Differential effect of lithium on spermidine/spermine N1-acetyltransferase expression in suicidal behaviour.

An altered polyamine system has been suggested to play a key role in mood disorders and suicide, a hypothesis corroborated by the evidence that lithium inhibits the polyamine mediated stress response in the rat brain. Recent post-mortem studies have shown that spermidine/spermine N1-acetyltransferase (SAT1), the key regulator of cellular polyamine content, is under-expressed in brains from suicide victims compared to controls. In our study we tested the effect of in vitro lithium treatment on SAT1 gene and protein expression in B lymphoblastoid cell lines (BLCLs) from bipolar disorder (BD) patients who committed suicide (and for which BLCLs were collected prior to their death), BD patients with high and low risk of suicide and a sample of non-psychiatric controls. Baseline mRNA levels were similar in the four groups of subjects (p > 0.05). Lithium had no effect in suicide completers (p > 0.05) while it significantly increased SAT1 expression in the high risk (p < 0.001) and low risk (p < 0.01) groups as well as in controls (p < 0.001). Protein and mRNA levels were not correlated; lithium significantly reduced protein levels only in the control sample (p < 0.05). Our findings suggest that SAT1 transcription is influenced by lithium and that this effect is altered in BD patients who completed suicide, further supporting a role for polyamines in suicide.

Over-expression of X-linked inhibitor of apoptosis protein modulates multiple aspects of neuronal Ca2+ signaling.

X-linked inhibitor of apoptosis (XIAP) protects and preserves the function of neurons in both in vitro and in vivo models of excitotoxicity. Since calcium (Ca(2+)) overload is a pivotal event in excitotoxic neuronal cell death, we have determined whether XIAP over-expression influences Ca(2+)-signaling in primary cultures of mouse cortical neurons. Using cortical neuron cultures derived from wild-type (Wt) mice transiently transfected with XIAP or from transgenic mice that over-express XIAP, we show that XIAP opposes the rise in intracellular Ca(2+) concentration by a variety of triggers. Relative to control neurons, XIAP over-expression produced a slight, but significant, elevation of resting Ca(2+) concentrations. By contrast, the rise in intracellular Ca(2+) concentrations produced by N-methyl-D-aspartate receptor stimulation and voltage gated Ca(2+) channel activation were markedly attenuated by XIAP over-expression. The release of Ca(2+) from intracellular stores induced by the sarco/endoplasmic reticulum Ca(2+) ATPase inhibitor thapsigargin was also inhibited in neurons transiently transfected with XIAP. The pan-caspase inhibitor zVAD did not, however, diminish the rise in intracellular Ca(2+) concentrations elicited by L-glutamate suggesting that XIAP influences Ca(2+) signaling in a caspase-independent manner. Taken together, these findings demonstrate that the ability of XIAP to block excessive rises in intracellular Ca(2+) by a variety of triggers may contribute to the neuroprotective effects of this anti-apoptotic protein.

Neuroprotective and anti-inflammatory effects of the flavonoid-enriched fraction AF4 in a mouse model of hypoxic-ischemic brain injury.

We report here neuroprotective and anti-inflammatory effects of a flavonoid-enriched fraction isolated from the peel of Northern Spy apples (AF4) in a mouse of model of hypoxic-ischemic (HI) brain damage. Oral administration of AF4 (50 mg/kg, once daily for 3 days) prior to 50 min of HI completely prevented motor performance deficits assessed 14 days later that were associated with marked reductions in neuronal cell loss in the dorsal hippocampus and striatum. Pre-treatment with AF4 (5, 10, 25 or 50 mg/kg, p.o.; once daily for 3 days) produced a dose-dependent reduction in HI-induced hippocampal and striatal neuron cell loss, with 25 mg/kg being the lowest dose that achieved maximal neuroprotection. Comparison of the effects of 1, 3 or 7 doses of AF4 (25 mg/kg; p.o.) prior to HI revealed that at least 3 doses of AF4 were required before HI to reduce neuronal cell loss in both the dorsal hippocampus and striatum. Quantitative RT-PCR measurements revealed that the neuroprotective effects of AF4 (25 mg/kg; p.o.; once daily for 3 days) in the dorsal hippocampus were associated with a suppression of HI-induced increases in the expression of IL-1ß, TNF-α and IL-6. AF4 pre-treatment enhanced mRNA levels for pro-survival proteins such as X-linked inhibitor of apoptosis and erythropoietin following HI in the dorsal hippocampus and striatum, respectively. Primary cultures of mouse cortical neurons incubated with AF4 (1 µg/ml), but not the same concentrations of either quercetin or quercetin-3-O-glucose or its metabolites, were resistant to cell death induced by oxygen glucose deprivation. These findings suggest that the inhibition of HI-induced brain injury produced by AF4 likely involves a transcriptional mechanism resulting from the co-operative actions of various phenolics in this fraction which not only reduce the expression of pro-inflammatory mediators but also enhance pro-survival gene signalling.

