Publications by authors named "Pradoldej Sompol"

24 Publications

  • Page 1 of 1

Q134R: Small chemical compound with NFAT inhibitory properties improves behavioral performance and synapse function in mouse models of amyloid pathology.

Aging Cell 2021 07 12;20(7):e13416. Epub 2021 Jun 12.

Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY, USA.

Inhibition of the protein phosphatase calcineurin (CN) ameliorates pathophysiologic and cognitive changes in aging rodents and mice with aging-related Alzheimer's disease (AD)-like pathology. However, concerns over adverse effects have slowed the transition of common CN-inhibiting drugs to the clinic for the treatment of AD and AD-related disorders. Targeting substrates of CN, like the nuclear factor of activated T cells (NFATs), has been suggested as an alternative, safer approach to CN inhibitors. However, small chemical inhibitors of NFATs have only rarely been described. Here, we investigate a newly developed neuroprotective hydroxyquinoline derivative (Q134R) that suppresses NFAT signaling, without inhibiting CN activity. Q134R partially inhibited NFAT activity in primary rat astrocytes, but did not prevent CN-mediated dephosphorylation of a non-NFAT target, either in vivo, or in vitro. Acute (≤1 week) oral delivery of Q134R to APP/PS1 (12 months old) or wild-type mice (3-4 months old) infused with oligomeric Aβ peptides led to improved Y maze performance. Chronic (≥3 months) oral delivery of Q134R appeared to be safe, and, in fact, promoted survival in wild-type (WT) mice when given for many months beyond middle age. Finally, chronic delivery of Q134R to APP/PS1 mice during the early stages of amyloid pathology (i.e., between 6 and 9 months) tended to reduce signs of glial reactivity, prevented the upregulation of astrocytic NFAT4, and ameliorated deficits in synaptic strength and plasticity, without noticeably altering parenchymal Aβ plaque pathology. The results suggest that Q134R is a promising drug for treating AD and aging-related disorders.
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http://dx.doi.org/10.1111/acel.13416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282246PMC
July 2021

Molecular elevation of insulin receptor signaling improves memory recall in aged Fischer 344 rats.

Aging Cell 2020 10 27;19(10):e13220. Epub 2020 Aug 27.

Department of Pharmacology and Nutritional Sciences, Lexington, Kentucky, USA.

As demonstrated by increased hippocampal insulin receptor density following learning in animal models and decreased insulin signaling, receptor density, and memory decline in aging and Alzheimer's diseases, numerous studies have emphasized the importance of insulin in learning and memory processes. This has been further supported by work showing that intranasal delivery of insulin can enhance insulin receptor signaling, alter cerebral blood flow, and improve memory recall. Additionally, inhibition of insulin receptor function or expression using molecular techniques has been associated with reduced learning. Here, we sought a different approach to increase insulin receptor activity without the need for administering the ligand. A constitutively active, modified human insulin receptor (IRβ) was delivered to the hippocampus of young (2 months) and aged (18 months) male Fischer 344 rats in vivo. The impact of increasing hippocampal insulin receptor expression was investigated using several outcome measures, including Morris water maze and ambulatory gait performance, immunofluorescence, immunohistochemistry, and Western immunoblotting. In aged animals, the IRβ construct was associated with enhanced performance on the Morris water maze task, suggesting that this receptor was able to improve memory recall. Additionally, in both age-groups, a reduced stride length was noted in IRβ-treated animals along with elevated hippocampal insulin receptor levels. These results provide new insights into the potential impact of increasing neuronal insulin signaling in the hippocampus of aged animals and support the efficacy of molecularly elevating insulin receptor activity in vivo in the absence of the ligand to directly study this process.
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http://dx.doi.org/10.1111/acel.13220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576226PMC
October 2020

Single-Molecule Detection of Nanoparticles for Multiphoton Fluorescence Correlation Spectroscopy to Quantify Cerebral Blood Flow.

Nano Lett 2020 08 8;20(8):6135-6141. Epub 2020 Jul 8.

Department of Chemistry, University of Kentucky, Lexington, Kentucky 40506, United States.

We present the application of multiphoton fluorescence correlation spectroscopy (FCS) of fluorescent nanoparticles for the measurement of cerebral blood flow with excellent spatial and temporal resolution. Through the detection of single nanoparticles within the complex vessel architecture of a live mouse, this new approach enables the quantification of nanoparticle dynamics occurring within the vasculature along with simultaneous measurements of blood flow properties in the brain. In addition to providing high resolution blood flow measurements, this approach enables real-time quantification of nanoparticle concentration, degradation, and transport. This method is capable of quantifying flow rates at each pixel with submicron resolution to enable monitoring of dynamic changes in flow rates in response to changes in the animal's physiological condition. Scanning the excitation beam using FCS provides pixel by pixel mapping of flow rates with subvessel resolution across capillaries 300 μm deep in the brains of mice.
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http://dx.doi.org/10.1021/acs.nanolett.0c02280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405275PMC
August 2020

Ca, Astrocyte Activation and Calcineurin/NFAT Signaling in Age-Related Neurodegenerative Diseases.

