PubMed Health⌕ Search

Biomedical subjects

William R Woodward

Publications and source records attributed to William R Woodward.

5 recordsLinked to original sources
PubMed2006

Chronic depolarization stimulates norepinephrine transporter expression via catecholamines.

Chronic depolarization increases norepinephrine (NE) uptake and expression of the norepinephrine transporter (NET) in sympathetic neurons, but the mechanisms are unknown. Depolarization of sympathetic neurons stimulates catecholamine synthesis, and several studies suggest that NET can be regulated by catecholamines. It is not clear if the depolarization-induced increase in NET is because of nerve activity per se, or is secondary to elevated catecholamines. To determine if induction of NET mRNA was a result of increased catecholamines, we used pharmacological manipulations to (i) inhibit tyrosine hydroxylase activity in neurons depolarized with 30 mm KCl, thereby preventing increased catecholamines, or (ii) stimulate tyrosine hydroxylase activity in the absence of depolarization. Inhibiting the depolarization-induced increase in catecholamines prevented the up-regulation of NET mRNA, but did not block the increase in tyrosine hydroxylase (TH) mRNA. Furthermore, stimulating catecholamine production in the absence of depolarization elevated NE uptake, NET protein, and NET mRNA in sympathetic neurons. Similarly, elevating endogenous catecholamines in SK-N-BE2M17 neuroblastoma cells increased NE uptake and NET expression. These data suggest that chronic depolarization of sympathetic neurons induces NET expression through increasing catecholamines, and that M17 neuroblastoma cells provide a model system in which to investigate catechol regulation of NET expression.

Action Potentials↗
PubMed2003

Inflammation and cerebral amyloidosis are disconnected in an animal model of Alzheimer's disease.

The hypothesis that inflammation and beta amyloid deposition are causally linked in Alzheimer's disease (AD) was tested in a transgenic mouse model. Untreated beta amyloid plaque-bearing Tg2576 mice did not differ from wild type animals in brain levels of most inflammatory mediators. Indomethacin treatment suppressed brain levels of prostaglandins by 90%, but reduced hippocampal beta amyloid by only 20%, with no effect on cortical beta amyloid. The discordant effects on beta amyloid and cyclooxygenase (COX) suggest that these effects of nonsteroidal anti-inflammatory drugs (NSAIDs) are not causally linked. Further evidence against a causal relationship is seen in an unexpected trend to lower levels of beta amyloid after an inflammatory stimulus [lipopolysaccharide (LPS)].

Alzheimer Disease↗
PubMed2003

Regulation of noradrenergic function by inflammatory cytokines and depolarization.

Although the sympathetic neurons innervating the heart are exposed to the inflammatory cytokines cardiotrophin-1 (CT-1), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFalpha) after myocardial infarction, the effects of these cytokines on noradrenergic function are not well understood. We used cultured sympathetic neurons to investigate the effects of these cytokines on catecholamine content, the tyrosine hydroxylase co-factor, tetrahydrobiopterin (BH4), and norepinephrine (NE) uptake. CT-1, but not IL-6 or TNFalpha, suppressed NE uptake and catecholamines in these neurons, whereas CT-1 and, to a lesser extent, IL-6 decreased BH4 content. CT-1 exerted these effects by decreasing tyrosine hydroxylase, GTP cyclohydrolase (GCH) and NE transporter mRNAs, while IL-6 lowered only GCH mRNA. The neurons innervating the heart are also activated by the central nervous system after myocardial infarction. We examined the combined effect of depolarization and cytokines on noradrenergic function. In CT-1-treated cells, depolarization caused a small increase in BH4 and NE uptake, and a large increase in catecholamines. These changes were accompanied by increased TH, GCH and NE transporter mRNAs. CT-1 and depolarization regulate expression of noradrenergic properties in an opposing manner, and the combined treatment results in elevated cellular catecholamines and decreased NE uptake relative to control cells.

Animals↗
PubMed2002

Developmental regulation of neurotransmitter phenotype through tetrahydrobiopterin.

During development, sympathetic neurons innervating rodent sweat glands undergo a target-induced change in neurotransmitter phenotype from noradrenergic to cholinergic. Although the sweat gland innervation in the adult mouse is cholinergic and catecholamines are absent, these neurons continue to express tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. The developmental suppression of noradrenergic function in these mouse sympathetic neurons is not well understood. We investigated whether the downregulation of the enzyme aromatic l-amino acid decarboxylase (AADC) or the TH cofactor tetrahydrobiopterin (BH4) could account for the loss of catecholamines in these neurons. AADC levels did not decrease during development, and adult cholinergic sympathetic neurons were strongly immunoreactive for AADC. In contrast, BH4 levels dropped significantly in murine sweat gland-containing footpads during the time period when the gland innervation was switching from making norepinephrine to acetylcholine. Immunoreactivity for the rate-limiting BH4 synthetic enzyme GTP cyclohydrolase (GCH) became undetectable in the sweat gland neurons during this phenotypic conversion, suggesting that sweat glands reduce BH4 levels by suppressing GCH expression during development. Furthermore, extracts from sweat gland-containing footpads suppressed BH4 in cultured mouse sympathetic neurons, and addition of the BH4 precursor sepiapterin rescued catecholamine production in neurons treated with footpad extracts. Together, these results suggest that the mouse sweat gland-derived cholinergic differentiation factor functionally suppresses the noradrenergic phenotype during development by inhibiting production of the TH cofactor, BH4. These data also indicate that GCH expression, which is often coordinately regulated with TH expression, can be controlled independently of TH during development.

Acetylcholine↗