Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined MPTP toxicity to dopamine neurons of mice homozygous for a transgenic knockout of the p53 growth control gene (p53-/-). MPTP at a total dose of 96 mg/kg administered in four doses over two days produced a non-homogeneous loss of striatal dopamine transport sites and quantitatively reduced 3H-mazindol binding to similar degrees in p53-/- and wild type controls 2 and 3 weeks after starting MPTP. Nigral DA neurons stained immunohistochemically for tyrosine hydroxylase were counted using both manual and automated methods and found to be reduced 29-34% in wild type controls but were not reduced in p53-/-. Mean DA neuronal surface areas were reduced 63-68% by MPTP in controls and 35-50% in p53-/-. We conclude that p53 protein appears necessary for complete expression of MPTP neurotoxicity to dopamine neurons. Our findings suggest that the p53 gene and other growth control genes may regulate dopamine neuronal death in PD.
 ...
PMID:Dopamine neurons from transgenic mice with a knockout of the p53 gene resist MPTP neurotoxicity. 891 Sep 1

Over the past several years, we have developed a number of novel aliphatic propargylamine-related compounds. These can be divided into 14 main chemical families. These families have been shown to possess members that selectively and stereochemically (i.e. R-enantiomer) rescue neurons from p53-dependent apoptosis in vitro. In contrast, no rescue has been observed by the enantiomers of the opposite configuration or in p53-independent apoptosis. In vivo, several compounds have been shown to possess neural rescue properties in models of unilateral hypoxia/ischaemia, focal ischaemia, facial nerve axotomy, pmn mice, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse and MPTP non-human primate. Our prototype compound, R-2HMP, has been shown to be metabolised in a manner analogous to that of R-deprenyl but devoid of amphetaminergic metabolites. These compounds have been shown to be active through an interaction with the same binding site as R-deprenyl and CGP 3466. This site is suggested to be the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH).
 ...
PMID:Aliphatic propargylamines as symptomatic and neuroprotective treatments for neurodegenerative diseases. 1220 Jan 97

Sporadic Parkinson's disease (PD) affects primarily dopaminergic neurons of the substantia nigra pars compacta. There is evidence of necrotic and apoptotic neuronal death in PD, but the mechanisms behind selected dopaminergic neuronal death remain unknown. The tumor suppressor protein p53 functions to selectively destroy stressed or abnormal cells during life and development by means of necrosis and apoptosis. Activation of p53 leads to death in a variety of cells including neurons. p53 is a target of the nuclear enzyme Poly(ADP-ribose)polymerase (PARP), and PARP is activated following DNA damage that occurs following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. MPTP is the favored in vivo model of PD, and reproduces the pathophysiology, anatomy and biochemistry of PD. p53 protein normally exhibits a fleeting half-life, and regulation of p53 stability and activation is achieved mainly by post-translational modification. We find that p53 is heavily poly(ADP-ribosyl)ated by PARP-1 following MPTP intoxication. This post-translational modification serves to stabilize p53 and alters its transactivation of downstream genes. These influences of PARP-1 on p53 may underlie the mechanisms of MPTP-induced parkinsonism and other models of neuronal death.
 ...
PMID:A novel in vivo post-translational modification of p53 by PARP-1 in MPTP-induced parkinsonism. 1235 42

Drugs currently used for patients with Parkinson's disease provide temporary relief of symptoms but do not halt or slow the underlying neurodegenerative disease process. Increasing evidence suggests that neurons die in Parkinson's disease by a process called apoptosis, which may be triggered by mitochondrial impairment and oxidative stress. We report that two novel synthetic inhibitors of the tumor suppressor protein p53, pifithrin-alpha (PFT-alpha) and Z-1-117, are highly effective in protecting midbrain dopaminergic neurons and improving behavioral outcome in a mouse model of Parkinson's disease. Mice given intraperitoneal injections of PFT-alpha or Z-1-117 exhibited improved motor function, reduced damage to nigrostriatal dopaminergic neurons and reduced depletion of dopamine and its metabolites after exposure to the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP caused an increase in the level of the proapoptotic protein Bax, which was prevented by giving mice PFT-alpha and Z-1-117. PFT-alpha and Z-1-117 also suppressed Bax production and apoptosis in cultured dopaminergic cells exposed to MPP(+). Our findings demonstrate a pivotal role for p53 in experimental parkinsonism and identify a novel class of synthetic p53 inhibitors with clinical potential.
 ...
PMID:p53 inhibitors preserve dopamine neurons and motor function in experimental parkinsonism. 1240 57

