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1.  Experience Modulates the Effects of Histone Deacetylase Inhibitors on Gene and Protein Expression in the Hippocampus: Impaired Plasticity in Aging 
The Journal of Neuroscience  2015;35(33):11729-11742.
The therapeutic potential of histone deacetylase inhibitor (HDACi) treatment has attracted considerable attention in the emerging area of cognitive neuroepigenetics. The possibility that ongoing cognitive experience importantly regulates the cell biological effects of HDACi administration, however, has not been systematically examined. In an initial experiment addressing this issue, we tested whether water maze training influences the gene expression response to acute systemic HDACi administration in the young adult rat hippocampus. Training powerfully modulated the response to HDACi treatment, increasing the total number of genes regulated to nearly 3000, including many not typically linked to neural plasticity, compared with <300 following HDACi administration alone. Although water maze training itself also regulated nearly 1800 genes, the specific mRNAs, gene networks, and biological pathways involved were largely distinct when the same experience was provided together with HDACi administration. Next, we tested whether the synaptic protein response to HDACi treatment is similarly dependent on recent cognitive experience, and whether this plasticity is altered in aged rats with memory impairment. Whereas synaptic protein labeling in the young hippocampus was selectively increased when HDACi administration was provided in conjunction with water maze training, combined treatment had no effect on synaptic proteins in the aged hippocampus. Our findings indicate that ongoing experience potently regulates the molecular consequences of HDACi treatment and that the interaction of recent cognitive experience with histone acetylation dynamics is disrupted in the aged hippocampus.
SIGNIFICANCE STATEMENT The possibility that interventions targeting epigenetic regulation could be effective in treating a range of neurodegenerative disorders has attracted considerable interest. Here we demonstrate in the rat hippocampus that ongoing experience powerfully modifies the molecular response to one such intervention, histone deacetylase inhibitor (HDACi) administration. A single learning episode dramatically shifts the gene expression profile induced by acute HDACi treatment, yielding a qualitatively distinct hippocampal transcriptome compared with the influence of behavioral training alone. The downstream synaptic protein response to HDACi administration is similarly experience-dependent, and we report that this plasticity is disrupted in the aged hippocampus. The findings highlight that accommodating the modulatory influence of ongoing experience represents a challenge for therapeutic development in the area of cognitive neuroepigenetics.
PMCID: PMC4540806  PMID: 26290249
cognitive aging; epigenetics; histone acetylation; microarray; synaptic protein
2.  Neuroprotection with Non-Feminizing Estrogen Analogues: An Overlooked Possible Therapeutic Strategy 
Hormones and behavior  2012;63(2):278-283.
Although many of the effects of estrogens on the brain are mediated through estrogen receptors (ERs), there is evidence that neuroprotective activity of estrogens can be mediated by non-ER mechanisms. Herein, we review the substantial evidence that estrogens neuroprotection is in large part non-ER mediated and describe in vitro and in vivo studies that support this conclusion. Also, we described our drug discovery strategy for capitalizing on enhancement in neuroprotection while at the same time, reducing ER binding of a group of synthetic non-feminizing estrogens. Finally, we offer evidence that part of the neuroprotection of these non-feminizing estrogens is due to enhancement in redox potential of the synthesized compounds.
PMCID: PMC4446729  PMID: 22498694
Estrogens; non-feminizing estrogens; neuroprotection; stroke; hormone therapy; estrogen receptors
3.  Age-related Brain Expression and Regulation of the Chemokine CCL4/MIP-1β in APP/PS1 Double Transgenic Mice 
The detrimental effect of activation of the chemokine CCL4/MIP-1β on neuronal integrity in patients with HIV-associated dementia has directed attention to the potential role of CCL4 expression and regulation in Alzheimer disease (AD). Here, we show that CCL4 mRNA and protein are overexpressed in the brains of APPswe/PS1 E9 (APP/PS1) double transgenic mice, a model of cerebral amyloid deposition; expression was minimal in brains from non-transgenic littermates or single mutant controls. Increased levels of CCL4 mRNA and protein directly correlated with the age-related progression of cerebral amyloid-β (Aβ) levels in APP/PS1 mice. We also found significantly increased expression of activating transcription factor 3 (ATF3), which was positively correlated with age-related Aβ deposition and CCL4 in the brains of APP/PS1 mice. Results from chromatin immunoprecipitation-quantitative PCR confirmed that ATF3 binds to the promoter region of the CCL4 gene, consistent with a potential role in regulating CCL4 transcription. Finally, elevated ATF3 mRNA expression in APP/PS1 brains was associated with hypomethylation of the ATF3 gene promoter region. These observations prompt the testable hypothesis for future study that CCL4 overexpression, regulated in part by hypomethylation of the ATF3 gene, may contribute to neuropathological progression associated with amyloid deposition in AD.
