Protection with estradiol in developmental models of apoptotic neurodegeneration

Abstract

Medical measures that bear no known danger for the adult brain may trigger active neuronal death in the developing brain. Pharmacological blockade of N-methyl-D-aspartate or activation of GABA(A) receptors, blockade of voltage-dependent sodium channels, and oxygen induce widespread apoptotic neurodegeneration during the period of rapid brain growth in rodents. Because such measures are often necessary in critically ill infants and toddlers, search for adjunctive neuroprotective strategies is warranted. We report that 17beta-estradiol ameliorates neurotoxicity of drugs that block N-methyl-D-aspartate receptors, activate GABA(A) receptors, or block voltage-gated sodium channels and reduces neurotoxicity of oxygen in the infant rat brain. This neuroprotective effect is reversed by tamoxifen and cannot be reproduced by 17alpha-estradiol. 17Beta-estradiol did not affect GABA(A) or N-methyl-D-aspartate currents in hippocampal neuronal cultures, indicating that direct modulation of neurotransmitter receptor/channel properties by this compound cannot explain neuroprotective effect. 17beta-Estradiol did, however, increase levels of phosphorylated extracellular signal-regulated kinase 1/2 and AKT, suggesting that activation of these prosurvival proteins may represent one mechanism for its neuroprotective action. 17Beta-estradiol and related compounds may be neuroprotective agents suitable for use in critically ill infants and toddlers. Its supplementation may particularly help to improve neurocognitive outcome in preterm infants who are prematurely deprived of maternal estrogen.

The anaesthetic combination of ketamine/midazolam does not alter the acquisition of spatial and motor tasks in adult mice

“…43,44 To the best of our knowledge, there is no record of studies performed in adult rodents treated with a ketamine/midazolam combination regarding the learning of a spatial task. Hence, the observation of deficits in adulthood after treatment of neonates with the ketamine/GABA A agonist combination may be due to the vulnerability of the infant brain during the growth spurt, 45 as we did not detect any effects of the ketamine/midazolam combination on the spatial acquisition of the radial maze task in adult mice. This is in contrast with that observed for volatile anaesthetics, which have been shown to cause cognitive impairment in adult animals, 4 especially in low concentrations.…”

Evaluation of neurotoxic and neuroprotective pathways affected by antiepileptic drugs in cultured hippocampal neurons

“…Abbreviations of the AEDs as indicated in Fig. 1. induce apoptotic death (Asimiadou et al, 2005;Bittigau et al, 2003).…”

The Role of Caspase-3 Activation in Phencyclidine-Induced Neuronal Death in Postnatal Rats

“…In addition, transgenic constitutive activation of Ras, a component of the ERK1/2 signaling pathway for cell survival, was associated with marked protection against MK-801-induced apoptotic neuronal death. As certain neurotrophins exert their neuroprotective powers through the activation of CREB, coadministration of 17 betaestradiol and MK-801 to P7 rats also ameliorated MK-801 neurotoxicity possibly by increasing levels of phosphorylated ERK1/2 and AKT (Asimiadou et al, 2005). Coadministration of recombinant EPO and MK-801 conferred 50% neuroprotection with partial restoration of MK-801-induced reduction of BDNF and glial cell line-derived neurotrophic factor (GDNF) mRNA, as well as prevention of the decrease in phosphorylation levels of ERK1/2 and Akt .…”