Front Aging Neurosci 2018 9;10:199. Epub 2018 Jul 9.

Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY, United States.

Mounting evidence supports a fundamental role for Ca dysregulation in astrocyte activation. Though the activated astrocyte phenotype is complex, cell-type targeting approaches have revealed a number of detrimental roles of activated astrocytes involving neuroinflammation, release of synaptotoxic factors and loss of glutamate regulation. Work from our lab and others has suggested that the Ca/calmodulin dependent protein phosphatase, calcineurin (CN), provides a critical link between Ca dysregulation and the activated astrocyte phenotype. A proteolyzed, hyperactivated form of CN appears at high levels in activated astrocytes in both human tissue and rodent tissue around regions of amyloid and vascular pathology. Similar upregulation of the CN-dependent transcription factor nuclear factor of activated T cells (NFAT4) also appears in activated astrocytes in mouse models of Alzheimer's disease (ADs) and traumatic brain injury (TBI). Major consequences of hyperactivated CN/NFAT4 signaling in astrocytes are neuroinflammation, synapse dysfunction and glutamate dysregulation/excitotoxicity, which will be covered in this review article.
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http://dx.doi.org/10.3389/fnagi.2018.00199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046440PMC
July 2018

An emerging role of astrocytes in vascular contributions to cognitive impairment and dementia.

J Neurochem 2018 03 22;144(5):644-650. Epub 2018 Jan 22.

Department of Physiology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA.

Vascular contributions to cognitive impairment and dementia (VCID) is understood to be the second most common cause of dementia after Alzheimer's disease, and is also a frequent comorbidity with Alzheimer's disease. While VCID is widely acknowledged as a key contributor to dementia, the mechanistic underpinnings of VCID remain poorly understood. In this review, we address the potential role of astrocytes in the pathophysiology of VCID. The vast majority of the blood vessels in the brain are surrounded by astrocytic end-feet. Given that astrocytes make up a significant proportion of the cells in the brain, and that astrocytes are usually passively connected to one another through gap junctions, we hypothesize that astrocytes are key mediators of cognitive impairment because of cerebrovascular disease. In this review, we discuss the existing body of literature regarding the role of astrocytes at the vasculature in the brain, and the known consequences of their dysfunction, as well as our hypotheses regarding the role astrocytes play in VCID. This article is part of the Special Issue "Vascular Dementia".
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http://dx.doi.org/10.1111/jnc.14273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907924PMC
March 2018

Calcineurin/NFAT Signaling in Activated Astrocytes Drives Network Hyperexcitability in Aβ-Bearing Mice.

J Neurosci 2017 06 30;37(25):6132-6148. Epub 2017 May 30.

Sanders-Brown Center on Aging,

Hyperexcitable neuronal networks are mechanistically linked to the pathologic and clinical features of Alzheimer's disease (AD). Astrocytes are a primary defense against hyperexcitability, but their functional phenotype during AD is poorly understood. Here, we found that activated astrocytes in the 5xFAD mouse model were strongly associated with proteolysis of the protein phosphatase calcineurin (CN) and the elevated expression of the CN-dependent transcription factor nuclear factor of activated T cells 4 (NFAT4). Intrahippocampal injections of adeno-associated virus vectors containing the astrocyte-specific promoter Gfa2 and the NFAT inhibitory peptide VIVIT reduced signs of glutamate-mediated hyperexcitability in 5xFAD mice, measured with microelectrode arrays and brain slices, using whole-cell voltage clamp. VIVIT treatment in 5xFAD mice led to increased expression of the astrocytic glutamate transporter GLT-1 and to attenuated changes in dendrite morphology, synaptic strength, and NMDAR-dependent responses. The results reveal astrocytic CN/NFAT4 as a key pathologic mechanism for driving glutamate dysregulation and neuronal hyperactivity during AD. Neuronal hyperexcitability and excitotoxicity are increasingly recognized as important mechanisms for neurodegeneration and dementia associated with Alzheimer's disease (AD). Astrocytes are profoundly activated during AD and may lose their capacity to regulate excitotoxic glutamate levels. Here, we show that a highly active calcineurin (CN) phosphatase fragment and its substrate transcription factor, nuclear factor of activated T cells (NFAT4), appear in astrocytes in direct proportion to the extent of astrocyte activation. The blockade of astrocytic CN/NFAT signaling in a common mouse model of AD, using adeno-associated virus vectors normalized glutamate signaling dynamics, increased astrocytic glutamate transporter levels and alleviated multiple signs of neuronal hyperexcitability. The results suggest that astrocyte activation drives hyperexcitability during AD through a mechanism involving aberrant CN/NFAT signaling and impaired glutamate transport.
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http://dx.doi.org/10.1523/JNEUROSCI.0877-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481945PMC
June 2017

Peripheral administration of the soluble TNF inhibitor XPro1595 modifies brain immune cell profiles, decreases beta-amyloid plaque load, and rescues impaired long-term potentiation in 5xFAD mice.

