Alterations in Retinal Signaling Across Age and Sex in 3xTg Alzheimer's Disease Mice
Background: Visual disturbances often precede cognitive dysfunction in patients with Alzheimer's disease (AD) and may coincide with early accumulation of amyloid-β (Aβ) protein in the retina. These findings have inspired critical research on in vivo ophthalmic Aβ imaging for disease biomarker detection but have not fully answered mechanistic questions on how retinal pathology affects visual signaling between the eye and brain.
Objective: The goal of this study was to provide a functional and structural assessment of eye-brain communication between retinal ganglion cells (RGCs) and their primary projection target, the superior colliculus, in female and male 3xTg-AD mice across disease stages.
Methods: Retinal electrophysiology, axonal transport, and immunofluorescence were used to determine RGC projection integrity, and retinal and collicular Aβ levels were assessed with advanced protein quantitation techniques.
Results: 3xTg mice exhibited nuanced deficits in RGC electrical signaling, axonal transport, and synaptic integrity that exceeded normal age-related decrements in RGC function in age- and sex-matched healthy control mice. These deficits presented in sex-specific patterns among 3xTg mice, differing in the timing and severity of changes.
Conclusion: These data support the premise that retinal Aβ is not just a benign biomarker in the eye, but may contribute to subtle, nuanced visual processing deficits. Such disruptions might enhance the biomarker potential of ocular amyloid and differentiate patients with incipient AD from patients experiencing normal age-related decrements in visual function.
Gabrielle Frame
Adam Schuller
Matthew A Smith
Samuel D Crish
Christine M Dengler-Crish
J Alzheimers Dis
. 2022;88(2):471-492. doi: 10.3233/JAD-220016.
2022
English
Anthocyanin-rich black currant extract suppresses the growth of human hepatocellular carcinoma cells.
Humans; Cell Proliferation/drug effects; Fruit/chemistry; *Phytotherapy; Plant Extracts/pharmacology/therapeutic use; Hep G2 Cells; Antioxidants/*therapeutic use; *Ribes/chemistry; Liver Neoplasms/*prevention & control; Carcinoma; Drug Evaluation; Preclinical; Antineoplastic Agents; Hepatocellular/*prevention & control; Phytogenic/analysis
Dietary antioxidants, such as anthocyanins, are helpful in the prevention and control of various diseases by counteracting the imbalance of oxidative and antioxidative factors in the living systems. Black currant (Ribes nigrum L., Grossulariaceae) is known to contain high amounts of anthocyanins (250 mg/100 g fresh fruit). Black currant fruits have been used in Asian and European traditional medicine for the treatment of a variety of diseases. Black currant extract has recently been found to be the second most effective amongst nine different berry extracts studied for their free radical scavenging activity. Constituents present in black currant juice have been found to exert a number of health-promoting effects, including immunomodulatory, antimicrobial and antiinflammatory actions, inhibition of low-density lipoprotein, and reduction of cardiovascular diseases. Although antioxidant and antiinflammatory effects of black currant juice could be of value in preventing and treating oxidative stress- and inflammation-driven cancers, no experimental evidence is available to now. The objective of the present study was to evaluate the potential antiproliferative effects of black currant fruit skin extract against HepG2 human liver cancer cells. The aqueous extract yielded an anthocyanin-rich fraction with cyanidin-3-O-rutinoside as one of the major anthocyanins. This fraction exhibited a potent cytotoxic effect on HepG2 cells and this effect was more pronounced than that of delphinidin and cyanidin, two major aglycones of anthocyanins present in black currant. Our results indicate, for the first time, that black currant skin containing an anthocyanin-rich fraction inhibits the proliferation of liver cancer cells, possibly due to additive as well as synergistic effects. This product could be useful in the prevention and treatment of human hepatocellular carcinoma.
Bishayee Anupam; Haznagy-Radnai Erzsebet; Mbimba Thomas; Sipos Peter; Morazzoni Paolo; Darvesh Altaf S; Bhatia Deepak; Hohmann Judit
Natural product communications
2010
2010-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Noncanonical mechanisms to regulate nuclear receptor signaling.