Putting the plants back into plant ecology: six pragmatic models for understanding and conserving plant diversity.

BACKGROUND: There is a compelling need to protect natural plant communities and restore them in degraded landscapes. Activities must be guided by sound scientific principles, practical conservation tools, and clear priorities. With perhaps one-third of the world's flora facing extinction, scientists and conservation managers will need to work rapidly and collaboratively, recognizing each other's strengths and limitations. As a guide to assist managers in maintaining plant diversity, six pragmatic models are introduced that are already available. Although theoretical models continue to receive far more space and headlines in scientific journals, more managers need to understand that pragmatic, rather than theoretical, models have the most promise for yielding results that can be applied immediately to plant communities. SIX PRAGMATIC MODELS: For each model, key citations and an array of examples are provided, with particular emphasis on wetlands, since "wet and wild" was my assigned theme for the Botanical Society of America in 2003. My own work may seem rather prominent, but the application and refinement of these models has been a theme for me and my many students over decades. The following models are reviewed: (1) species-area: larger areas usually contain more species; (2) species-biomass: plant diversity is maximized at intermediate levels of biomass; (3) centrifugal organization: multiple intersecting environmental gradients maintain regional landscape biodiversity; (4) species-frequency: a few species are frequent while most are infrequent; (5) competitive hierarchies: in the absence of constraints, large canopy-forming species dominate patches of landscape, reducing biological diversity; and (6) intermediate disturbance: perturbations such as water level fluctuations, fire and grazing are essential for maintaining plant diversity. CONCLUSIONS: The good news is that managers faced with protecting or restoring landscapes already have this arsenal of tools at their disposal. The bad news is that far too few of these models are appreciated.

Population ecology on an environmental gradient: Cakile edentula on a sand dune.

A naturally-occurring sand dune population of the annual plant Cakile edentula (Brassicaceae) was studied for two years. The plants grew along an environmental gradient stretching from open sand beach (seaward) to densely vegetated dunes (landward). Survivorship and reproductive output were estimated from plants in permanent quadrats. The dispersal of seeds was documented by sifting fruits from the sand substrate at different seasons.Seedlings germinate in April and May and begin flowering in July and August. They may continue to flower until October unless destroyed by autumn winds or heavy frost. Although seaward plants germinate approximately a month later than landward plants, they grow more rapidly and by September may be two orders of magnitude larger than landward plants (dry weight of vegetative parts 6.86±3.97 g compared to 0.029±0.006 g; dry weight of fruits 5.92±4.27 g compared to 0.016±0.005 g; mean with 95% CI). In both years, seedling survivorship and mature plant reproductive output declined significantly with distance landward. The large plants at the seaward end of the gradient produced most of the fruits (144 and 278 fruits per capita in 1975 and 1976 respectively) but a large proportion of these were moved landward by wind and waves during the winter. Thus, at the seaward end of the gradient, the main influx on individuals was from reproduction, and the main loss of individuals was from dispersal landward during the winter. The small plants at the landward end of the gradient produced few fruits (1.8 and 1.2 fruits per capita in 1975 and 1976 respectively), and mortality greatly exceeded this reproductive output. Thus, at the landward end of the gradient, the main loss of individuals was through seedling mortality, but this was balanced by a large annual influx of individuals from the seaward end of the gradient. Plants at the landward end of the gradient therefore exist only because of annual dispersal of seeds landward. Most seeds produced at the seaward end of the gradient disperse from an area of good habitat (high survivorship and high reproductive output) to an area of poor habitat (low survivorship and low reproductive output).