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Nigel H Greig

Publications and source records attributed to Nigel H Greig.

At least 37 records · Page 2Linked to original sources
PubMed2005

Inhibition of P53-related apoptosis had no effect on PrP(Sc) accumulation and prion disease incubation time.

Results from several laboratories indicate that apoptosis via the P53 pathway is involved in prion disease pathogenesis. Prion diseases, among them scrapie and BSE, are a group of fatal neurodegenerative disorders associated with the conversion of PrP(C) to PrP(Sc), its conformational abnormal isoform. In this work, we tested whether an established anti-apoptotic reagent, PFT, which has been shown in different systems to inhibit P53 activity, can delay the outbreak of prion disease in infected animals. Our findings indicate that although PFT efficiently reduced caspase 3 expression in brains from scrapie sick hamsters, as well as inhibited PrP(Sc) accumulation in cell culture, it had no effect on disease incubation time or PrP(Sc) accumulation in vivo. We conclude that the P53 dependent apoptosis may not be an obligatory mechanism for prion disease-induced cell death.

Animals↗
PubMed2005

Amyloid, cholinesterase, melatonin, and metals and their roles in aging and neurodegenerative diseases.

The aging brain shows selective neurochemical changes involving several neural cell populations. Increased brain metal levels have been associated with normal aging and a variety of diseases, including Alzheimer's disease (AD). Melatonin levels are decreased in aging, particularly in AD subjects. The loss of melatonin, which is synthesized by the pineal gland, together with the degeneration of cholinergic neurons of the basal forebrain and the deposition of aggregated proteins, such as the amyloid beta peptides (Abeta), are believed to contribute to the development of cognitive symptoms of dementia. Aging and its variants, such as AD, should be viewed as the result of multiple "hits," including alterations in the levels of Abeta, metals, cholinesterase enzymes, and neuronal gene expression. Herein, we present evidence in support of this theory, based on several studies. We discuss melatonin's neuroprotective function, which plays an important role in aging, prolongation of life span, and health in the aged individual. It interacts with metals and, in some cases, neutralizes their toxic effects. Dietary supplementation of melatonin restores its age-related loss. In mice, an elevated brain melatonin significantly reduced levels of potentially toxic Abeta peptides. Thus, compensation of melatonin loss in aging by dietary supplementation could well be beneficial in terms of reducing metal-induced toxicity, lipid peroxidation, and losses in cholinergic signaling. We propose that certain cholinesterase inhibitors and the NMDA partial antagonist memantine, which are FDA-approved drugs for AD and useful to boost central nervous system functioning, can be made more effective by their combination with melatonin or other neuroprotectants. Herein, we highlight studies elucidating the role of the amyloid pathway, metals, melatonin, and the cholinergic system in the context of aging and AD. Finally, melatonin is present in edible plants and walnuts, and consuming foodstuffs containing melatonin would be beneficial by enhancing the antioxidative capacity of the organisms.

Aging↗
PubMed2005

In vivo biological activity of exendin (1-30).

Activation of the glucagon-like peptide-1 (GLP-1) receptor on pancreatic beta cells by GLP-1 and exendin-4 increases insulin secretion. Exendin-4 is 39 amino acids long, unlike GLP-1 which has 30 amino acids. Because of its non-mammalian (lizard) origin and unique C-terminal sequence, exendin-4 may be immunogenic in humans. We showed previously that the C terminally truncated exendin peptide exendin (1-30) has a reduced affinity for the GLP-1 receptor and a diminished ability to increase intracellular cAMP in insulinoma cells. Here we show that daily intraperitoneal injection of exendin (1-30) (1 nmol/kg) for 20 d followed by 31 d twice daily to Lepr(db)/Lepr(db) (db/db) mice significantly reduced the amount of visceral fat relative to saline-treated controls and improved HbA1C (control 9.5 +/- 0.2% vs treated 7.9 +/- 0.2%, p = 0.001) but was not as effective as exendin-4. To examine the ability of exendin (1-30) to stimulate beta-cell growth, we injected one group of 3-mo-old Fisher rats with exendin (1-30) (1 nmol/kg) and another group with saline for 8 d. We observed no change in beta-cell area, but did see a change in the number of islets with nuclei positive for BrdU [10.7 +/- 1.8% exendin (1-30) vs 6.5 +/- 0.5% control].

