Neurotrophins support neuronal survival and differentiation via Trk receptors, yet can also induce cell death via the p75 receptor. In these studies, we investigated signaling mechanisms governing p75-mediated death of hippocampal neurons, specifically the role of caspases. Although p75 is structurally a member of the Fas/TNFR1 receptor family, caspase-8 was not required for p75-mediated death, unlike other members of this receptor family. In contrast, p75-mediated neuronal death was associated with mitochondrial loss of cytochrome c and required Apaf-1 and caspase-9, -6, and -3. In particular, caspase-6 plays a central role in mediating neurotrophin-induced death, illuminating a novel role for this caspase. Inhibition of DIABLO/Smac, which blocks inhibitor of apoptosis proteins, protected cells from death, whereas simultaneous inhibition of both DIABLO/Smac and MIAP3 allowed trophin-induced death to proceed. In vivo, pilocarpine-induced seizures, previously shown to up-regulate p75 expression and increase neurotrophin production, caused activation of caspase-6 and -3 and cleavage of poly(ADP-ribose) polymerase in p75-expressing hippocampal neurons. In p75 ؊/؊ mice, no activated caspase-3 was detected, and there was a marked reduction in the number of dying neurons after pilocarpine treatment compared with wild type mice. Neurotrophin-induced p75-mediated death is likely to play an important role in mediating neuronal loss consequent to brain injury.

No abstract

Although we and others have previously shown that newborn central mammalian neurons are more tolerant to anoxia than their adult counterparts, we do not know whether neonatal nerve cells accumulate free cytosolic calcium (Cat+) less than adults in response to 0, deprivation. In order to determine whether anoxia increases Ca:+ in adult and neonatal neurons, we monitored calcium in CA1 hippocampal neurons using the calcium-sensitive probe fluo-3 and confocal microscopy. These neurons were studied in the dissociated state in order to study their inherent response to anoxia without the influence of modulatory factors such as synaptic input and neurotransmitters. Severe anoxia caused a rapid increase in Cat+ in adult

No abstract

Disturbance in metallochemical reactions and metal‐protein association are associated with chronic neurodegenerative conditions, such as Alzheimer's and Parkinson's disease, as well as with neurodegeneration triggered by acute cerebral ischaemia. Many neurological diseases have been linked directly or indirectly to perturbed homeostasis of Ca, Fe, Zn, or Cu ions. Consequently, acute or chronic neurodegenerative disorders represent excellent targets for exploiting metal ion chelator approaches. Drug Dev. Res. 56: 300–309, 2002. © 2002 Wiley‐Liss, Inc.