Charlie Norwood Veterans Administration Medical Center

Augusta, GA, United States

Charlie Norwood Veterans Administration Medical Center

Augusta, GA, United States

Time filter

Source Type

Buccafusco J.J.,Georgia Regents University | Buccafusco J.J.,Charlie Norwood Veterans Administration Medical Center | Terry Jr. A.V.,Georgia Regents University | Vazdarjanova A.,Charlie Norwood Veterans Administration Medical Center | And 3 more authors.
Pain | Year: 2010

Current clinical treatments for neuropathic pain include amitriptyline, a tricyclic antidepressant with mixed pharmacology that is also clinically reported to impair cognitive performance; and gabapentin, a compound that selectively interacts with α2δ-1 calcium channel subunits. Since few assessments of cognitive performance have been made in non-human primates with these marketed treatments, the purpose of this study was to determine their relative abilities to alter working memory as measured in mature macaques in their performance of a delayed matching-to-sample task. Four delay intervals of increasing duration provided increasing impairment in task accuracies during vehicle sessions. Administration of clinically relevant doses of amitriptyline significantly decreased task accuracy at the highest dose tested (3 mg/kg). Administration of gabapentin increased mean task accuracy, though the effect was not statistically significant until intra-subject variability was reduced by selecting the individual best dose for each animal (which averaged 12.8 mg/kg). Most of the effect was obtained during the presentation of long delay trials (18.2% above vehicle). Task improvement was sustained during sessions run 24 h after gabapentin administration. In a series that used a task-relevant distractor to determine gabapentin's effect on attention, drug treatment reversed distractor-impaired accuracy during long delay trials (25.4% above vehicle). The selective improvement in long delay accuracy in both paradigms suggests improvement in encoding or retention components of working memory. It is currently unclear whether the ability of acute administration of gabapentin to modestly improve working memory occurs by a mechanism that could be related to its anti-allodynic mechanism of action.


Garretson X.T.,Georgia State University | Teubner B.J.,Georgia State University | Grove K.L.,Oregon Health And Science University | Vazdarjanova A.,Georgia Regents University | And 3 more authors.
Journal of Neuroscience | Year: 2015

Peroxisome proliferator-activated receptor γ (PPARγ) is clinically targeted for type II diabetes treatment; however, rosiglitazone (ROSI), a PPARγ agonist, increases food intake and body/fat mass as side-effects. Mechanisms for these effects and the role of PPARγ in feeding are not understood. Therefore, we tested this role in Siberian hamsters, a model of human energy balance, and C57BL/6 mice. We tested the following: (1) how ROSI and/or GW9662 (2-chloro-5-nitro-N-phenylbenzamide;PPARγ antagonist) injected intraperitoneally or into the third ventricle (3V) affected Siberian hamster feeding behaviors; (2) whether food deprivation (FD) co-increases agouti-related protein (AgRP) and PPARγ mRNAexpression in Siberian hamsters and mice; (3) whether intraperitoneally administered ROSI increases AgRP andNPYin ad libitum-fed animals; (4) whether intraperitoneally administeredPPARγ antagonism blocks FD-induced increases in AgRP and NPY; and finally, (5) whether intraperitoneally administered PPAR γ modulation affects plasma ghrelin. Third ventricular and intraperitoneally administered ROSI increased food hoarding and intake for 7 d, an effect attenuated by 3V GW9662, and also prevented (intraperitoneal) FD-induced feeding. FD hamsters and mice increased AgRP within the arcuate hypothalamic nucleus with concomitant increases in PPAR γ exclusively within AgRP/NPY neurons. ROSI increased AgRP and NPY similarly to FD, and GW9662 prevented FD-induced increases in AgRP and NPY in both species. Neither ROSI nor GW9662 affected plasma ghrelin. Thus, we demonstrated that PPAR γ activation is sufficient to trigger food hoarding/intake, increase AgRP/NPY, and possibly is necessary for FD-induced increases in feeding and AgRP/NPY. These findings provide initial evidence that FD-induced increases in AgRP/NPY may be a direct PPARγ-dependent process that controls ingestive behaviors. ©2015 the authors.