Adipose Tissue↗
PubMed2005

An overview of phenserine tartrate, a novel acetylcholinesterase inhibitor for the treatment of Alzheimer's disease.

Existing cholinesterase (ChE) inhibitor therapies for Alzheimer's disease (AD), while effective in improving cognitive, behavioral and functional impairments, do not alter disease progression. Novel drug design studies have focused on the classical ChE inhibitor, (-)-physostigmine, producing alterations in chemical composition and three-dimensional structure, which may offer an improved therapeutic index. The phenylcarbamate derivative, (-)-phenserine, is a selective, non-competitive inhibitor of acetylcholinesterase (AChE). In vivo, (-)-phenserine produces rapid, potent, and long-lasting AChE inhibition. As a possible result of its preferential brain selectivity, (-)-phenserine is significantly less toxic than (-)-physostigmine. In studies using the Stone maze paradigm, (-)-phenserine has been shown to improve cognitive performance in both young learning-impaired and elderly rats. In addition to reducing inactivation of acetylcholine in the brain, (-)-phenserine appears to have a second mode of action. Reduced secretion of beta-amyloid (Abeta) has been observed in cell lines exposed to (-)-phenserine, occurring through translational regulation of beta-amyloid precursor protein (beta-APP) mRNA via a non-cholinergic mechanism. These in vitro findings appear to translate in vivo into animal models and humans. In a small study of patients with AD, (-)-phenserine treatment tended to reduce beta-APP and Abeta levels in plasma samples. Clinical studies also reveal that (-)-phenserine (5-10 mg b.i.d.) had a favorable safety and pharmacological profile, produced significant improvements in cognitive function and was well tolerated in patients with AD treated for 12 weeks. Further randomized, double-blind, placebo-controlled Phase III studies assessing the efficacy, safety/tolerability and potential disease-modifying effects of (-)-phenserine in patients with AD are currently ongoing.

Alzheimer Disease↗
PubMed2005

Cholinesterases: roles in the brain during health and disease.

The cholinergic hypothesis of decline in dementia, whereby deficits in learning, memory and behavior are caused, at least in part, by decreased levels of acetylcholine (ACh) in the brain, first emerged more than 20 years ago. The role for acetylcholinesterase (AChE) and its inhibition in this scheme has long been accepted, but findings from preclinical experiments and clinical trials have placed butyrylcholinesterase (BuChE) alongside AChE as an important contributor to the occurrence, symptoms, progression and responses to treatment in dementia. A number of new lines of evidence suggest that both cholinesterase inhibitors (ChEs) may have broader functions in the CNS than previously thought, which relate to both 'classical' esterase activities of the enzymes as well as non-classical actions unrelated to their enzymatic function. Data suggest involvement of the ChEs in modulating glial activation, cerebral blood flow, the amyloid cascade, and tau phosphorylation. It has therefore been speculated that some actions of the ChEs could affect the underlying disease processes in Alzheimer's disease (AD), and that pharmacological manipulation with ChE inhibitors may affect long-term disease progression. Focusing on new findings relating to BuChE, we review recent evidence that has extended knowledge into the roles of ChEs in health, disease and aging.

Acetylcholinesterase↗
PubMed2005

Enhancing central nervous system endogenous GLP-1 receptor pathways for intervention in Alzheimer's disease.

Glucagon-like peptide-1 (7-36)--amide (GLP-1) is an endogenous insulinotropic peptide that is secreted from the gastrointestinal tract in response to food. It enhances pancreatic islet beta-cell proliferation, glucose-dependent insulin secretion, and lowers blood glucose and food intake in patients with type 2 diabetes mellitus. GLP-1 receptors, are coupled to the cyclic AMP second messenger pathway, and are expressed throughout the brain of rodents and humans. We previously reported that GLP-1 and exendin-4, a naturally occurring, long-acting analogue of GLP-1 that binds the GLP-1 receptor (GLP-1R), possess neurotrophic properties. GLP-1R agonists protect neurons against amyloid-beta peptide (Abeta) and glutamate-induced apoptosis in cell culture studies and attenuate cholinergic neuron atrophy in the basal forebrain of the rat following an excitotoxic lesion. The biochemical cascades activated by neural GLP-1R stimulation are discussed in comparison to those activated by pancreatic receptors, and, additionally, are compared to signaling pathways associated with the classical neurotrophins. GLP-1R stimulation promotes pathways that favour cell survival over apoptosis. GLP-1 readily enters brain, and its diverse physiological actions, which include insulinotropic, cardiovascular as well as neurotrophic ones, may prove beneficial in a variety of diseases prevalent in aging, including Alzheimer's disease (AD). Its ability to lower brain levels of Abeta in mice would appear to be particularly pertinent in this regard. Furthermore, the ready availability of clinical material and the clinical history of its long term use in subjects with type 2 diabetes would support testing the value of GLP-1R agonists in AD trials.

