Biomedical subjects

Victoria M Perreau

Publications and source records attributed to Victoria M Perreau.

7 recordsLinked to original sources

PubMed2006

Effects of melatonin and age on gene expression in mouse CNS using microarray analysis.

The expression levels of a number of genes associated with inflammation and immune function change with advancing age. Melatonin modulates gene expression levels of several of these genes. Therefore the declining levels of melatonin associated with age may play a role in the physiological effects of aging. We used oligonucleotide microarrays to measure age-related changes in mRNA expression in the murine CNS, and to study the effect of prolonged administration of dietary melatonin upon these changes. CB6F1 male mice were fed 40 ppm melatonin for 2.1 months prior to sacrifice at age 26.5 months, and compared with both age-matched controls and young, 4.5-month-old untreated controls. Total RNA was extracted from whole brain (excluding cerebellum and brain stem) and individual samples were hybridized to Affymetrix Mouse 430-2.0 arrays. The expression of a substantial number of genes was modulated by melatonin treatment and changes in selected genes were validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A subset of these genes did not change with age. Conversely, some genes modulated by age were also modulated by melatonin treatment. In general, melatonin treatment drove the expression levels of these genes closer to the expression levels detected in the younger animals. Notably, the abundance of lipocalin 2 (Lcn2) mRNA increased with age and was decreased in old animals treated with melatonin. Lcn2 is a member of the acute phase response family of proteins and its mRNA levels in the brain increase in response to inflammation. Many of the genes with expression reduced by melatonin are involved in inflammation and the immune system. This suggests that melatonin treatment may influence the inflammatory responses of old animals, driving them to resemble more closely those occurring in young animals.

Acute-Phase Proteins↗

PubMed2005

Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there are few therapeutics that affect the underlying disease mechanism. Recent epidemiological studies, however, suggest that lifestyle changes may slow the onset/progression of AD. Here we have used TgCRND8 mice to examine directly the interaction between exercise and the AD cascade. Five months of voluntary exercise resulted in a decrease in extracellular amyloid-beta (Abeta) plaques in the frontal cortex (38%; p = 0.018), the cortex at the level of the hippocampus (53%; p = 0.0003), and the hippocampus (40%; p = 0.06). This was associated with decreased cortical Abeta1-40 (35%; p = 0.005) and Abeta1-42 (22%; p = 0.04) (ELISA). The mechanism appears to be mediated by a change in the processing of the amyloid precursor protein (APP) after short-term exercise, because 1 month of activity decreased the proteolytic fragments of APP [for alpha-C-terminal fragment (alpha-CTF), 54% and p = 0.04; for beta-CTF, 35% and p = 0.03]. This effect was independent of mRNA/protein changes in neprilysin and insulin-degrading enzyme and, instead, may involve neuronal metabolism changes that are known to affect APP processing and to be regulated by exercise. Long-term exercise also enhanced the rate of learning of TgCRND8 animals in the Morris water maze, with significant (p < 0.02) reductions in escape latencies over the first 3 (of 6) trial days. In support of existing epidemiological studies, this investigation demonstrates that exercise is a simple behavioral intervention sufficient to inhibit the normal progression of AD-like neuropathology in the TgCRND8 mouse model.

Alzheimer Disease↗

PubMed2005

The exercise-induced expression of BDNF within the hippocampus varies across life-span.

Voluntary exercise increases hippocampal brain-derived neurotrophic factor (BDNF) expression in young animals. In this investigation we examined the induction of BDNF protein in the hippocampus of young (2 months), late middle-aged (15 months) and old (24 months) animals over 4 weeks of exercise. Average running distances decreased with age, with the old animals also maintaining a constant level of activity over time, whereas the other groups tended to increase their average running distance. All animals demonstrated a biphasic profile of BDNF protein induction, with a significant (P<0.05) increase after 1 week of exercise followed by a decrease to near sedentary levels at 2 weeks. After this, BDNF protein levels increased significantly (P<0.05), as compared to baseline, primarily only in the young animals. In whole hippocampal homogenates, only particular BDNF mRNA exons were significantly (P<0.05) changed as a result of exercise, with the largest induction occurring in young animals. BDNF protein induction may, therefore, not be directly correlated with significant mRNA changes. Exercise may represent a therapeutic tool for disorders which involve a decrease in BDNF.