PMCID: PMC3977177  PMID: 24607962
Alzheimer disease; ATF3; CCL4/MIP-1β; Epigenetics; Neuroinflammation
4.  Neuroprotective effects of high affinity sigma 1 receptor selective compounds 
Brain research  2011;1441:17-26.
We previously reported that the antipsychotic drug haloperidol, a multifunctional D2-like dopamine and sigma receptor subtype antagonist, has neuroprotective properties. In this study we further examined the association between neuroprotection and receptor antagonism by evaluating a panel of novel compounds with varying affinity at sigma and D2-like dopamine receptors. These compounds were evaluated using an in vitro cytotoxicity assay that utilizes a hippocampal-derived cell line, HT-22, in the presence or absence of varying concentrations (5 to 20 mM) of glutamate. While haloperidol was found to be a potent neuroprotective agent in this in vitro cell assay, the prototypic sigma 1 receptor agonist (+)-pentazocine was found not to be neuroprotective. Subsequently, the potency for the neuroprotection of HT-22 cells was evaluated for a) three SV series indoles which have nMolar affinity at D2-like receptors but varying affinity at sigma 1 receptor and b) two benzyl phenylacetamides sigma 1 receptor selective compounds which bind with low affinity at D2-like receptors but have nMolar affinity for the sigma 1 receptor. We observed that cytoprotection correlated with the affinity of the compounds for sigma 1 receptors. Based upon results from the HT-22 cell-based in vitro assay, two phenylacetamides, LS-127 and LS-137, were further evaluated in vivo using a transient middle cerebral artery occlusion (t-MCAO) model of stroke. At a dose of 100 µg/kg, both LS-127 and LS-137 attenuated infarct volume by approximately 50%. These studies provide further evidence that sigma 1 receptor selective compounds can provide neuroprotection in cytotoxic situations. These results also demonstrate that sigma 1 receptor selective benzyl phenylacetamides are candidate pharmacotherapeutic agents that could be used to minimize neuronal death after a stroke or head trauma.
PMCID: PMC4054954  PMID: 22285434
Sigma receptors; Sigma 1 receptors; Neuroprotection
5.  Changes in mouse cognition and hippocampal gene expression observed in a mild physical- and blast-traumatic brain injury 
Neurobiology of disease  2013;54:1-11.
Warfare has long been associated with traumatic brain injury (TBI) in militarized zones. Common forms of TBI can be caused by a physical insult to the head-brain or by the effects of a high velocity blast shock wave generated by the detonation of an explosive device. While both forms of trauma are distinctly different regarding the mechanism of trauma induction, there are striking similarities in the cognitive and emotional status of survivors. Presently, proven effective therapeutics for the treatment of either form of TBI are unavailable. To be able to develop efficacious therapies, studies involving animal models of physical- and blast-TBI are required to identify possible novel or existing medicines that may be of value in the management of clinical events. We examined indices of cognition and anxiety-like behavior and the hippocampal gene transcriptome of mice subjected to both forms of TBI. We identified common behavioral deficits and gene expression regulations, in addition to unique injury-specific forms of gene regulation. Molecular pathways presented a pattern similar to that seen in gene expression. Interestingly, pathways connected to Alzheimer’s disease displayed a markedly different form of regulation depending on the type of TBI. While these data highlight similarities in behavioral outcomes after trauma, the divergence in hippocampal transcriptome observed between models suggests that, at the molecular level, the TBIs are quite different. These models may provide tools to help define therapeutic approaches for the treatment of physical- and blast-TBIs. Based upon observations of increasing numbers of personnel displaying TBI related emotional and behavioral changes in militarized zones, the development of efficacious therapies will become a national if not a global priority.