Alzheimer Disease↗
PubMed2005

Anticholinesterase and pharmacokinetic profile of phenserine in healthy elderly human subjects.

OBJECTIVE: To evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of the acetyl-selective anticholinesterase, phenserine tartrate, in healthy elderly subjects. METHODS: 32 healthy elderly volunteers received single oral doses of phenserine tartrate (5-20 mg). Physical and vital signs were monitored over the ensuing 24 hours. Analyses were performed on plasma samples to determine PK, and PD were assessed using an erythrocyte acetylcholinesterase (AChE) inhibition assay. RESULTS: No serious adverse events (AEs) occurred; the most common were headache and vomiting. The MTD of phenserine tartrate was 10 mg. The Cmax and AUC(0-24) of phenserine increased with dose, but neither were dose-proportional. Subjects receiving 10 mg of phenserine tartrate had a Cmax of 1.95 ng/mL at 1.5 hours, and the mean peak inhibition (Imax) of AChE was 26% (range: 18-34%) at 1.75 hours (tImax) following dosing. The half-life of AChE inhibition (tI1/2) was 11 hours. Evaluation of PK/PD relationships suggested a linear correlation between plasma phenserine concentration and AChE inhibition in the blood. CONCLUSIONS: Phenserine tartrate was safe and well tolerated when administered as a single oral dose of either 5 mg or 10 mg. An increase in the severity and frequency of AEs occurred at the 20 mg dose level.

Acetylcholinesterase↗
PubMed2004

Suppression of uracil-DNA glycosylase induces neuronal apoptosis.

A chronic imbalance in DNA precursors, caused by one-carbon metabolism impairment, can result in a deficiency of DNA repair and increased DNA damage. Although indirect evidence suggests that DNA damage plays a role in neuronal apoptosis and in the pathogenesis of neurodegenerative disorders, the underlying mechanisms are poorly understood. In particular, very little is known about the role of base excision repair of misincorporated uracil in neuronal survival. To test the hypothesis that repair of DNA damage associated with uracil misincorporation is critical for neuronal survival, we employed an antisense (AS) oligonucleotide directed against uracil-DNA glycosylase encoded by the UNG gene to deplete UNG in cultured rat hippocampal neurons. AS, but not a scrambled control oligonucleotide, induced apoptosis, which was associated with DNA damage analyzed by comet assay and up-regulation of p53. UNG mRNA and protein levels were decreased within 30 min and were undetectable within 6-9 h of exposure to the UNG AS oligonucleotide. Whereas UNG expression is significantly higher in proliferating as compared with nonproliferating cells, such as neurons, the levels of UNG mRNA were increased in brains of cystathionine beta-synthase knockout mice, a model for hyperhomocysteinemia, suggesting that one-carbon metabolism impairment and uracil misincorporation can induce the up-regulation of UNG expression.

Animals↗
PubMed2004

The role of p53-induced apoptosis in cerebral ischemia: effects of the p53 inhibitor pifithrin alpha.

No neuroprotective compounds are clinically available for the treatment of ischemic stroke. The potential salutary effect of pifithrin alpha, a novel-specific inhibitor of the transcription factor p53, administered 1-6 h following focal reversible cerebral ischemia, was investigated. Studies measuring histological, motor, and behavioral outcomes showed significant improvements in pifithrin alpha-treated animals. Pifithrin alpha reduced the number of apoptotic cells in the ischemic brain by inhibiting the binding of p53 to its DNA sites as it reduced the expression of the p53-related gene p21(WAF) without changing the amount of p53 protein itself.

Animals↗
PubMed2004

Pyridoxine-induced toxicity in rats: a stereological quantification of the sensory neuropathy.