Bean J.C.,Georgia Regents University | Lin T.W.,Georgia Regents University | Sathyamurthy A.,Georgia Regents University | Liu F.,Georgia Regents University | And 6 more authors.
Journal of Neuroscience | Year: 2014

Neuregulin 1 (NRG1) and its receptor ErbB4 are schizophrenia risk genes. NRG1-ErbB4 signaling plays a critical role in neural development and regulates neurotransmission and synaptic plasticity. Nevertheless, its cellular targets remain controversial. ErbB4 was thought to express in excitatory neurons, although recent studies disputed this view. Using mice that express a fluorescent protein under the promoter of the ErbB4 gene, we determined in what cells ErbB4 is expressed and their identity. ErbB4 was widely expressed in the mouse brain, being highest in amygdala and cortex. Almost all ErbB4-positive cells were GABAergic in cortex, hippocampus, basal ganglia, and most of amygdala in neonatal and adult mice, suggesting GABAergic transmission as a major target of NRG1-ErbB4 signaling in these regions. Non-GABAergic, ErbB4-positive cells were present in thalamus, hypothalamus, midbrain, and hindbrain. In particular, ErbB4 is expressedinserotoninergicneurons of raphenuclei but not innorepinephrinergicneurons of thelocus ceruleus. Inhypothalamus, ErbB4 is present in neurons that express oxytocin. Finally, ErbB4 is expressed in a group of cells in the subcortical areas that are positive for S100 calcium binding protein β. These results identify novel cellular targets of NRG1-ErbB4 signaling. © 2014 the authors.


Prakash R.,Charlie Norwood Veterans Administration Medical Center | Prakash R.,University of Georgia | Li W.,Charlie Norwood Veterans Administration Medical Center | Li W.,Georgia Regents University | And 7 more authors.
Stroke | Year: 2013

Background and Purpose-Pre-existing diabetes mellitus worsens brain functionality in ischemic stroke. We have previously shown that type 2 diabetic rats exhibit enhanced dysfunctional cerebral neovascularization and when these rats are subjected to cerebral ischemic reperfusion injury develop hemorrhagic transformation and greater neurological deficits. However, our knowledge of vascular and functional plasticity during the recovery phase of diabetic stroke is limited. This study tested the hypothesis that vascular repair is impaired in the poststroke period in diabetes mellitus, and this is associated with poor sensorimotor and cognitive function. We further hypothesized that glycemic control prevents impaired vascularization and improves functional outcome in diabetes mellitus. Methods-Vascularization was assessed in the ipsilateral and contralateral hemispheres in control, diabetes mellitus and diabetes mellitus plus metformin groups 14 days after ischemic reperfusion injury, as well as in respective sham controls. Three-dimensional reconstruction of the fluorescein isothiocyanate (FITC)-stained vasculature was achieved by confocal microscopy, and stereological parameters, including vascular volume and surface area, were measured. Astrogliosis was determined by glial fibrillary acidic protein staining. The relative rates of sensorimotor recovery, cognitive decline, and spontaneous activity were assessed. Results-Vascular density in the peri-infarct area was significantly reduced in diabetes mellitus, whereas there was reparative neovascularization in control rats. Astroglial swelling and reactivity were more pronounced in diabetic stroke compared with control stroke. Diabetes mellitus blunted sensorimotor recovery and also exacerbated anxiety-like symptoms and cognitive deficits. Glycemic control started after stroke partially prevented these changes. Conclusions-Diabetes mellitus impairs poststroke reparative neovascularization and impedes the recovery. Glycemic control after stroke can improve neurovascular repair and improve functional outcome. © 2013 American Heart Association, Inc.


Weinberger P.M.,Georgia Regents University | Merkley M.A.,Georgia Regents University | Khichi S.S.,Georgia Regents University | Lee J.R.,Charlie Norwood Veterans Administration Medical Center | And 3 more authors.
Laryngoscope | Year: 2010