Neurobiol Dis 2017 Jun 24;102:81-95. Epub 2017 Feb 24.

Emory University School of Medicine, 30322, United States. Electronic address:

Clinical and animal model studies have implicated inflammation and peripheral immune cell responses in the pathophysiology of Alzheimer's disease (AD). Peripheral immune cells including T cells circulate in the cerebrospinal fluid (CSF) of healthy adults and are found in the brains of AD patients and AD rodent models. Blocking entry of peripheral macrophages into the CNS was reported to increase amyloid burden in an AD mouse model. To assess inflammation in the 5xFAD (Tg) mouse model, we first quantified central and immune cell profiles in the deep cervical lymph nodes and spleen. In the brains of Tg mice, activated (MHCII, CD45, and Ly6C) myeloid-derived CD11b immune cells are decreased while CD3 T cells are increased as a function of age relative to non-Tg mice. These immunological changes along with evidence of increased mRNA levels for several cytokines suggest that immune regulation and trafficking patterns are altered in Tg mice. Levels of soluble Tumor Necrosis Factor (sTNF) modulate blood-brain barrier (BBB) permeability and are increased in CSF and brain parenchyma post-mortem in AD subjects and Tg mice. We report here that in vivo peripheral administration of XPro1595, a novel biologic that sequesters sTNF into inactive heterotrimers, reduced the age-dependent increase in activated immune cells in Tg mice, while decreasing the overall number of CD4 T cells. In addition, XPro1595 treatment in vivo rescued impaired long-term potentiation (LTP) measured in brain slices in association with decreased Aβ plaques in the subiculum. Selective targeting of sTNF may modulate brain immune cell infiltration, and prevent or delay neuronal dysfunction in AD.

Significance Statement: Immune cells and cytokines perform specialized functions inside and outside the brain to maintain optimal brain health; but the extent to which their activities change in response to neuronal dysfunction and degeneration is not well understood. Our findings indicate that neutralization of sTNF reduced the age-dependent increase in activated immune cells in Tg mice, while decreasing the overall number of CD4 T cells. In addition, impaired long-term potentiation (LTP) was rescued by XPro1595 in association with decreased hippocampal Aβ plaques. Selective targeting of sTNF holds translational potential to modulate brain immune cell infiltration, dampen neuroinflammation, and prevent or delay neuronal dysfunction in AD.
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http://dx.doi.org/10.1016/j.nbd.2017.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464789PMC
June 2017

Calcineurin proteolysis in astrocytes: Implications for impaired synaptic function.

Biochim Biophys Acta 2016 09 20;1862(9):1521-32. Epub 2016 May 20.

Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA; Sanders Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY, USA. Electronic address:

Mounting evidence suggests that astrocyte activation, found in most forms of neural injury and disease, is linked to the hyperactivation of the protein phosphatase calcineurin. In many tissues and cell types, calcineurin hyperactivity is the direct result of limited proteolysis. However, little is known about the proteolytic status of calcineurin in activated astrocytes. Here, we developed a polyclonal antibody to a high activity calcineurin proteolytic fragment in the 45-48kDa range (ΔCN) for use in immunohistochemical applications. When applied to postmortem human brain sections, the ΔCN antibody intensely labeled cell clusters in close juxtaposition to amyloid deposits and microinfarcts. Many of these cells exhibited clear activated astrocyte morphology. The expression of ΔCN in astrocytes near areas of pathology was further confirmed using confocal microscopy. Multiple NeuN-positive cells, particularly those within microinfarct core regions, also labeled positively for ΔCN. This observation suggests that calcineurin proteolysis can also occur within damaged or dying neurons, as reported in other studies. When a similar ΔCN fragment was selectively expressed in hippocampal astrocytes of intact rats (using adeno-associated virus), we observed a significant reduction in the strength of CA3-CA1 excitatory synapses, indicating that the hyperactivation of astrocytic calcineurin is sufficient for disrupting synaptic function. Together, these results suggest that proteolytic activation of calcineurin in activated astrocytes may be a central mechanism for driving and/or exacerbating neural dysfunction during neurodegenerative disease and injury.
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http://dx.doi.org/10.1016/j.bbadis.2016.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026189PMC
September 2016

MW151 Inhibited IL-1β Levels after Traumatic Brain Injury with No Effect on Microglia Physiological Responses.

PLoS One 2016 12;11(2):e0149451. Epub 2016 Feb 12.

Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, United States of America.