Excess ingestion of pyridoxine (vitamin B6) causes a severe sensory neuropathy in humans. The mechanism of action has not been fully elucidated, and studies of pyridoxine neuropathy in experimental animals have yielded disparate results. Pyridoxine intoxication appears to produce a neuropathy characterized by necrosis of dorsal root ganglion (DRG) sensory neurons and degeneration of peripheral and central sensory projections, with large diameter neurons being particularly affected. The major determinants affecting the severity of the pyridoxine neuropathy appear to be duration and dose of pyridoxine administration, differential neuronal vulnerability, and species susceptibility. The present study used design-based stereological techniques in conjunction with electrophysiological measures to quantify the morphological and physiological changes that occur in the DRG and the distal myelinated axons of the sciatic nerve following pyridoxine intoxication. This combined stereological and electrophysiological method demonstrates a general approach that could be used for assessing the correlation between pathophysiological and functional parameters in animal models of toxic neuropathy.

Animals↗
PubMed2004

The integrated role of desferrioxamine and phenserine targeted to an iron-responsive element in the APP-mRNA 5'-untranslated region.

The Alzheimer's amyloid precursor protein (APP) is the metalloprotein that is cleaved to generate the pathogenic Abeta peptide. We showed that iron closely regulated the expression of APP by 5'-untranslated region (5'-UTR) sequences in APP mRNA. Iron modulated APP holoprotein expression by a pathway similar to iron control of the translation of the ferritin-L and -H mRNAs by iron-responsive elements in their 5'-UTRs. APP gene transcription is also responsive to copper deficit where the Menkes protein depleted fibroblasts of copper to suppress transcription of APP through metal regulatory and copper regulatory sequences upstream of the APP 5' cap site. APP is a copper-zinc metalloprotein and chelation of Fe(3+) by desferrioxamine and Cu(2+) by clioquinol appeared to provide effective therapy for the treatment of AD in limited patient studies. We have introduced an RNA-based screen for small APP 5'-UTR binding molecules to identify leads that limit APP translation (but not APLP-1 and APLP-2) and amyloid Abeta peptide production. A library of 1200 drugs was screened to identify lead drugs that limited APP 5'-UTR-directed translation of a reporter gene. The efficacy of these leads was confirmed for specificity in a cell-based secondary assay to measure the steady-state levels of APP holoprotein relative to APLP-1/APLP-2 by Western blotting. Several chelators were identified among the APP 5'-UTR directed leads consistent with the presence of an IRE stem-loop in front of the start codon of the APP transcript. The APP 5'-UTR-directed drugs--desferrioxamine (Fe(3+) chelator), tetrathiomolybdate (Cu(2+) chelator), and dimercaptopropanol (Pb(2+) and Hg(2+) chelator)--each suppressed APP holoprotein expression (and lowered Abeta peptide secretion). The novel anticholinesterase phenserine also provided "proof of concept" for our strategy to target the APP 5'-UTR sequence to identify "anti-amyloid" drugs. We further defined the interaction between iron chelation and phenserine action to control APP 5'-UTR-directed translation in neuroblastoma (SY5Y) transfectants. Phenserine was most efficient to block translation under conditions of intracellular iron chelation with desferrioxamine suggesting that this anticholinesterase operated through an iron (metal)-dependent pathway at the APP 5'-UTR site.

5' Untranslated Regions↗
PubMed2004

Melatonin, metals, and gene expression: implications in aging and neurodegenerative disorders.

Melatonin is a hormone secreted by the pineal gland, mostly in the dark period of the light/dark cycle, with corresponding fluctuations reflected in the plasma melatonin levels. This hormone plays a critical role in the regulation of various neural and endocrine processes that are synchronized with daily change in photoperiod. Abnormal melatonin levels are associated with metabolic disturbances and other disorders. Melatonin potentially plays an important role in aging, prolongation of life span, and health in the aged individual. It may exert a beneficial action on neurodegenerative conditions in those with debilitating diseases. It interacts with metals and, in some cases, neutralizes their toxic effects. Levels of melatonin decrease with aging in mice. Its dietary supplementation has recently been shown to result in a significant rise in levels of endogenous melatonin in serum as well as all other tissue samples tested. The effects of dietary melatonin have been studied in the brain of mice with regard to nitric oxide synthase, synaptic proteins, and amyloid beta peptides (Abeta), which are involved in amyloid deposition and plaque formation in Alzheimer's disease (AD). Melatonin supplementation has no significant effect on cerebral cortical levels of nitric oxide synthase or synaptic proteins, such as synaptophysin and SNAP-25. Notably, however, elevated brain melatonin levels resulted in a significant reduction in levels of toxic cortical Abeta of both 40- and 42-amino-acid forms. Taken together, these results suggest that dietary melatonin supplementation may slow the neurodegenerative changes associated with brain aging and that the depletion of melatonin in the brain of aging mice may, in part, account for this adverse change.