PMCID: PMC3628969  PMID: 23454194
Physical-traumatic brain injury; Blast-traumatic brain injury; Cognitive dysfunction; Gene expression; Molecular pathway(s); Neurodegeneration; Stem cells; Alzheimer’s disease
6.  Effects of Extended Release Methylphenidate Treatment on Ratings of Attention-Deficit/Hyperactivity Disorder (ADHD) and Associated Behavior in Children with Autism Spectrum Disorders and ADHD Symptoms 
The purpose of this study was to examine the behavioral effects of four doses of psychostimulant medication, combining extended-release methylphenidate (MPH) in the morning with immediate-release MPH in the afternoon.
The sample comprised 24 children (19 boys; 5 girls) who met American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV-TR) criteria for an autism spectrum disorder (ASD) on the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS), and had significant symptoms of attention-deficit/hyperactivity disorder (ADHD). This sample consisted of elementary school-age, community-based children (mean chronological age=8.8 years, SD=1.7; mean intelligence quotient [IQ]=85; SD=16.8). Effects of four dose levels of MPH on parent and teacher behavioral ratings were investigated using a within-subject, crossover, placebo-controlled design.
MPH treatment was associated with significant declines in hyperactive and impulsive behavior at both home and school. Parents noted significant declines in inattentive and oppositional behavior, and improvements in social skills. No exacerbation of stereotypies was noted, and side effects were similar to those seen in typically developing children with ADHD. Dose response was primarily linear in the dose range studied.
The results of this study suggest that MPH formulations are efficacious and well-tolerated for children with ASD and significant ADHD symptoms.
PMCID: PMC3689935  PMID: 23782128
7.  CREB-binding protein (CBP) levels in the rat hippocampus fail to predict chronological or cognitive aging 
Neurobiology of aging  2012;34(3):832-844.
Normal cognitive aging is associated with deficits in memory processes dependent on the hippocampus, along with large-scale changes in the hippocampal expression of many genes. Histone acetylation can broadly influence gene expression and has been recently linked to learning and memory. We hypothesized that cAMP response element binding (CREB)-binding protein (CBP), a key histone acetyltransferase, may contribute to memory decline in normal aging. Here, we quantified CBP protein levels in the hippocampus of young, aged unimpaired and aged impaired rats, classified on the basis of spatial memory capacity documented in the Morris water maze. First, CBP-immunofluorescence was quantified across the principal cell layers of the hippocampus using both low and high resolution laser scanning imaging approaches. Second, digital images of CBP immunostaining were analyzed by a multi-purpose classifier algorithm (WND-CHARM) with validated sensitivity across many types of input materials. Finally, CBP protein levels in the principal subfields of the hippocampus were quantified by quantitative western blotting. CBP levels were equivalent as a function of age and cognitive status in all analyses. The sensitivity of the techniques used was substantial, sufficient to reveal differences across the principal cell fields of the hippocampus, and to correctly classify images from young and aged animals independent of CBP-immunoreactivity. The results are discussed in the context of recent evidence suggesting that CBP decreases may be most relevant in conditions of aging that, unlike normal cognitive aging, involve significant neuron loss.
PMCID: PMC3518677  PMID: 22884549
epigenetics; memory; image analysis; stereology; quantitative microscopy
8.  Preserved learning and memory following 5-fluorouracil and cyclophosphamide treatment in rats 
Some patients experience enduring cognitive impairment after cancer treatment, a condition termed “chemofog”. Animal models allow assessment of chemotherapy effects on learning and memory per se, independent of changes due to cancer itself or associated health consequences such as depression. The present study examined the long-term learning and memory effects of a chemotherapy cocktail used widely in the treatment of breast cancer, consisting of 5-fluorouracil (5FU) and cyclophosphamide (CYP). Eighty 5-month old male F344 rats received contextual and cued fear conditioning before treatment with saline, or a low or high dose drug cocktail (50 mg/kg CYP and 75 mg/kg 5FU, or 75 mg/kg CYP and 120 mg/kg 5FU, i.p., respectively) every 30 days for 2 months. After a 2-month, no-drug recovery, both long-term retention and new task acquisition in the water maze and 14-unit T-maze were assessed. Neither dose of the CYP/5FU cocktail impaired retrograde fear memory despite marked toxicity documented by enduring weight loss and 50% mortality at the higher dose. Acquisition in the water maze and Stone maze was also normal relative to controls in rats treated with CYP/5FU. The results contribute to a growing literature suggesting that learning and memory mediated by the hippocampus can be relatively resistant to chemotherapy. Future investigation may need to focus on assessments of processing speed, executive function and attention, and the possible interactive contribution of cancer itself and aging to the post-treatment development of cognitive impairment.