A prevailing neuroinflammation hypothesis is that increased production of proinflammatory cytokines contributes to progressive neuropathology, secondary to the primary damage caused by a traumatic brain injury (TBI). In support of the hypothesis, post-injury interventions that inhibit the proinflammatory cytokine surge can attenuate the progressive pathology. However, other post-injury neuroinflammatory responses are key to endogenous recovery responses. Therefore, it is critical that pharmacological attenuation of detrimental or dysregulated neuroinflammatory processes avoid pan-suppression of inflammation. MW151 is a CNS-penetrant, small molecule experimental therapeutic that restores injury- or disease-induced overproduction of proinflammatory cytokines towards homeostasis without immunosuppression. Post-injury administration of MW151 in a closed head injury model of mild TBI suppressed acute cytokine up-regulation and downstream cognitive impairment. Here, we report results from a diffuse brain injury model in mice using midline fluid percussion. Low dose (0.5-5.0 mg/kg) administration of MW151 suppresses interleukin-1 beta (IL-1β) levels in the cortex while sparing reactive microglia and astrocyte responses. To probe molecular mechanisms, we used live cell imaging of the BV-2 microglia cell line to demonstrate that MW151 does not affect proliferation, migration, or phagocytosis of the cells. Our results provide insight into the roles of glial responses to brain injury and indicate the feasibility of using appropriate dosing for selective therapeutic modulation of injurious IL-1β increases while sparing other glial responses to injury.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149451PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752278PMC
July 2016

Blockade of Astrocytic Calcineurin/NFAT Signaling Helps to Normalize Hippocampal Synaptic Function and Plasticity in a Rat Model of Traumatic Brain Injury.

J Neurosci 2016 Feb;36(5):1502-15

Department of Pharmacology and Nutritional Sciences, Sanders-Brown Center on Aging, and

Unlabelled: Increasing evidence suggests that the calcineurin (CN)-dependent transcription factor NFAT (Nuclear Factor of Activated T cells) mediates deleterious effects of astrocytes in progressive neurodegenerative conditions. However, the impact of astrocytic CN/NFAT signaling on neural function/recovery after acute injury has not been investigated extensively. Using a controlled cortical impact (CCI) procedure in rats, we show that traumatic brain injury is associated with an increase in the activities of NFATs 1 and 4 in the hippocampus at 7 d after injury. NFAT4, but not NFAT1, exhibited extensive labeling in astrocytes and was found throughout the axon/dendrite layers of CA1 and the dentate gyrus. Blockade of the astrocytic CN/NFAT pathway in rats using adeno-associated virus (AAV) vectors expressing the astrocyte-specific promoter Gfa2 and the NFAT-inhibitory peptide VIVIT prevented the injury-related loss of basal CA1 synaptic strength and key synaptic proteins and reduced the susceptibility to induction of long-term depression. In conjunction with these seemingly beneficial effects, VIVIT treatment elicited a marked increase in the expression of the prosynaptogenic factor SPARCL1 (hevin), especially in hippocampal tissue ipsilateral to the CCI injury. However, in contrast to previous work on Alzheimer's mouse models, AAV-Gfa2-VIVIT had no effects on the levels of GFAP and Iba1, suggesting that synaptic benefits of VIVIT were not attributable to a reduction in glial activation per se. Together, the results implicate the astrocytic CN/NFAT4 pathway as a key mechanism for disrupting synaptic remodeling and homeostasis in the hippocampus after acute injury.

Significance Statement: Similar to microglia, astrocytes become strongly "activated" with neural damage and exhibit numerous morphologic/biochemical changes, including an increase in the expression/activity of the protein phosphatase calcineurin. Using adeno-associated virus (AAV) to inhibit the calcineurin-dependent activation of the transcription factor NFAT (Nuclear Factor of Activated T cells) selectively, we have shown that activated astrocytes contribute to neural dysfunction in animal models characterized by progressive/chronic neuropathology. Here, we show that the suppression of astrocytic calcineurin/NFATs helps to protect synaptic function and plasticity in an animal model in which pathology arises from a single traumatic brain injury. The findings suggest that at least some astrocyte functions impair recovery after trauma and may provide druggable targets for treating victims of acute nervous system injury.
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http://dx.doi.org/10.1523/JNEUROSCI.1930-15.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737766PMC
February 2016

Pycnogenol protects CA3-CA1 synaptic function in a rat model of traumatic brain injury.

Exp Neurol 2016 Feb 29;276:5-12. Epub 2015 Nov 29.

Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY 40536, United States; Anatomy and Neurobiology, University of Kentucky, College of Medicine, Lexington, KY 40536, United States. Electronic address:

Pycnogenol (PYC) is a patented mix of bioflavonoids with potent anti-oxidant and anti-inflammatory properties. Previously, we showed that PYC administration to rats within hours after a controlled cortical impact (CCI) injury significantly protects against the loss of several synaptic proteins in the hippocampus. Here, we investigated the effects of PYC on CA3-CA1 synaptic function following CCI. Adult Sprague-Dawley rats received an ipsilateral CCI injury followed 15 min later by intravenous injection of saline vehicle or PYC (10 mg/kg). Hippocampal slices from the injured (ipsilateral) and uninjured (contralateral) hemispheres were prepared at seven and fourteen days post-CCI for electrophysiological analyses of CA3-CA1 synaptic function and induction of long-term depression (LTD). Basal synaptic strength was impaired in slices from the ipsilateral, relative to the contralateral, hemisphere at seven days post-CCI and susceptibility to LTD was enhanced in the ipsilateral hemisphere at both post-injury timepoints. No interhemispheric differences in basal synaptic strength or LTD induction were observed in rats treated with PYC. The results show that PYC preserves synaptic function after CCI and provides further rationale for investigating the use of PYC as a therapeutic in humans suffering from neurotrauma.
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http://dx.doi.org/10.1016/j.expneurol.2015.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715929PMC
February 2016

SRPK2 phosphorylates tau and mediates the cognitive defects in Alzheimer's disease.

J Neurosci 2012 Nov;32(48):17262-72

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

Serine-arginine protein kinases 2 (SRPK2) is a cell cycle-regulated kinase that phosphorylates serine/arginine domain-containing proteins and mediates pre-mRNA splicing with unclear function in neurons. Here, we show that SRPK2 phosphorylates tau on S214, suppresses tau-dependent microtubule polymerization, and inhibits axonal elongation in neurons. Depletion of SRPK2 in dentate gyrus inhibits tau phosphorylation in APP/PS1 mouse and alleviates the impaired cognitive behaviors. The defective LTP in APP/PS1 mice is also improved after SRPK2 depletion. Moreover, active SRPK2 is increased in the cortex of APP/PS1 mice and the pathological structures of human Alzheimer's disease (AD) brain. Therefore, our study suggests SRPK2 may contribute to the formation of hyperphosphorylated tau and the pathogenesis of AD.
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http://dx.doi.org/10.1523/JNEUROSCI.3300-12.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518045PMC
November 2012

Crude caffeine reduces memory impairment and amyloid β(1-42) levels in an Alzheimer's mouse model.

Food Chem 2012 Dec 29;135(3):2095-102. Epub 2012 Jun 29.

Kraft Foods Global Brands LLC, 801 Waukegan Road, Glenview, IL 60025, USA.

Alzheimer's disease (AD), a chronic neurodegenerative disorder associated with the abnormal accumulations of amyloid β (Aβ) peptide and oxidative stress in the brain, is the most common form of dementia among the elderly. Crude caffeine (CC), a major by-product of the decaffeination of coffee, has potent hydrophilic antioxidant activity and may reduce inflammatory processes. Here, we showed that CC and pure caffeine intake had beneficial effects in a mouse model of AD. Administration of CC or pure caffeine for 2months partially prevented memory impairment in AD mice, with CC having greater effects than pure caffeine. Furthermore, consumption of CC, but not pure caffeine, reduced the Aβ(1-42) levels and the number of amyloid plaques in the hippocampus. Moreover, CC and caffeine protected primary neurons from Aβ-induced cell death and suppressed Aβ-induced caspase-3 activity. Our data indicate that CC may contain prophylactic agents against the cell death and the memory impairment in AD.
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http://dx.doi.org/10.1016/j.foodchem.2012.04.148DOI Listing
December 2012

Early stage drug treatment that normalizes proinflammatory cytokine production attenuates synaptic dysfunction in a mouse model that exhibits age-dependent progression of Alzheimer's disease-related pathology.

J Neurosci 2012 Jul;32(30):10201-10

Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky 40536, USA.

Overproduction of proinflammatory cytokines in the CNS has been implicated as a key contributor to pathophysiology progression in Alzheimer's disease (AD), and extensive studies with animal models have shown that selective suppression of excessive glial proinflammatory cytokines can improve neurologic outcomes. The prior art, therefore, raises the logical postulation that intervention with drugs targeting dysregulated glial proinflammatory cytokine production might be effective disease-modifying therapeutics if used in the appropriate biological time window. To test the hypothesis that early stage intervention with such drugs might be therapeutically beneficial, we examined the impact of intervention with MW01-2-151SRM (MW-151), an experimental therapeutic that selectively attenuates proinflammatory cytokine production at low doses. MW-151 was tested in an APP/PS1 knock-in mouse model that exhibits increases in AD-relevant pathology progression with age, including increases in proinflammatory cytokine levels. Drug was administered during two distinct but overlapping therapeutic time windows of early stage pathology development. MW-151 treatment attenuated the increase in microglial and astrocyte activation and proinflammatory cytokine production in the cortex and yielded improvement in neurologic outcomes, such as protection against synaptic protein loss and synaptic plasticity impairment. The results also demonstrate that the therapeutic time window is an important consideration in efficacy studies of drugs that modulate glia biological responses involved in pathology progression and suggest that such paradigms should be considered in the development of new therapeutic regimens that seek to delay the onset or slow the progression of AD.
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http://dx.doi.org/10.1523/JNEUROSCI.1496-12.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419360PMC
July 2012

N-acetyl serotonin derivatives as potent neuroprotectants for retinas.