Humans; Protein Binding; MicroRNAs/metabolism; Signal Transduction/drug effects; Ligands; DNA/metabolism; Peptides/chemistry/pharmacology; Small Molecule Libraries/chemistry/pharmacology; Receptors; Drug Evaluation; Preclinical; Cytoplasmic and Nuclear/antagonists & inhibitors/*metabolism
Nuclear receptor (NR)-targeted therapies comprise a large class of clinically employed drugs. A number of drugs currently being used against this protein class were designed as structural analogs of the endogenous ligand of these receptors. In recent years, there has been significant interest in developing newer strategies to target NRs, especially those that rely on mechanistic pathways of NR function. Prominent among these are noncanonical means of targeting NRs, which include selective NR modulation, NR coactivator interaction inhibition, inhibition of NR DNA binding, modulation of NR cellular localization, modulation of NR ligand biosynthesis and downregulation of NR levels in target tissues. This article reviews each of these promising emerging strategies for NR drug development and highlights some of most significant successes achieved in using them.
Sadana Prabodh
Future medicinal chemistry
2012
2012-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.4155/fmc.12.72" target="_blank" rel="noreferrer noopener">10.4155/fmc.12.72</a>
Role of serotonin in Alzheimer's disease: a new therapeutic target?
Humans; Animals; Serotonin/*metabolism; Clinical Trials as Topic; Alzheimer Disease/*drug therapy/*metabolism; Serotonin/*pharmacology/*therapeutic use; Clinical Trials; Receptors; Drug Evaluation; Preclinical; Alzheimer's Disease – Drug Therapy; Alzheimer's Disease – Metabolism; Cell Surface – Metabolism; Serotonin – Pharmacodynamics; Serotonin – Therapeutic Use
Mounting evidence accumulated over the past few years indicates that the neurotransmitter serotonin plays a significant role in cognition. As a drug target, serotonin receptors have received notable attention due in particular to the role of several serotonin-receptor subclasses in cognition and memory. The intimate anatomical and neurochemical association of the serotonergic system with brain areas that regulate memory and learning has directed current drug discovery programmes to focus on this system as a major therapeutic drug target. Thus far, none of these programmes has yielded unambiguous data that suggest that any of the new drug entities possesses disease-modifying properties, and significantly more research in this promising area of investigation is required. Compounds are currently being investigated for activity against serotonin 5-HT(1), 5-HT(4) and
Geldenhuys Werner J; Van der Schyf Cornelis J
CNS Drugs
2011
2011-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.2165/11590190-000000000-00000" target="_blank" rel="noreferrer noopener">10.2165/11590190-000000000-00000</a>
Curcumin and neurodegenerative diseases: a perspective.
Humans; Animals; Oxidative Stress/drug effects; Neurodegenerative Diseases/*drug therapy/metabolism; Curcumin/adverse effects/pharmacokinetics/*pharmacology/*therapeutic use; Neuroprotective Agents/adverse effects/pharmacokinetics/*pharmacology/*therapeutic use; Drug Evaluation; Preclinical
INTRODUCTION: Curcumin, a dietary polyphenol found in the curry spice turmeric, possesses potent antioxidant and anti-inflammatory properties and an ability to modulate multiple targets implicated in the pathogenesis of chronic illness. Curcumin has shown therapeutic potential for neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD). AREAS COVERED: This article highlights the background and epidemiological evidence of curcumin's health benefits and its pharmacodynamic and pharmacokinetic profile. Curcumin's ability to counteract oxidative stress and inflammation and its capacity to modulate several molecular targets is reviewed. We highlight the neuroprotective properties of curcumin including pre-clinical evidence for its pharmacological effects in experimental models of AD and PD. The bioavailability and safety of curcumin, the development of semi-synthetic curcuminoids as well as novel formulations of curcumin are addressed. EXPERT OPINION: Curcumin possesses therapeutic potential in the amelioration of a host of neurodegenerative ailments as evidenced by its antioxidant, anti-inflammatory and anti-protein aggregation effects. However, issues such as limited bioavailability and a paucity of clinical studies examining its therapeutic effectiveness in illnesses such as AD and PD currently limit its therapeutic outreach. Considerable effort will be required to adapt curcumin as a neuroprotective agent to be used in the treatment of AD, PD and other neurodegenerative diseases.