PMCID: PMC3183356  PMID: 21875615
Chemofog; Chemobrain; spatial memory; fear conditioning; cognition
9.  Effects of Long-Term Cranberry Supplementation on Endocrine Pancreas in Aging Rats 
The effects of long-term cranberry consumption on age-related changes in endocrine pancreas are not fully understood. Here we treated male Fischer 344 rats with either 2% whole cranberry powder supplemented or normal rodent chow from 6 to 22 month old. Both groups displayed an age-related decline in basal plasma insulin concentrations, but this age-related decline was delayed by cranberry. Cranberry supplementation led to increased β-cell glucose responsiveness during the oral glucose tolerance test. Portal insulin concentration was 7.6-fold higher in rats fed cranberry, coupled with improved β-cell function. However, insulin resistance values were similar in both groups. Total β-cell mass and expression of pancreatic and duodenal homeobox 1 and insulin within islets were significantly enhanced in rats fed cranberry relative to controls. Furthermore, cranberry increased insulin release of an insulin-producing β-cell line, revealing its insulinotropic effect. These findings suggest that cranberry is of particular benefit to β-cell function in normal aging rats.
PMCID: PMC3193520  PMID: 21768504
Cranberry; Insulin release; Pancreatic β-cell function; Pancreatic β-cell mass; Aging
10.  Nutrient-Sensitive Mitochondrial NAD+ Levels Dictate Cell Survival 
Cell  2007;130(6):1095-1107.
A major cause of cell death caused by genotoxic stress is thought to be due to the depletion of NAD+ from the nucleus and the cytoplasm. Here we show that NAD+ levels in mitochondria remain at physiological levels following genotoxic stress and can maintain cell viability even when nuclear and cytoplasmic pools of NAD+ are depleted. Rodents fasted for 48 hr show increased levels of the NAD+ biosynthetic enzyme Nampt and a concomitant increase in mitochondrial NAD+. Increased Nampt provides protection against cell death and requires an intact mitochondrial NAD+ salvage pathway as well as the mitochondrial NAD+-dependent deacetylases SIRT3 and SIRT4. We discuss the relevance of these findings to understanding how nutrition modulates physiology and to the evolution of apoptosis.
PMCID: PMC3366687  PMID: 17889652
11.  The Assessment of Non-Feminizing Estrogens for Use in Neuroprotection 
Brain research  2010;1379:61-70.
The menopause is associated with a precipitous decline in circulating estrogens and a resulting loss of the neuroprotective actions of this steroid hormone. In view of the results of the Women’s Health Initiative and the preceding knowledge that orally administered estrogens has a variety of adverse side effects, likely through actions on peripheral estrogen receptor alpha (ERα), we initiated a program of research to synthesis and assess a group of non-feminizing estrogens that lack ability to interact with ERs but retain much of the neuroprotective action of feminizing estrogens. This program of research is aimed at the identification of compounds which do not stimulate ERs but are potentially neuroprotective in vitro and in animal models of neuronal cell death. We discovered that the most effective non-feminizing estrogens were those with large bulky groups in the 2 and/or 4 carbon of the phenolic A ring of the steroid. These compounds were 8- to 114-fold more potent than 17 β-estradiol (βE2), but lacked ER binding capacity in vitro and feminizing effects in vivo. The success of this program of research suggests that strategies to optimize non-feminizing estrogens for use in postmenopausal women can be successful.