Proc Natl Acad Sci U S A 2012 Feb 13;109(9):3540-5. Epub 2012 Feb 13.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.

N-acetylserotonin (NAS) is synthesized from serotonin by arylalkylamine N-acetyltransferase (AANAT), which is predominantly expressed in the pineal gland and retina. NAS activates TrkB in a circadian manner and exhibits antidepressant effects in a TrkB-dependent manner. It also enhances neurogenesis in hippocampus in sleep-deprived mice. Here we report the identification of NAS derivatives that possess much more robust neurotrophic effects with improved pharmacokinetic profiles. The compound N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide (HIOC) selectively activates TrkB receptor with greater potency than NAS. It potently protects retinas from light-induced retinal degeneration (LIRD), which is tightly coupled with pronounced TrkB activation in retinas. Pharmacokinetic studies demonstrate that this compound is stable in serum and liver microsomes. It can pass the blood-brain barrier and blood-retinal barrier. Hence, HIOC is a good lead compound for further drug development for treating retinal degenerative diseases.
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http://dx.doi.org/10.1073/pnas.1119201109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295250PMC
February 2012

Phosphoinositide 3-kinase enhancer regulates neuronal dendritogenesis and survival in neocortex.

J Neurosci 2011 Jun;31(22):8083-92

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

Phosphoinositide 3-kinase enhancer (PIKE) binds and enhances phosphatidylinositol 3-kinase (PI3K)/Akt activities. However, its physiological functions in brain have never been explored. Here we show that PIKE is important in regulating the neuronal survival and development of neocortex. During development, enhanced apoptosis is observed in the ventricular zone of PIKE knock-out (PIKE(-/-)) cortex. Moreover, PIKE(-/-) neurons show reduced dendritic complexity, dendritic branch length, and soma size. These defects are due to the reduced PI3K/Akt activities in PIKE(-/-) neurons, as the impaired dendritic arborization can be rescued when PI3K/Akt cascade is augmented in vitro or in PIKE(-/-)PTEN(-/-) double-knock-out mice. Interestingly, PIKE(-/-) mice display behavioral abnormality in locomotion and spatial navigation. Because of the diminished PI3K/Akt activities, PIKE(-/-) neurons are more vulnerable to glutamate- or stroke-induced neuronal cell death. Together, our data established the critical role of PIKE in regulating neuronal survival and development by substantiating the PI3K/Akt pathway.
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http://dx.doi.org/10.1523/JNEUROSCI.1129-11.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3551346PMC
June 2011

N-acetylserotonin promotes hippocampal neuroprogenitor cell proliferation in sleep-deprived mice.

Proc Natl Acad Sci U S A 2011 May 9;108(21):8844-9. Epub 2011 May 9.

Department of Pathology and Laboratory Medicine and Ophthalmology and Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.

N-acetylserotonin (NAS), the immediate precursor of melatonin, the pineal gland indole, is regulated in a circadian rhythm. NAS swiftly activates TrkB in a circadian manner and exhibits antidepressant effect in a TrkB-dependent manner. Here we show that NAS regulates an early event of neurogenesis by increasing neuronal progenitor cell (NPC) proliferation. Subchronic and chronic NAS administration induces NPC proliferation in adult mice. Chronic NAS treatment triggers TrkB receptor activation and its downstream signaling in NPCs. Blockade of TrkB abolishes NAS-elicited neurogenesis in TrkBF616A knockin mice, suggesting that TrkB activation is essential for the effect of NAS-induced NPC proliferation. Moreover, NAS induces NPC proliferation in both active and sleeping phases of the mice. Strikingly, NAS significantly enhances NPC proliferation in sleep-deprived mice. Thus, our finding demonstrates a unique function of NAS in promoting robust NPC proliferation, which may contribute to hippocampal plasticity during sleeping period.
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http://dx.doi.org/10.1073/pnas.1105114108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102377PMC
May 2011

A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect.

J Med Chem 2010 Dec 12;53(23):8274-86. Epub 2010 Nov 12.

Department of Pathology and Laboratory Medicine Emory University School of Medicine, Room 141 Whitehead Building, 615 Michael Street, Atlanta, Georgia 30322, United States.