Aging↗
PubMed2004

New therapeutic strategies and drug candidates for neurodegenerative diseases: p53 and TNF-alpha inhibitors, and GLP-1 receptor agonists.

Owing to improving preventative, diagnostic, and therapeutic measures for cardiovascular disease and a variety of cancers, the average ages of North Americans and Europeans continue to rise. Regrettably, accompanying this increase in life span, there has been an increase in the number of individuals afflicted with age-related neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and stroke. Although different cell types and brain areas are vulnerable among these, each disorder likely develops from activation of a common final cascade of biochemical and cellular events that eventually lead to neuronal dysfunction and death. In this regard, different triggers, including oxidative damage to DNA, the overactivation of glutamate receptors, and disruption of cellular calcium homeostasis, albeit initiated by different genetic and/or environmental factors, can instigate a cascade of intracellular events that induce apoptosis. To forestall the neurodegenerative process, we have chosen specific targets to inhibit that are at pivotal rate-limiting steps within the pathological cascade. Such targets include TNF-alpha, p53, and GLP-1 receptor. The cytokine TNF-alpha is elevated in Alzheimer's disease, Parkinson's disease, stroke, and amyotrophic lateral sclerosis. Its synthesis can be reduced via posttranscriptional mechanisms with novel analogues of the classic drug, thalidomide. The intracellular protein and transcription factor, p53, is activated by the Alzheimer's disease toxic peptide, Abeta, as well as by excess glutamate and hypoxia to trigger neural cell death. It is inactivated by novel tetrahydrobenzothiazole and -oxazole analogues to rescue cells from lethal insults. Stimulation of the glucagon-like peptide-1 receptor (GLP-1R) in brain is associated with neurotrophic functions that, additionally, can protect cells against excess glutamate and other toxic insults.

Animals↗
PubMed2004

A new Alzheimer's disease interventive strategy: GLP-1.

Glucagon-like peptide-1 (7-36)-amide (GLP-1) is an endogenous 30-amino acid gut peptide, which binds at the GLP-1 receptor coupled to the cyclic AMP second messenger pathway. GLP-1 receptor stimulation enhances pancreatic islet beta-cell proliferation, glucose-dependent insulin secretion and lowers blood glucose and food intake in patients with type 2 diabetes mellitus. Not limited to the pancreas, the chemoarchitecture of GLP-1 receptor distribution in the brain of rodents and humans correlates with a central role for GLP-1 in the regulation of food intake. However emerging evidence suggests that stimulation of neuronal GLP-1 receptors plays an important role in regulating neuronal plasticity and cell survival. GLP-1 has been documented to induce neurite outgrowth and to protect against excitotoxic cell death and oxidative injury in cultured neuronal cells. Moreover, GLP-1 and exendin-4, a naturally occurring more stable analogue of GLP-1 that likewise binds at the GLP-1 receptor, were shown to reduce endogenous levels of amyloid-beta peptide (Abeta) in mouse brain and to reduce levels of beta-amyloid precursor protein (betaAPP) in neurons. Collectively these data suggest that treatment with GLP-1 or a related peptide beneficially affects a number of the therapeutic targets associated with Alzheimer's disease (AD). Although much remains to be elucidated with regards to the downstream signaling pathways involved in the pro-survival properties of GLP-1, modulation of calcium homeostasis may be critical. This review will consider the potential therapeutic relevance of GLP-1 to CNS disorders, such as AD.

Alzheimer Disease↗
PubMed2004

Cholesterol and Alzheimer's disease: clinical and experimental models suggest interactions of different genetic, dietary and environmental risk factors.