PMCID: PMC3048764  PMID: 21111714
12.  The Potential for Estrogens in Preventing Alzheimer's Disease 
Estrogens are the best studied class of drugs for potential use in the prevention of Alzheimer's disease (AD). These steroids have been shown to be potent neuroprotectants both in vitro and in vivo, and to exert effects that are consistent with their potential use in prevention of AD. These include the prevention of the processing of amyloid precursor protein (APP) into beta-amyloid (Aβ), the reduction in tau hyperphosphorylation, and the elimination of catastrophic attempts at neuronal mitosis. Further, epidemiological data support the efficacy of early post-menopausal use of estrogens for the delay or prevention of AD. Collectively, this evidence supports the further development of estrogen-like compounds for prevention of AD. Several approaches to enhance brain specificity of estrogen action are now underway in an attempt to reduce the side effects of chronic estrogen therapy in AD.
PMCID: PMC2771945  PMID: 19890493
Estrogens; estradiol; Alzheimer's disease; neurodegeneration; memory and cognition
13.  Dietary Activators of Sirt1 
Calorie restriction (CR) is a non-genetic manipulation that reliably results in extended lifespan of several species ranging from yeast to dogs. The lifespan extension effect of CR has been strongly associated with an increased level and activation of the Sir2 histone deacetylase and its mammalian ortholog Sirt1. This association led to the search for potential Sirt1-activating, life-extending molecules. This review briefly outlines the experimental findings on resveratrol and other dietary activators of Sirt1.
PMCID: PMC2727669  PMID: 19010386
Calorie restriction; lifespan; resveratrol; sirtuins
14.  Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending lifespan 
Cell metabolism  2008;8(2):157-168.
A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging including reduced albuminuria, decreased inflammation and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started mid-life.
PMCID: PMC2538685  PMID: 18599363
15.  The Potential for Estrogens in Preventing Alzheimer's Disease and Vascular Dementia 
Estrogens are the best-studied class of drugs for potential use in the prevention of Alzheimer's disease (AD). These steroids have been shown to be potent neuroprotectants both in vitro and in vivo, and to exert effects that are consistent with their potential use in prevention of AD. These include the prevention of the processing of amyloid precursor protein (APP) into beta-amyloid (Aß), the reduction in tau hyperphosphorylation, and the elimination of catastrophic attempts at neuronal mitosis. Further, epidemiological data support the efficacy of early postmenopausal use of estrogens for the delay or prevention of AD. Collectively, this evidence supports the further development of estrogen-like compounds for prevention of AD. Several approaches to enhance brain specificity of estrogen action are now underway in an attempt to reduce the side effects of chronic estrogen therapy in AD.
PMCID: PMC2771945  PMID: 19890493
estrogens; estradiol; Alzheimer's disease; neurodegeneration; memory and cognition
16.  Pyruvate Protects Mitochondria from Oxidative Stress in Human Neuroblastoma SK-N-SH Cells 
Brain research  2006;1132(1):1-9.
Oxidative stress is implicated in neurodegenerative diseases including stroke, Alzheimer’s disease and Parkinson’s disease, and has been extensively studied as a potential target for therapeutic intervention. Pyruvate, a natural metabolic intermediate and energy substrate, exerts antioxidant effects in brain and other tissues susceptible to oxidative stress. We tested the protective effects of pyruvate on hydrogen peroxide (H2O2) toxicity in human neuroblastoma SK-N-SH cells and the mechanisms underlying its protection. Hydrogen peroxide insult resulted in 85% cell death, but co-treatment with pyruvate dose-dependently attenuated cell death. At concentrations of ≥ 1 mM, pyruvate totally blocked the cytotoxic effects of H2O2. Pyruvate exerted its protective effects even when its administration was delayed up to 2 hr after H2O2 insult. As a scavenger of reactive oxygen species (ROS), pyruvate dose-dependently attenuated H2O2-induced ROS formation, assessed from 2,7-dichlorofluorescein diacetate fluorescence. Furthermore, pyruvate suppressed superoxide production by submitochondrial particles, and attenuated oxidative stress-induced collapse of the mitochondrial membrane potential. Collectively, these results suggest pyruvate protects neuronal cells through its antioxidant actions on mitochondria.
PMCID: PMC1853247  PMID: 17174285
pyruvate; mitochondria; oxidative stress; neuroprotection; hydrogen peroxide; superoxide

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