychological and behavioral problems. Our findings suggest that comprehensive treatment for mothers with major depression needs to address their parenting style and any psychological problems experienced by their children.

Measurement of tetracycline levels in parakeets.

Parakeets were fed hulled millet seed containing 0.5% chlortetracycline (CTC) or minocycline. Blood concentrations of more than 1 micrograms CTC/ml and more than 5 micrograms minocycline/ml were obtained. Equivalent drug assay results were obtained from blood specimens collected by venipuncture or by use of treated filter-paper discs. The latter is a fairly simple method for assaying CTC concentrations in blood of treated psittacines.