Darvesh Altaf S; Carroll Richard T; Bishayee Anupam; Novotny Nicholas A; Geldenhuys Werner J; Van der Schyf Cornelis J
Expert opinion on investigational drugs
2012
2012-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1517/13543784.2012.693479" target="_blank" rel="noreferrer noopener">10.1517/13543784.2012.693479</a>
Propofol causes vasodilation in vivo via TRPA1 ion channels: role of nitric oxide and BKCa channels.
Female; Male; Animals; Mice; Signal Transduction; TRPA1 Cation Channel; Arterial Pressure/drug effects; Vasodilator Agents/*pharmacology; Propofol/*pharmacology; Transient Receptor Potential Channels/genetics/*metabolism; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/*physiology; Nitric Oxide/*physiology; TRPV Cation Channels/genetics/metabolism; Inbred C57BL; Knockout; Drug Evaluation; Preclinical
BACKGROUND: Transient receptor potential (TRP) ion channels of the A1 (TRPA1) and V1 (TRPV1) subtypes are key regulators of vasomotor tone. Propofol is an intravenous anesthetic known to cause vasorelaxation. Our objectives were to examine the extent to which TRPA1 and/or TRPV1 ion channels mediate propofol-induced depressor responses in vivo and to delineate the signaling pathway(s) involved. METHODS: Mice were subjected to surgery under 1.5-2.5% sevoflurane gas with supplemental oxygen. After a stable baseline in mean arterial pressure (MAP) was achieved propofol (2.5, 5.0, 10.0 mg/kg/min) was administered to assess the hemodynamic actions of the intravenous anesthetic. The effect of nitric oxide synthase (NOS) inhibition with L-NAME and/or calcium-gated K+ channel (BKCa) inhibition with Penetrim A (Pen A), alone and in combination, on propofol-induced decreases in mean arterial pressure were assessed in control C57Bl/6J, TRPA1-/-, TRPV1-/- and double-knockout mice (TRPAV-/-). RESULTS: Propofol decreased MAP in control mice and this effect was markedly attenuated in
Sinha Sayantani; Sinharoy Pritam; Bratz Ian N; Damron Derek S
PloS one
2015
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1371/journal.pone.0122189" target="_blank" rel="noreferrer noopener">10.1371/journal.pone.0122189</a>
Discriminative characteristics of high and low cocaine administration: effect of other psychostimulants.
Amphetamine/pharmacology; Animals; Central Nervous System Stimulants/pharmacology; Cocaine/*pharmacology; Conditioning; Discrimination Learning/*drug effects; Dopamine Agents/*pharmacology; Dose-Response Relationship; Drug; Drug Evaluation; Generalization; Male; Methamphetamine/pharmacology; Operant/*drug effects; Preclinical; Propiophenones/pharmacology; Psychotropic Drugs/*pharmacology; Rats; Response/*drug effects
Two groups of N/Nih male rats were trained to discriminate saline vehicle from either 2.0 mg/kg (n = 10) or 10.0 mg/kg (n = 10) cocaine in a food-motivated, two-lever operant paradigm. The rats trained at the low-dose cocaine took a significantly longer training period to reach criterion performance than did the high-dose cocaine group. In addition, the ED50 value for the 2.0 mg/kg cocaine-trained animals (0.465 mg/kg) was significantly lower than the ED50 value (2.105 mg/kg) for those animals trained at the 10.0 mg/kg dose of cocaine. This correlation of ED50 values for stimulus generalization decreasing with reduction in training dose was in contrast to the time-course of the two groups when tested from 15 to 240 min post-injection; this experimentation indicated that there was a non-significant difference in half-life for the 2.0 mg/kg (t1/2: 97.1 min) vs. that of the 10.0 mg/kg cocaine-trained group (t1/2: 83.4 min). Generalization tests with other purportedly dopaminergically-active drugs of abuse including 0.05-0.8 mg/kg d-amphetamine, 0.125-1.5 mg/kg methamphetamine and 0.125-1.0 mg/kg methcathinone indicated that the highest doses of each produced generalization and, with the exception of methcathinone, the ED50 values were significantly lower in the low-cocaine trained group. The stimulus properties of cocaine, as they generalize to amphetamine, methamphetamine and methcathinone, can be explained by effects upon central dopaminergic neurons and may be qualitatively different in low-and high-dose trained rats.
