Browse Health
Neurologist (brain, nervous system)
16 years of experience
Accepting new patients


Education ?

Medical School Score Rankings
Yale University (1996)
Top 25%

Awards & Distinctions ?

American Board of Psychiatry and Neurology

Publications & Research

Dr. Widnell has contributed to 7 publications.
Title Role of Comt Inhibitors and Dopamine Agonists in the Treatment of Motor Fluctuations.
Date August 2005
Journal Movement Disorders : Official Journal of the Movement Disorder Society

Although levodopa remains the most effective drug for the symptomatic treatment of Parkinson's disease (PD), there are significant limitations to its chronic use. Growing preclinical and clinical evidence suggests that the severity of motor fluctuations is influenced both by PD severity and pulsatile stimulation of striatal dopamine receptors. Current management of motor fluctuations is based primarily on strategies to prolong the effects of dopaminergic stimulation. This prolongation is accomplished either through the use of long-acting dopaminergic drugs or prolonging of the effects of levodopa. During the past decade, the armamentarium of dopamine agonists increased and agents that prolong the plasma half-life of levodopa became available. Furthermore, recent clinical trials provide evidence-based approaches to improve the management of motor fluctuations in patients with advanced and early PD.

Title Cell Type-specific Regulation of Creb Gene Expression: Mutational Analysis of Creb Promoter Activity.
Date November 1998
Journal Journal of Neurochemistry

Previous studies have shown that activation of the cyclic AMP (cAMP) pathway down-regulates CREB expression in CATH.a cells, an effect that appears to be mediated via inhibition of CREB gene transcription. In the current study, we compared this effect in CATH.a cells with regulation of CREB expression in another cell line, C6 glioma cells. In contrast to the findings in CATH.a cells, activation of the cAMP pathway up-regulates CREB expression in C6 glioma cells. To determine whether these opposite effects can be explained by regulation of CREB promoter activity, chloramphenicol acetyltransferase (CAT) assays were performed in CATH.a and C6 glioma cells that were transiently transfected with a CREB promoter-CAT fusion plasmid. Activation of the cAMP pathway decreased levels of CAT activity in transfected CATH.a cells but increased CAT activity in transfected C6 glioma cells. We next investigated the effect of mutations in the CREB promoter on such regulation in these two cell lines. Mutations of single CRE or Sp1 binding sites in the CREB promoter reduced basal levels of CAT activity but did not significantly attenuate regulation of the promoter in CATH.a or C6 glioma cells. However, mutation or deletion of two CRE sites in the CREB promoter completely abolished up-regulation of CAT activity in the C6 glioma cells and abolished basal levels of CAT activity in CATH.a cells. CREB promoter activity was also studied in cultured SHSY5Y cells and in primary cultures of striatal neurons as further comparisons. Activation of the cAMP pathway was found to increase CAT activity in both cell types. In the striatal cultures, this effect was obliterated by mutation or deletion of either of the two CREs in the promoter. These findings demonstrate cell type-specific effects of the cAMP pathway on CREB expression, which appear to be mediated via differential regulation of the CREB promoter.

Title Differential Regulation of Corticotropin-releasing Factor1 Receptor Expression by Stress and Agonist Treatments in Brain and Cultured Cells.
Date December 1996
Journal Molecular Pharmacology

Corticotropin-releasing factor (CRF) is known to play a major role in coordinating neuroendocrine and behavioral responses to stress. We demonstrate that expression of the CRF1 receptor (CRF-R1) is regulated by stress in the brain and by agonist treatments in cultured cells. Expression of CRF-R1 mRNA was decreased in the frontal cortex but increased in the hippocampus by chronic unpredictable stress. Chronic corticosterone administration did not influence levels of CRF-R1 mRNA in either region, suggesting that regulation of CRF-R1 expression is mediated by CRF itself or by another stress-related factor. Differential regulation of CRF-R1 mRNA by agonist treatment was also observed in two cultured cell lines. In CATH.a cells, a neuron-derived cell line, incubation with CRF decreased levels of CRF-R1 mRNA, whereas in AtT-20 cells, a pituitary-derived cell line, agonist (CRF) treatment increased levels of CRF-R1 mRNA. Further studies demonstrated that the observed changes in both cell lines could be accounted for by regulation of CRF-R1 gene transcription and not by altered mRNA stability. Furthermore, agonist-induced down-regulation of CRF-R1 transcription rate in CATH.a cells was found to be dependent on de novo protein synthesis, suggesting the involvement of an inducible repressor. The results show that different cell types show differential transcriptional regulation of the CRF-R1, which could explain the region-specific regulation of receptor expression in the brain.