Objectives/Hypothesis: Mortality for black males with head and neck squamous cell carcinoma (HNSCC) is twice that of white males or females. Human papillomavirus (HPV)-active HNSCC, defined by the concurrent presence of high-risk type HPV DNA and host cell p16INK4a expression, is associated with decreased mortality. We hypothesized that prevalence of this HPV-active disease class would be lower in black HNSCC patients compared to white patients. Study Design: Multi-institutional retrospective cohort analysis. Methods: Real-time polymerase chain reaction was used to evaluate for high-risk HPV DNA presence. Immunohistochemistry for p16INK4a protein was used as a surrogate marker for HPV oncoprotein activity. Patients were classified as HPV-negative (HPV DNA-negative, p16INK4a low), HPV-inactive (HPV DNA-positive, p16INK4a low), and HPV-active (HPV DNA-positive, p16INK4a high). Overall survival and recurrence rates were compared by Fisher exact test and Kaplan-Meier analysis. Results: There were 140 patients with HNSCC who met inclusion criteria. Self-reported ethnicity was white (115), black (25), and other (0). Amplifiable DNA was recovered from 102/140 patients. The presence of HPV DNA and the level of p16INK4a expression were determined, and the results were used to classify these patients as HPV-negative (44), HPV-inactive (33), and HPV-active (25). Patients with HPV-active HNSCC had improved overall 5-year survival (59.7%) compared to HPV-negative and HPV-inactive patients (16.9%) (P = .003). Black patients were less likely to have HPV-active disease (0%) compared to white patients (21%) (P = .017). Conclusions: The favorable HPV-active disease class is less common in black than in white patients with HNSCC, which appears to partially explain observed ethnic health disparities. © 2010 The American Laryngological, Rhinological and Otological Society, Inc.


Singh N.,Georgia Regents University | Gurav A.,Georgia Regents University | Sivaprakasam S.,Georgia Regents University | Brady E.,Georgia Regents University | And 9 more authors.
Immunity | Year: 2014

Commensal gut microflora and dietary fiber protect against colonic inflammation and colon cancer through unknown targets. Butyrate, a bacterial product from fermentation of dietary fiber in the colon, has been implicated in this process. GPR109A (encoded by Niacr1) is a receptor for butyrate in the colon. GPR109A is also a receptor for niacin, which is also produced by gut microbiota and suppresses intestinal inflammation. Here we showed that Gpr109a signaling promoted anti-inflammatory properties in colonic macrophages and dendritic cells and enabled them to induce differentiation of Treg cells and IL-10-producing Tcells. Moreover, Gpr109a was essential for butyrate-mediated induction of IL-18 incolonicepithelium. Consequently, Niacr1-/- mice were susceptible to development of colonic inflammation and colon cancer. Niacin, a pharmacological Gpr109a agonist, suppressed colitis and colon cancer in a Gpr109a-dependent manner. Thus, Gpr10a has an essential role in mediating the beneficial effects of gut microbiota and dietary fiber in colon. © 2014 Elsevier Inc.


Barik A.,Georgia Regents University | Lu Y.,Georgia Regents University | Sathyamurthy A.,Georgia Regents University | Bowman A.,Georgia Regents University | And 6 more authors.
Journal of Neuroscience | Year: 2014

The neuromuscular junction (NMJ) is a synapse between motor neurons and skeletal muscle fibers, and is critical for control of muscle contraction. Its formation requires neuronal agrin that acts by binding to LRP4 to stimulate MuSK. Mutations have been identified in agrin, MuSK, and LRP4 in patients with congenital myasthenic syndrome, and patients with myasthenia gravis develop antibodies against agrin, LRP4, and MuSK. However, it remains unclear whether the agrin signaling pathway is critical for NMJ maintenance because null mutation of any of the three genes is perinatal lethal. In this study, we generated imKO mice, a mutant strain whose LRP4 gene can be deleted in muscles by doxycycline (Dox) treatment. Ablation of the LRP4 gene in adult muscle enabled studies of its role in NMJ maintenance. We demonstrate that Dox treatment of P30 mice reduced muscle strength and compound muscle action potentials. AChR clusters became fragmented with diminished junctional folds and synaptic vesicles. The amplitude and frequency of miniature endplate potentials were reduced, indicating impaired neuromuscular transmission and providing cellular mechanisms of adult LRP4 deficiency. We showed that LRP4 ablation led to the loss of synaptic agrin and the 90 kDa fragments, which occurred ahead of other prejunctional and postjunctional components, suggesting that LRP4 may regulate the stability of synaptic agrin. These observations demonstrate that LRP4 is essential for maintaining the structural and functional integrity of the NMJ and that loss of muscle LRP4 in adulthood alone is sufficient to cause myasthenic symptoms. © 2014 the authors.