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model constitutes the best-characterized toxin paradigm for Parkinson's disease, faithfully replicating most of its clinical and pathological hallmarks. Many lines of evidence point to a significant contribution of apoptosis to cell death after application of 1-methyl-4-phenylpyridinium (MPP(+)) in cell culture or MPTP in vivo. This holds true for apoptotic DNA strand breaks, activation of the JNK pathway and caspases, induction of Par-4 protein and the protection conferred by interference with p53, Apaf-1 or Bax signalling. In MPTP models, intervention in upstream events of apoptosis, e.g. by inhibition of the JNK pathway, provides morphological and functional rescue. In contrast, inhibition of the propagation and execution phase of apoptosis, e.g. by inhibition of caspases, blocks or delays cell death but may not recover neuronal function. At this stage, the combination of an anti-apoptotic together with a neurorestorative therapy may be promising.
 ...
PMID:Apoptotic mechanisms and antiapoptotic therapy in the MPTP model of Parkinson's disease. 1262 49

The evidence for a role of apoptosis in the neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and in the more acute conditions of cerebral ischemia, traumatic brain injury (TBI), and spinal cord injury (SCI) is reviewed with regard to potential intervention by means of small antiapoptotic molecules. In addition, the available animal models for these diseases are discussed with respect to their relevance for testing small antiapoptotic molecules in the context of what is known about the apoptotic pathways involved in the diseases and the models. The principal issues related to pharmacotherapy by apoptosis inhibition, i.e., functionality of rescued neurons and potential interference with physiologically occurring apoptosis, are pointed out. Finally, the properties of a number of small antiapoptotic molecules currently under clinical investigation are summarized. It is concluded that the evidence for a role of apoptosis at present is more convincing for PD and ALS than for AD. In PD, damage to dopaminergic neurons may occur through oxidative stress and/or mitochondrial impairment and culminate in activation of an apoptotic, presumably p53-dependent cascade; some neurons experiencing energy failure may not be able to complete apoptosis, end up in necrosis and give rise to inflammatory processes. These events are reasonably well reflected in some of the PD animal models, notably those involving 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone. In sporadic ALS, an involvement of pathways involving p53 and Bcl-2 family members appears possible if not likely, but is not established. The issue is important for the development of antiapoptotic compounds for the treatment of this disease because of differential involvement of p53 in different mutant superoxide dismutase (SOD) mice. Most debated is the role of apoptosis in AD; this implies that little is known about potentially involved pathways. Moreover, there is a lack of suitable animal models for compound evaluation. Apoptosis or related phenomena are likely involved in secondary cell death in cerebral ischemia, TBI, and SCI. Most of the pertinent information comes from animal experiments, which have provided some evidence for prevention of cell death by antiapoptotic treatments, but little for functional benefit. Much remains to be done in this area to explore the potential of antiapoptotic drugs. There is a small number of antiapoptotic compounds in clinical development. With some of them, evidence for maintenance of functionality of the rescued neurons has been obtained in some animal models, and the fact that they made it to phase II studies in patients suggests that interference with physiological apoptosis is not an obligatory problem. The prospect that small antiapoptotic molecules will have an impact on the therapy of neurodegenerative diseases, and perhaps also of ischemia and trauma, is therefore judged cautiously positively.
 ...
PMID:Prospects for antiapoptotic drug therapy of neurodegenerative diseases. 1265 69

Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme that is activated primarily by DNA damage. Upon activation, the enzyme hydrolyzes NAD(+) to nicotinamide and transfers ADP ribose units to a variety of nuclear proteins, including histones and PARP-1 itself. This process is important in facilitating DNA repair. However, excessive activation of PARP-1 can lead to significant decrements in NAD(+), and ATP depletion, and cell death (suicide hypothesis). In response to cellular damage by oxygen radicals or excitotoxicity, a rapid and strong activation of PARP-1 occurs in neurons. Excessive PARP-1 activation is implicated in a variety of insults, including cerebral and cardiac ischemia, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism, traumatic spinal cord injury, and streptozotocin-induced diabetes. The use of PARP inhibitors has, therefore, been proposed as a protective therapy in decreasing excitotoxic neuronal cell death, as well as ischemic and other tissue damage. Excitotoxic brain lesions initially result in the primary destruction of brain parenchyma and subsequently in secondary damage of neighboring neurons hours after the insult. This secondary damage of initially surviving neurons accounts for most of the volume of the infarcted area and the loss of brain function after a stroke. One major component of secondary neuronal damage is the migration of macrophages and microglial cells toward the sites of injury, where they produce large quantities of toxic cytokines and oxygen radicals. Recent evidence indicates that this microglial migration is strongly controlled in living brain tissue by expression of the integrin CD11a, which is regulated in turn by PARP-1, proposing that PARP-1 downregulation may, therefore, be a promising strategy in protecting neurons from this secondary damage, as well. Studies demonstrating an important role for PARP-1 in the regulation of gene transcription have further increased the intricacy of poly(ADP-ribosyl)ation in the control of cell homeostasis and challenge the notion that energy collapse is the sole mechanism by which poly(ADP-ribose) formation contributes to cell death. The hypothesis that PARPs might regulate cell fate as essential modulators of death and survival transcriptional programs is discussed with relation to nuclear factor kappaB and p53.
 ...
PMID:Poly(ADP-Ribose) polymerase-1 in acute neuronal death and inflammation: a strategy for neuroprotection. 1285 16