Schechter M D
Pharmacology, biochemistry, and behavior
1997
1997-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0091-3057(96)00301-2" target="_blank" rel="noreferrer noopener">10.1016/s0091-3057(96)00301-2</a>
Discrete versus cumulative dosing in dose-response discrimination studies.
4-methylenedioxyamphetamine/*pharmacology; Animals; Chemical; Cocaine/*pharmacology; Discrimination Learning/*drug effects; Dose-Response Relationship; Drug; Drug Administration Schedule; Drug Evaluation; Male; N-Methyl-3; Preclinical; Rats; Sprague-Dawley; Stimulation
This study describes the results of a 'side-by-side' comparison of two measurement techniques and two dosing regimens in a discrimination study using rats trained to either 10 mg/kg cocaine or 2 mg/kg 3,4-methylenedioxymethamphetamine (MDMA). The measurements employed were either quantal or quantitative; the former an all-or-none correct lever selection measure and the latter a measure of all responses made at the time that the criterion for selection was met. The dosing regimens were either a discrete single injection of lower doses than used in training or a cumulative dose administration sequence, in an ascending order, during one session on two separate occasions. Results indicate that the cumulative dose-response relationships, as indicated by both the slope of the curve or the generated ED50 value, for the discrete and cumulative dose response curves do not significantly differ. In addition, both the quantal and quantitative measurements yield almost identical ED50 values, thus allowing for accurate comparability of drug-discrimination data using different techniques. The present experimentation employed two drugs known to produce heightened response rates which would not allow for behavioral suppression at the highest doses used either in discrete or cumulative regimens. The pharmacokinetics of the two drugs employed in the discrimination tests are considered and discussed in light of the advantages and disadvantages of each of the two methods employed.
Schechter M D
European journal of pharmacology
1997
1997-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0014-2999(97)85404-0" target="_blank" rel="noreferrer noopener">10.1016/s0014-2999(97)85404-0</a>
Effect of resveratrol on herpes simplex virus vaginal infection in the mouse.
Animals; Antiviral Agents/administration & dosage/pharmacology/*therapeutic use; Drug Evaluation; Female; Herpes Genitalis/*drug therapy/pathology/virology; Herpesvirus 1; Herpesvirus 2; Human/*drug effects/physiology; Human/drug effects/isolation & purification/physiology; Mice; Placebos; Preclinical; Resveratrol; Stilbenes/administration & dosage/pharmacology/*therapeutic use; Survival Analysis; Vaginal Diseases/*drug therapy/virology; Viral Plaque Assay; Virus Replication/drug effects
Resveratrol (3,5,4'-trihydroxystilbene) is a natural component of certain foods, such as grapes, that, when topically applied, has been shown to limit HSV-1 lesion formation in the skin of mice [Antiviral Res. 61:19-26, 2004]. To determine if it is active on genital HSV infection, the vagina of mice were infected with HSV-2 or HSV-1 and treated with a cream formulation of resveratrol. Mice were evaluated daily for extravaginal disease and vaginal swabs were taken regularly and assayed for infectious virus. Initial studies demonstrated that 19% resveratrol cream administered intravaginally five times a day for 5 days beginning 1h after infection significantly reduced HSV-2 replication beginning on day 1 of infection and prevented extravaginal disease when compared to animals treated with placebo. When resveratrol was tested at a concentration of 6.25% and 12.5% administered five times a day, 6.25% limited virus replication