Alzheimer's disease (AD) is a progressive senile dementia characterized by deposition of a 4 kDa peptide of 39-42 residues known as amyloid beta-peptide (Abeta) in the form of senile plaques and the microtubule associated protein tau as paired helical filaments. Genetic studies have identified mutations in the Abeta precursor protein (APP) as the key triggers for the pathogenesis of AD. Other genes such as presenilins 1 and 2 (PS1/2) and apolipoprotein E (APOE) also play a critical role in increased Abeta deposition. Several biochemical and molecular studies using transfected cultured cells and transgenic animals point to mechanisms by which Abeta is generated and aggregated to trigger the neurodegeneration that may cause AD. Three important enzymes collectively known as 'secretases' participate in APP processing leading to the generation of either Abeta or non-amyloid proteins. However, the mechanisms of neurotoxicity of Abeta and the role of APP function in AD remain important unanswered questions. Although early studies recognized the loss of cholesterol and other lipids in the brain, these findings have been poorly connected with AD pathogenesis, despite the identification of the epsilon4 allele of APOE as a major risk factor in AD. The recent finding that cholesterol can modulate the yield of potentially toxic Abeta has boosted research on its role in AD. Consequently, several cholesterol-reducing drugs are currently being evaluated for the treatment of AD. The present review summarizes our current understanding of the relationship of AD pathogenesis with cholesterol, lipids and other genetic and environmental risk factors.

Alzheimer Disease↗
PubMed2004

Thalidomide-based TNF-alpha inhibitors for neurodegenerative diseases.

Inflammatory processes associated with the over-production of cytokines, particularly of TNF-alpha, accompany numerous neurodegenerative diseases, such as Alzheimer's disease, in addition to numerous systemic conditions, exemplified by rheumatoid arthritis and erythema nodosum leprosum (ENL). TNF-alpha has been validated as a drug target with Remicade and Enbrel available as prescription medications. Both, however, are large macromolecules, require injection and have limited brain access. The classical drug, thalidomide is being increasingly used in the clinical management of a wide spectrum of diseases. As its clinical value in treating ENL derives from its TNF-alpha inhibitory activity, thalidomide was chosen for structural modification for the discovery of novel and more potent isosteric analogues with appropriate lipophilicity to insure high brain penetration. TNF-alpha inhibitory activity was evaluated against lipopolysacharide (LPS) stimulated peripheral blood mononuclear cells (PBMC) in cell culture, whose viability was quantified to differentiate reductions in TNF-alpha secretion from that associated with cellular toxicity. Specific analogues potently inhibited TNF-alpha secretion, compared to thalidomide. This involved a post-transcriptional mechanism, as they decreased TNF-alpha mRNA stability via its 3'-untranslated region (UTR), as determined by luciferase activity in stably transfected cells with and without the 3'-UTR of human TNF-alpha.

Cells, Cultured↗
PubMed2003

Thiothalidomides: novel isosteric analogues of thalidomide with enhanced TNF-alpha inhibitory activity.

Thalidomide is being increasingly used in the clinical management of a wide spectrum of immunologically-mediated and infectious diseases, and cancers. However, the mechanisms underlying its pharmacological action are still under investigation. In this regard, oral thalidomide is clinically valuable in the treatment of erythema nodosum leprosum (ENL) and multiple myeloma and effectively reduces tumor necrosis factor-alpha (TNF-alpha) levels and angiogenesis in vivo. This contrasts with its relatively weak effects on TNF-alpha and angiogenesis in in vitro studies and implies that active metabolites contribute to its in vivo pharmacologic action and that specific analogues would be endowed with potent activity. Our focus in the structural modification of thalidomide is toward the discovery of novel isosteric active analogues. In this regard, a series of thiothalidomides and analogues were synthesized and evaluated for their TNF-alpha inhibitory activity against lipopolysacharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC), This was combined with a PBMC viability assay to differentiate reductions in TNF-alpha secretion from cellular toxicity. Two isosteric analogues of thalidomide, compounds 15 and 16, that mostly reflect the parent compound, together with the simple structure, dithioglutarimide 19, potently inhibited TNF-alpha secretion, compared to thalidomide, 1. The mechanism underpinning this most likely is posttranscriptional, as each of these compounds decreased TNF-alpha mRNA stability via its 3'-UTR. The potency of 19 warrants further study and suggests that replacement of the amide carbonyl with a thiocarbonyl may be beneficial for increased TNF-alpha inhibitory action. In addition, an intact phthalimido moiety appeared to be requisite for TNF-alpha inhibitory activity.

3' Untranslated Regions↗