Poly(ADP-ribose) polymerase 1 (PARP-1) protects the genome by functioning in the DNA damage surveillance network. In response to stresses that are toxic to the genome, PARP-1 activity increases substantially, an event that appears crucial for maintaining genomic integrity. Massive PARP-1 activation, however, can deplete the cell of NAD(+) and ATP, ultimately leading to energy failure and cell death. The discovery that cell death may be suppressed by PARP inhibitors or by deletion of the parp-1 gene has prompted a great deal of interest in the process of poly(ADP-ribosyl)ation. Suppression of PARP-1 is capable of protecting against cerebral and cardiac ischemia, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, traumatic spinal cord injury, and streptozotocin-induced diabetes. The secondary damage of initially surviving neurons in brain stroke accounts for most of the volume of the infarcted area and the subsequent loss of brain function. Microglial migration is strongly controlled in living brain tissue by expression of the integrin CD11a, which is regulated in turn by PARP-1, proposing that PARP-1 downregulation may therefore be a promising strategy in protecting neurons from this secondary damage, as well. As PARP-1 is now recognised as playing a role also in the regulation of gene transcription, this further increases the intricacy of poly(ADP-ribosyl)ation in the control of cell homeostasis and challenges the notion that energy collapse is the sole mechanism by which poly(ADP-ribose) formation contributes to cell death. PARP(s) might regulate cell fate as essential modulators of death and survival transcriptional programs with relation to NF-kappaB and p53, proposing that inhibitors of poly(ADP-ribosyl)ation could therefore prevent the deleterious consequences of neuroinflammation by reducing NF-kappaB activity.
 ...
PMID:Poly(ADP-ribosyl)ation enzyme-1 as a target for neuroprotection in acute central nervous system injury. 1452 60

1-Methyl-4-phenylpyridinium ion (MPP(+)), an active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, induces cell death and inhibition of cell proliferation in various cells. However, the mechanism whereby MPP(+) inhibits cell proliferation is still unclear. In this study, we found that MPP(+) suppressed the proliferation with accumulation in G(1) phase without inducing cell death in p53-deficient MG63 osteosarcoma cells. MPP(+) induced hypophosphorylation of retinoblastoma protein and rapidly down-regulated the protein but not mRNA levels of cyclin D1 in MG63 cells. The down-regulation of cyclin D1 protein was suppressed by a proteasome inhibitor, MG132. The cyclin D1 down-regulation by MPP(+) was also observed in p53-positive PC12, HeLa S3, and HeLa rho(0) cells, which are a subclone of HeLa S3 lacking mitochondrial DNA. Moreover, MPP(+) dephosphorylated Akt in PC12 cells, which was rescued by the pretreatment with nerve growth factor. In addition, the pretreatment with nerve growth factor or lithium chloride, a glycogen synthase kinase-3beta inhibitor, suppressed the cyclin D1 down-regulation caused by MPP(+). Our results demonstrate that MPP(+) induces cell cycle arrest independently of its mitochondrial toxicity or the p53 status of the target cells, but rather through the proteasome- and phosphatidylinositol 3-Akt-glycogen synthase kinase-3beta-dependent cyclin D1 degradation.
 ...
PMID:Proteasome-dependent degradation of cyclin D1 in 1-methyl-4-phenylpyridinium ion (MPP+)-induced cell cycle arrest. 1524 82

There is a growing body of evidence suggesting that iron chelation may be a useful therapy in the treatment of Parkinson's Disease (PD). Experiments were designed to test the impact of dietary iron availability on the pathogenic process and functional outcome in a mouse model of PD. Mice were fed diets containing low (4 ppm) or adequate (48 ppm) amounts of iron for 6 weeks before the administration of MPTP, a mitochondrial toxin that damages nigrostriatal dopaminergic neurons and induces Parkinson-like symptoms. Low dietary iron increased serum total iron binding capacity (P < 0.001). Consistent with neuronal protection, iron restriction increased sphingomyelin C16:0 and decreased ceramide C16:0. However, there was a 35% decrease in striatal dopamine (DA) in iron-restricted mice. Motor behavior was also impaired in these animals. In vitro studies suggested that severe iron restriction could lead to p53-mediated neuronal apoptosis. Administration of MPTP reduced striatal DA (P < 0.01) and impaired motor behavior in iron-adequate mice. However, in iron-restricted mice, striatal dopamine levels and motor behavior were unchanged compared to saline-treated mice. Thus, while reduced iron may provide protection against PD-inducing insults such as MPTP, the role of iron in the synthesis of DA and neuronal survival should be considered, particularly in the development of iron-chelating agents to be used chronically in the clinical setting.
 ...
PMID:Role of dietary iron restriction in a mouse model of Parkinson's disease. 1553 Aug 89


1 2 3 4 Next >>