only on day 1 and delayed development of extravaginal disease by 1 day. However, 12.5% resveratrol inhibited HSV-2 replication beginning on day 1 and abolished extravaginal disease. If the number of applications per day was reduced to three for 5 days, 12.5% resveratrol inhibited HSV-2 replication only on day 1, while 19% resveratrol inhibited it throughout the 9-day assay period. When the animals with three treatments per day were examined for extravaginal disease, it was found that 12.5% resveratrol was ineffective when compared to placebo, while animals treated with 19% resveratrol did not exhibit extravaginal disease. When treatment was delayed 6h, 12.5% resveratrol did not inhibit HSV-2 replication or extravaginal lesion formation, but 19% resveratrol did. When resveratrol was used to treat vaginal HSV-1 infection, it was found that 12.5% resveratrol did not limit replication or prevent extravaginal lesion formation. In contrast, 19% resveratrol did significantly limit vaginal HSV-1 replication and reduced extravaginal lesion formation, but the latter was not significant. Mortality rates in placebo-treated animals was 37%, 6.25% resveratrol-treated animals was 40%, 12.5% resveratrol-treated animals was 24%, and 19% resveratrol-treated animals was 3%. Collectively, these results demonstrate that resveratrol cream inhibits or reduces HSV replication in the vagina of mice and limits extravaginal disease.
Docherty John J; Fu Ming Ming; Hah Jennifer M; Sweet Thomas J; Faith Seth A; Booth Tristan
Antiviral research
2005
2005-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.antiviral.2005.06.008" target="_blank" rel="noreferrer noopener">10.1016/j.antiviral.2005.06.008</a>
Harpagoside suppresses IL-6 expression in primary human osteoarthritis chondrocytes.
*c-FOS/AP-1; *harpagoside; *IL-6; *MMP-13; *osteoarthritis; CCAAT-Enhancer-Binding Protein-beta/metabolism; Chemokines/metabolism; Chondrocytes/*drug effects/metabolism; Drug Evaluation; Glycosides/pharmacology/*therapeutic use; Harpagophytum; Humans; Interleukin-1beta; Interleukin-6/antagonists & inhibitors/*metabolism; Matrix Metalloproteinase 13/metabolism; NF-kappa B/metabolism; Osteoarthritis/*drug therapy/metabolism; Phytotherapy; Plant Extracts/pharmacology/therapeutic use; Preclinical; Primary Cell Culture; Proto-Oncogene Proteins c-fos/metabolism; Pyrans/pharmacology/*therapeutic use; Reactive Oxygen Species/metabolism; Transcription Factor AP-1/metabolism
There is growing evidence in support of the involvement of inflammatory response in the pathogenesis of osteoarthritis (OA). Harpagoside, one of the bioactive components of Harpagophytum procumbens (Hp), has been shown to possess anti-inflammatory properties. Here we used an in vitro model of inflammation in OA to investigate the potential of harpagoside to suppress the production of inflammatory cytokines/chemokines such as IL-6 and matrix degrading proteases. We further investigated the likely targets of harpagoside in primary human OA chondrocytes. OA chondrocytes were pre-treated with harpagoside before stimulation with IL-1beta. mRNA expression profile of 92 cytokines/chemokines was determined using TaqMan Human Chemokine PCR Array. Expression levels of selected mRNAs were confirmed using TaqMan assays. Protein levels of IL-6 and MMP-13 were assayed by ELISA and immunoblotting. Total protein levels and phosphorylation of signaling proteins were determined by immunoblotting. Cellular localization of
Haseeb Abdul; Ansari Mohammad Yunus; Haqqi Tariq M
Journal of orthopaedic research : official publication of the Orthopaedic Research Society
2017
2017-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/jor.23262" target="_blank" rel="noreferrer noopener">10.1002/jor.23262</a>