Hafez S.,Charlie Norwood Veterans Administration Medical Center | Hafez S.,University of Georgia | Coucha M.,Georgia Regents University | Bruno A.,Georgia Regents University | And 6 more authors.
Translational Stroke Research | Year: 2014

Ischemic stroke is a leading cause of disability and is considered now the fourth leading cause of death. Many clinical trials have shown that stroke patients with acute elevation in blood glucose at onset of stroke suffer worse functional outcomes, longer in-hospital stay, and higher mortality rates. The only therapeutic hope for these patients is the rapid restoration of blood flow to the ischemic tissue through intravenous administration of the only currently proven effective therapy, tissue plasminogen activator (tPA). However, even this option is associated with the increased risk of intracerebral hemorrhage. Nonetheless, the underlying mechanisms through which hyperglycemia (HG) and tPA worsen the neurovascular injury after stroke are not fully understood. Accordingly, this review summarizes the latest updates and recommendations about the management of HG and coadministration of tPA in a clinical setting while focusing more on the various experimental models studying (1) the effect of HG on stroke outcomes, (2) the potential mechanisms involved in worsening the neurovascular injury, (3) the different therapeutic strategies employed to ameliorate the injury, and finally, (4) the interaction between HG and tPA. Developing therapeutic strategies to reduce the hemorrhage risk with tPA in hyperglycemic setting is of great clinical importance. This can best be achieved by conducting robust preclinical studies evaluating the interaction between tPA and other therapeutics in order to develop potential therapeutic strategies with high translational impact. © 2014 Springer Science+Business Media New York (Outside the USA).


Ward R.,Augusta University | Ergul A.,Augusta University | Ergul A.,Charlie Norwood Veterans Administration Medical Center
Life Sciences | Year: 2016

Diabetes increases the risk and worsens the progression of cognitive decline. Diabetic rats treated with the dual endothelin receptor antagonist bosentan, have been shown to improve hippocampal-based cognitive deficits. The NLRP3 inflammasome has been implicated in vascular complications of diabetes. We hypothesized that diabetes-mediated increase in endothelin-1 (ET-1) in hippocampal cells causes NLRP3 activation and inflammation. An in vitro model was employed by exposing HT22 hippocampal cells to normal (25. mM), low (5.5. mM) and high (50. mM) glucose conditions with and without palmitate (200. μM) in the presence and absence of 10. μM bosentan for 24. h. NLRP3 activity was measured by western blotting for cryopyrin and caspase-1. ET-1 and IL-1β expression was determined by ELISA. HT22 cells synthesize high levels of ET-1 in normal conditions, which was reduced with palmitate and bosentan as well as low and high glucose conditions. Decreased ET-1 levels were associated with greater activation of NLRP3 and IL-1β in normal glucose. High glucose increased NLRP3 markers and activation compared to normal and low glucose. These data suggest that ET-1 may be protective to neurons. Although endothelin antagonism may be beneficial in improving vascular dysfunction and cognitive impairment, its impact on hippocampal neurons should be further explored. © 2015.


Hafez S.,Charlie Norwood Veterans Administration Medical Center | Coucha M.,Charlie Norwood Veterans Administration Medical Center | Bruno A.,Charlie Norwood Veterans Administration Medical Center | Fagan S.C.,Charlie Norwood Veterans Administration Medical Center | Ergul A.,Charlie Norwood Veterans Administration Medical Center
Translational stroke research | Year: 2014

Ischemic stroke is a leading cause of disability and is considered now the fourth leading cause of death. Many clinical trials have shown that stroke patients with acute elevation in blood glucose at onset of stroke suffer worse functional outcomes, longer in-hospital stay, and higher mortality rates. The only therapeutic hope for these patients is the rapid restoration of blood flow to the ischemic tissue through intravenous administration of the only currently proven effective therapy, tissue plasminogen activator (tPA). However, even this option is associated with the increased risk of intracerebral hemorrhage. Nonetheless, the underlying mechanisms through which hyperglycemia (HG) and tPA worsen the neurovascular injury after stroke are not fully understood. Accordingly, this review summarizes the latest updates and recommendations about the management of HG and coadministration of tPA in a clinical setting while focusing more on the various experimental models studying (1) the effect of HG on stroke outcomes, (2) the potential mechanisms involved in worsening the neurovascular injury, (3) the different therapeutic strategies employed to ameliorate the injury, and finally, (4) the interaction between HG and tPA. Developing therapeutic strategies to reduce the hemorrhage risk with tPA in hyperglycemic setting is of great clinical importance. This can best be achieved by conducting robust preclinical studies evaluating the interaction between tPA and other therapeutics in order to develop potential therapeutic strategies with high translational impact.

Loading Charlie Norwood Veterans Administration Medical Center collaborators
Loading Charlie Norwood Veterans Administration Medical Center collaborators