The cyclooxygenase-2 pathway via the PGE₂ EP2 receptor contributes to oligodendrocytes apoptosis in cuprizone-induced demyelination.

Cyclooxygenases (COX)-1 and -2 are key enzymes required for the conversion of arachidonic acid to eicosanoids, potent mediators of inflammation. In patients with multiple sclerosis, COX-2 derived prostaglandins (PGs) are elevated in the CSF and COX-2 is up-regulated in demyelinating plaques. However, it is not known whether COX-2 activity contributes to oligodendrocyte death.

Altered mRNA editing and expression of ionotropic glutamate receptors after kainic acid exposure in cyclooxygenase-2 deficient mice.

Kainic acid (KA) binds to the AMPA/KA receptors and induces seizures that result in inflammation, oxidative damage and neuronal death. We previously showed that cyclooxygenase-2 deficient (COX-2(-/-)) mice are more vulnerable to KA-induced excitotoxicity. Here, we investigated whether the increased susceptibility of COX-2(-/-) mice to KA is associated with altered mRNA expression and editing of glutamate receptors.

NMDA-induced seizure intensity is enhanced in COX-2 deficient mice.

Pharmacological inhibition or genetic deletion of cyclooxygenase (COX)-2, but not COX-1, has been shown to increase susceptibility to kainic acid (KA)-induced excitotoxicity. However, it is unclear if susceptibility to excitotoxins that act through other neurotransmitter receptors is altered by COX-2 inhibition. To further understand the involvement of COX-2 in regulating susceptibility to excitotoxicity, we investigated the effect of COX-2 deletion on excitotoxicity induced by peripheral injection of N-methyl-d-aspartate (NMDA, a specific agonist of the NMDA receptors) or lindane (a GABA(A) receptor antagonist).

Altered GABAergic neurotransmission is associated with increased kainate-induced seizure in prostaglandin-endoperoxide synthase-2 deficient mice.

Excitotoxicity involves over activation of brain excitatory glutamate receptors and has been implicated in neurological, neurodegenerative and neuropsychiatric diseases. Metabolism of arachidonic acid (AA) through the phospholipase A(2) (PLA(2))/prostaglandin-endoperoxide synthase (PTGS) pathway is increased after excitotoxic stimulation. However, the individual roles of the PTGS isoforms in this process are not well established.

Is it time to standardize ethics guiding the peer review process?

While most scientific journals have well defined ethics requirements for authors, very few journals explicitly specify the ethics standards that govern the actions of editors, editorial board members, and reviewers. We believe it is time to create a standardized policy for all medical and scientific journals that guides the ethical conduct of all stakeholders in the peer review process.

Differential gene expression patterns in cyclooxygenase-1 and cyclooxygenase-2 deficient mouse brain.

Background: Cyclooxygenase (COX)-1 and COX-2 produce prostanoids from arachidonic acid and are thought to have important yet distinct roles in normal brain function. Deletion of COX-1 or COX-2 results in profound differences both in brain levels of prostaglandin E2 and in activation of the transcription factor nuclear factor-kappaB, suggesting that COX-1 and COX-2 play distinct roles in brain arachidonic acid metabolism and regulation of gene expression. To further elucidate the role of COX isoforms in the regulation of the brain transcriptome, microarray analysis of gene expression in the cerebral cortex and hippocampus of mice deficient in COX-1 (COX-1-/-) or COX-2 (COX-2-/-) was performed.

Experience-dependent regulation of zif268 gene expression and spatial learning.

Environmental enrichment (EE) is known to enhance the cognitive ability of rodents. To translate EE to the human condition, it is important to understand the parameters of its efficacy. In this study, we examine if the cognitive enhancement associated with EE is permanent and whether a developmental window exists for its efficacy.

Lead neurotoxicity: from exposure to molecular effects.

The effects of lead (Pb(2+)) on human health have been recognized since antiquity. However, it was not until the 1970s that seminal epidemiological studies provided evidence on the effects of Pb(2+) intoxication on cognitive function in children. During the last two decades, advances in behavioral, cellular and molecular neuroscience have provided the necessary experimental tools to begin deciphering the many and complex effects of Pb(2+) on neuronal processes and cell types that are essential for synaptic plasticity and learning and memory in the mammalian brain.

Calcium/calmodulin-dependent protein kinase II activity and expression are altered in the hippocampus of Pb2+-exposed rats.

In the present study, we examined whether calcium/calmodulin-dependent protein kinase II (CaMKII) is affected by chronic developmental Pb2+ exposure. The effects of Pb2+ exposure on rat hippocampal CaMKII were assessed by measuring CaMKII activity, phosphorylation of CaMKII at threonine-286, and CaMKII alpha and beta protein levels. In the hippocampus of Pb2+-exposed 50-day-old rats known to exhibit deficits in hippocampal long-term potentiation (LTP) and spatial learning, there was a marked reduction (41%) in the apparent maximal velocity (Vmax) of CaMKII and a significant increase (22%) in apparent affinity of the enzyme.

Lead exposure alters cyclic-AMP response element binding protein phosphorylation and binding activity in the developing rat brain.

We examined the effect of lead (Pb(2+)) exposure during development on cyclic-AMP response element binding protein (CREB) expression and phosphorylation in cortical and hippocampal nuclear extracts at postnatal (PN) days 7, 14, 21 and 50. We also examined the binding of CREB family proteins to the cyclic-AMP response element (CRE) using a novel filter-binding assay that provides a quantitative measure of binding kinetics. In the hippocampus and cerebral cortex of control rats, CREB and phospho-CREB (pCREB; serine-133) expression is highest at PN7 and decreases steadily until PN50.

Environmental enrichment reverses cognitive and molecular deficits induced by developmental lead exposure.

Long-term deficits in cognitive function are the principal effects of lead (Pb2+) exposure in children and can be modeled in experimental animals. Current therapeutic approaches in the treatment of childhood Pb2+ intoxication are not effective in reversing learning deficits once they have occurred. We report that environmental enrichment reverses long-term deficits in spatial learning produced by developmental Pb2+ exposure in rats.

Developmental Pb2+ exposure alters NMDAR subtypes and reduces CREB phosphorylation in the rat brain.

In the present study we show that chronic exposure to low levels of lead (Pb(2+)) during development alters the type of N-methyl-D-aspartate receptor (NMDAR) expressed in the developing and young adult rat brain. Ifenprodil inhibition of [3H]MK-801 binding to the NMDAR channel in cortical and hippocampal neuronal membranes expressed high and low affinity components. Previous studies have shown that the high affinity component is associated with NR1/NR2B receptor complexes while the low affinity component is associated with the appearance and insertion of the NR2A subunit to NMDAR complexes.