Age Factors↗

PubMed2005

Exercise-induced gene expression changes in the rat spinal cord.

There is growing evidence that exercise benefits recovery of neuromuscular function from spinal cord injury (SCI). However, the effect of exercise on gene expression in the spinal cord is poorly understood. We used oligonucleotide microarrays to compare thoracic and lumbar regions of spinal cord of either exercising (voluntary wheel running for 21 days) or sedentary rats. The expression data were filtered using statistical tests for significance, and K-means clustering was then used to segregate lists of significantly changed genes into sets based upon expression patterns across all experimental groups. Levels of brain-derived neurotrophic factor (BDNF) protein were also measured after voluntary exercise, across different regions of the spinal cord. BDNF mRNA increased with voluntary exercise, as has been previously shown for other forms of exercise, contributed to by increases in both exon I and exon III. The exercise-induced gene expression changes identified by microarray analysis are consistent with increases in pathways promoting neuronal health, signaling, remodeling, cellular transport, and development of oligodendrocytes. Taken together these data suggest cellular pathways through which exercise may promote recovery in the SCI population.

Animals↗

PubMed2004

Neutralization of the chemokine CXCL10 enhances tissue sparing and angiogenesis following spinal cord injury.

After spinal cord injury, there is a chemoattractant-mediated inflammatory response that is associated with secondary degeneration. The chemoattractant CXCL10 recruits CD4 Th1 cells via the CXCR3A receptor and inhibits growth and chemotaxis of endothelial cells via the CXCR3B receptor. To test the hypothesis that CXCL10 inhibits angiogenesis following spinal cord injury, we assayed the brainstems and spinal cords of spinal cord-injured mice treated with anti-CXCL10 antibodies for expression of angiogenesis-associated genes and quantified blood vessels within their spinal cords. Brainstem microarray analysis indicated eight angiogenesis-associated genes that had significantly higher expression levels in the treated mice than in the untreated mice. Ribonuclease protection assays of the spinal cords showed a significant increase in eight angiogenesis-associated genes in treated animals compared with untreated animals. Histological analysis of the spinal cords of treated and untreated mice showed a significant increase in the number of blood vessels in treated animals. We conclude that CXCL10 plays a critical role in vasculature remodeling following spinal cord injury and that angiogenesis is enhanced following anti-CXCL10 treatment of spinal cord injuries. Improved blood flow and oxygen supply to the injury site may contribute to the functional improvement associated with this treatment.

Animals↗

PubMed2004

The timecourse of induction of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus following voluntary exercise.

In this study we examined the timecourse of induction of brain-derived neurotrophic factor (BDNF) mRNA and protein after 1, 3, 5, 7, 14 and 28 days of exercise in the rat. To measure the expression of mRNA for individual BDNF exons we utilized a semi-quantitative RT-PCR technique, while BDNF protein was assessed using commercial ELISA kits. We demonstrated that the distance run by animals increased significantly (P<0.05) after 4 weeks. BDNF protein was significantly (P<0.05) increased after 4 weeks of exercise, while the mRNA for individual BDNF exons increased significantly (P<0.05) over the timecourse (exon I after 1 and 28 days and exons II and V after 28 days). The Morris water maze was then utilized to demonstrate that 3 weeks of prior exercise enhanced the rate of learning on this task. Exercise, therefore, was shown to modulate BDNF induction in a time-dependent manner, and this may translate to improvements in neurotrophin-mediated tasks within the CNS.

Analysis of Variance↗

PubMed2004

Spatial and temporal gene expression profiling of the contused rat spinal cord.

Microarray technology was used to examine gene expression changes following contusive injury of the adult rat spinal cord. To obtain a global understanding of the changes triggered by the injury, differential gene expression was examined spatially, using tissue samples from the epicenter of injury as well as 1 cm rostral and 1 cm caudal to the epicenter, and temporally, at 3 h, 24 h, 7 days, and 35 days post-injury. To filter out gene expression changes that were due to the laminectomy, samples of contused tissue were compared to laminectomy-only controls. We took advantage of four different, complementary methods of data analysis to detect differentially expressed genes. We have identified functional groups of genes that are differentially regulated in our model, including those associated with apoptosis, cell cycle, inflammation, and cholesterol metabolism. Our analysis has led to the identification of novel potential therapeutic targets within each group of genes that is discussed.

Animals↗