7,8-Dihydroxyflavone is a recently identified small molecular tropomyosin-receptor-kinase B (TrkB) agonist. Our preliminary structural-activity relationship (SAR) study showed that the 7,8-dihydroxy groups are essential for the agonistic effect. To improve the lead compound's agonistic activity, we have conducted an extensive SAR study and synthesized numerous derivatives. We have successfully identified 4'-dimethylamino-7,8-dihydroxyflavone that displays higher TrkB agonistic activity than that of the lead. This novel compound also exhibits a more robust and longer TrkB activation effect in animals. Consequently, this new compound reveals more potent antiapoptotic activity. Interestingly, chronic oral administration of 4'-dimethylamino-7,8-dihydroxyflavone and its lead strongly promotes neurogenesis in dentate gyrus and demonstrates marked antidepressant effects. Hence, our data support that the synthetic 4'-dimethylamino-7,8-dihydroxyflavone and its lead both are orally bioavailable TrkB agonists and possess potent antidepressant effects.
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http://dx.doi.org/10.1021/jm101206pDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150605PMC
December 2010

N-acetylserotonin activates TrkB receptor in a circadian rhythm.

Proc Natl Acad Sci U S A 2010 Feb 4;107(8):3876-81. Epub 2010 Feb 4.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.

Brain-derived neurotrophic factor (BDNF) is a cognate ligand for the TrkB receptor. BDNF and serotonin often function in a cooperative manner to regulate neuronal plasticity, neurogenesis, and neuronal survival. Here we show that NAS (N-acetylserotonin) swiftly activates TrkB in a circadian manner and exhibits antidepressant effect in a TrkB-dependent manner. NAS, a precursor of melatonin, is acetylated from serotonin by AANAT (arylalkylamine N-acetyltransferase). NAS rapidly activates TrkB, but not TrkA or TrkC, in a neurotrophin- and MT3 receptor-independent manner. Administration of NAS activates TrkB in BDNF knockout mice. Furthermore, NAS, but not melatonin, displays a robust antidepressant-like behavioral effect in a TrkB-dependent way. Endogenous TrkB is activated in wild-type C3H/f(+/+) mice but not in AANAT-mutated C57BL/6J mice, in a circadian rhythm; TrkB activation is high at night in the dark and low during the day. Hence, our findings support that NAS is more than a melatonin precursor, and that it can potently activate TrkB receptor.
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http://dx.doi.org/10.1073/pnas.0912531107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840510PMC
February 2010

SN52, a novel nuclear factor-kappaB inhibitor, blocks nuclear import of RelB:p52 dimer and sensitizes prostate cancer cells to ionizing radiation.

Mol Cancer Ther 2008 Aug;7(8):2367-76

Department of Radiation Medicine, University of Kentucky, College of Medicine, Lexington, KY 40536, USA.

The activation of nuclear factor-kappaB (NF-kappaB) is thought to protect cancer cells against therapy-induced cytotoxicity. RelB, a member of the NF-kappaB family in the alternative pathway, is uniquely expressed at a high level in prostate cancer with high Gleason scores. Here, we show that ionizing radiation (IR) enhances nuclear import of RelB, leading to up-regulation of its target gene, manganese superoxide dismutase (MnSOD), and renders prostate cancer cells resistant to IR. To selectively block RelB nuclear import, we designed a cell-permeable SN52 peptide, a variant of the SN50 peptide that has been shown to block nuclear import of NF-kappaB family members in the classic pathway. Inhibition of IR-induced NF-kappaB activation by SN50 and SN52 was achieved by selectively interrupting the association of p50 and p52 with nuclear import factors importin-alpha1 and importin-beta1. Importantly, SN52 seems to be more efficient for radiosensitization of prostate cancer cells at clinically relevant radiation doses and has less cytotoxicity to normal prostate epithelial cells compared with the toxicity observed with SN50. These results suggest that targeting the alternative pathway is a promising approach to selectively radiosensitize prostate cancers and that SN52 may serve as a prototype biological agent for sensitizing prostate cancers to clinically relevant doses of IR.
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http://dx.doi.org/10.1158/1535-7163.MCT-08-0238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692185PMC
August 2008

Suppression of RelB-mediated manganese superoxide dismutase expression reveals a primary mechanism for radiosensitization effect of 1alpha,25-dihydroxyvitamin D(3) in prostate cancer cells.

Mol Cancer Ther 2007 Jul 29;6(7):2048-56. Epub 2007 Jun 29.

Graduate Center for Toxicology, University of Kentucky College of Medicine, Lexington, KY 40536, USA.

Nuclear factor-kappaB provides an adaptive response to protect cancer cells against cytotoxicity induced by redox active therapeutics. RelB is uniquely expressed at a high level in prostate cancer with high Gleason scores. Recently, we showed that the level of RelB rapidly increases in androgen-independent prostate cancer cells after exposure to ionizing radiation (IR), leading to a reduction in intrinsic radiosensitivity. Here, we show that interaction of 1alpha,25-dihydroxyvitamin D(3) [1alpha,25-(OH)(2)D(3)] with the vitamin D receptor significantly enhances radiosensitivity of prostate cancer cells at clinically relevant radiation doses. The radiosensitization effect of 1alpha,25-(OH)(2)D(3) is mediated, at least in part, by selectively suppressing IR-mediated RelB activation, leading to a reduced expression of its target gene MnSOD, a primary antioxidant enzyme in mitochondria. These results suggest that suppression of manganese superoxide dismutase is a mechanism by which 1alpha,25-(OH)(2)D(3) exerts its radiosensitization effect and that 1alpha,25-(OH)(2)D(3) may serve as an effective pharmacologic agent for selectively sensitizing prostate cancer cells to IR via suppression of antioxidant responses in mitochondria.
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http://dx.doi.org/10.1158/1535-7163.MCT-06-0700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692592PMC
July 2007

Phenylbutyrate, a histone deacetylase inhibitor, protects against Adriamycin-induced cardiac injury.