Title Transcriptional Regulation of Creb (cyclic Amp Response Element-binding Protein) Expression in Cath.a Cells.
Date June 1996
Journal Journal of Neurochemistry

We have recently demonstrated that mRNA expression of cyclic AMP (cAMP) response element-binding protein (CREB) is down-regulated in CATH.a cells (a neural-derived cell line) by activation of the cAMP pathway. We now demonstrate that this down-regulation can be accounted for by a decrease in the rate of CREB gene transcription. It was found that cycloheximide, a protein synthesis inhibitor, prevented the forskolin-induced decrease in CREB mRNA levels in CATH.a cells. Nuclear run-on assays demonstrated that forskolin decreased the rate of CREB transcription by close to 50%. Moreover, forskolin decreased chloramphenicol acetyltransferase (CAT) activity in CATH.a cells transiently transfected with a construct containing 1,240 bp of CREB promoter fused to a CAT reporter plasmid. Possible mechanisms by which activation of the cAMP pathway leads to a decrease in CREB gene transcription are discussed.

Title Regulation of Creb Expression: in Vivo Evidence for a Functional Role in Morphine Action in the Nucleus Accumbens.
Date February 1996
Journal The Journal of Pharmacology and Experimental Therapeutics

Previous work has shown that chronic opiate administration regulates protein components of the cAMP signaling pathway, specifically in the nucleus accumbens (NAc), a brain region implicated in the reinforcing properties of opiates, and that such adaptations may contribute to changes in reinforcement mechanisms that characterize opiate addiction. In the present study, we examined a possible role for the transcription factor cAMP response element-binding protein (CREB) in mediating these long-term effects of opiates in the NAc. Chronic, but not acute, morphine administration was found to decrease levels of CREB immunoreactivity in the NAc, an effect not seen in other brain regions studied. The functional significance of this CREB down-regulation was then investigated by the use of an anti-sense oligonucleotide strategy that produces a specific and sustained decrease in CREB levels in the NAc, without detectable toxicity. It was found that the antisense oligonucleotide-induced reduction in CREB levels mimicked the effect of morphine on certain, but not all, cAMP pathway proteins in this brain region, whereas a large number of other signal transduction proteins tested were unaffected by this treatment. Our results support a role for CREB in autoregulation of the cAMP pathway in the nervous system, as well as in mediating some of the effects of morphine on this signaling pathway in the NAc.

Title Regulation of Expression of Camp Response Element-binding Protein in the Locus Coeruleus in Vivo and in a Locus Coeruleus-like Cell Line in Vitro.
Date December 1994
Journal Proceedings of the National Academy of Sciences of the United States of America

Expression of the cAMP response element (CRE)-binding protein (CREB) has been thought to be constitutive and not subject to regulation. In the course of investigating effects of chronic morphine on the cAMP pathway in the locus coeruleus, a brain region important for opiate addiction, we found that levels of CREB immunoreactivity and CRE binding were increased by chronic morphine administration. To further investigate possible mechanisms underlying this unexpected finding, we studied the regulation of CREB expression in a cell line (CATH.a) that exhibits many properties of locus coeruleus neurons. Agents that activate the cAMP pathway led to a > 60% decrease in CREB mRNA in this cell line. Moreover, these alterations in CREB mRNA levels were associated with changes in levels of CREB immunoreactivity and CRE-binding activity. In contrast, the same treatments fail to alter CREB expression in PC12 pheochromocytoma cells.

Title Drug Addiction: a Model for the Molecular Basis of Neural Plasticity.
Date February 1994
Journal Neuron

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