Free Radic Biol Med 2007 Jun 12;42(12):1818-25. Epub 2007 Mar 12.

Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40506, USA.

Cardiac injury is a major complication for oxidative-stress-generating anticancer agents exemplified by Adriamycin (ADR). Recently, several histone deacetylase inhibitors (HDACIs) including phenylbutyrate (PBA) have shown promise in the treatment of cancer with little known toxicity to normal tissues. PBA has been shown to protect against oxidative stress in normal tissues. Here, we examined whether PBA might protect heart against ADR toxicity in a mouse model. The mice were i.p. injected with ADR (20 mg/kg). PBA (400 mg/kg/day) was i.p. injected 1 day before and daily after the ADR injection for 2 days. We found that PBA significantly decreased the ADR-associated elevation of serum lactate dehydrogenase and creatine kinase activities and diminished ADR-induced ultrastructural damages of cardiac tissue by more than 70%. Importantly, PBA completely rescued ADR-caused reduction of cardiac functions exemplified by ejection fraction and fraction shortening, and increased cardiac manganese superoxide dismutase (MnSOD) protein and activity. Our results reveal a previously unrecognized role of HDACIs in protecting against ADR-induced cardiac injury and suggest that PBA may exert its cardioprotective effect, in part, by the increase of MnSOD. Thus, combining HDACIs with ADR could add a new mechanism to fight cancer while simultaneously decrease ADR-induced cardiotoxicity.
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http://dx.doi.org/10.1016/j.freeradbiomed.2007.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2151922PMC
June 2007

NF-kappaB-associated MnSOD induction protects against beta-amyloid-induced neuronal apoptosis.

J Mol Neurosci 2006 ;29(3):279-88

Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA.

Expression of manganese superoxide dismutase (MnSOD), a nuclear-encoded mitochondrial primary antioxidant enzyme, is protective against various paradigms of oxidative stress-induced brain injury. We have shown previously that the presence of an intronic nuclear factor site, kappaB (NF-kappaB), in the MnSOD gene is essential for the induction of MnSOD by tumor necrosis factor alpha (TNF-alpha). However, whether activation of NF-kappaB is protective against oxidative stress-induced neuronal injury is unclear. In the present study, we demonstrate that TNF-alpha activates NF-kappaB activity in neuronal, SH-SY5Y, cells and preferentially enhances the binding of p50 and p65 to the promoter/enhancer regions of the MnSOD gene. Binding of NF-kappaB members to the MnSOD gene leads to the induction of MnSOD mRNA and protein levels. Consequently, induction of MnSOD by TNF-alpha primes neuronal cells to develop resistance against subsequent exposure to beta-amyloid and FeSO(4). Taken together, these results suggest that NF-kappaB might exert its protective function by induction of MnSOD leading to subsequent protection against oxidative stress-induced neuronal injury.
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February 2007

NF-κB-Associated MnSOD induction protects against β-amyloid-induced neuronal apoptosis.

J Mol Neurosci 2006 Jul 6;29(3):279-288. Epub 2018 Jan 6.

Graduate Center for Toxicology, University of Kentucky, 40536, Lexington, KY.

Expression of manganese superoxide dismutase (MnSOD), a nuclear-encoded mitochondrial primary antioxidant enzyme, is protective against various paradigms of oxidative stress-induced brain injury. We have shown previously that the presence of an intronic nuclear factor site, κB (NF-κB), in the MnSOD gene is essential for the induction of MnSOD by tumor necrosis factor α (TNF-α). However, whether activation of NF-κB is protective against oxidative stress-induced neuronal injury is unclear. In the present study, we demonstrate that TNF-α activates NF-κB activity in neuronal, SH-SY5Y, cells and preferentially enhances the binding of p50 and p65 to the promoter/enhancer regions of the MnSOD gene. Binding of NF-κB members to the MnSOD gene leads to the induction of MnSOD mRNA and protein levels. Consequently, induction of MnSOD by TNF-α primes neuronal cells to develop resistance against subsequent exposure to β-amyloid and FeSO. Taken together, these results suggest that NF-κB might exert its protective function by induction of MnSOD leading to subsequent protection against oxidative stress-induced neuronal injury.
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http://dx.doi.org/10.1385/JMN:29:3:279DOI Listing
July 2006
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