Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since the discovery of cyclic nucleotide phosphodiesterase 30 years ago, there have been major advances in our knowledge of this group of isoenzymes. Five families, each composed of several isoforms and having differing tissue distributions, have been described. David Nicholson and colleagues compare the tissue distribution of phosphodiesterase isoenzymes and discuss the differential effects of inhibition of particular isoenzymes, with differing subcellular localization, on tissue function. They also review the potential use of isoenzyme selective phosphodiesterase inhibitors in a range of clinical disorders such as heart failure, asthma, depression and dementia.
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PMID:Differential modulation of tissue function and therapeutic potential of selective inhibitors of cyclic nucleotide phosphodiesterase isoenzymes. 184 33

Cascading glial cell activation is believed to play an essential pathogenic role in the development of dementia. Reactive microglia may contribute to neuronal damage by the generation of free oxygen radicals and nitric oxide (NO), which forms the particularly aggressive peroxynitrites, and by the release of potentially neurotoxic cytokines such as tumor necrosis factor-alpha (TNF-alpha). The pathologically stimulated release of interleukin-1beta (IL-1beta) from microglial cells triggers secondary activation of astrocytes, which are forced to proliferate and to give up their differentiated state. As a consequence, physiologically required astrocyte functions may be impaired, such as uptake of glutamate and K+ from the extracellular space and release of neurotrophic factors. At the same time, production of inflammatory proteins which, for example, promote the formation of toxic beta-amyloids, is reported to be stimulated in reactive astrocytes. Because the complex molecular signaling that controls glial cell activation is only beginning to be elaborated, we attempted to elucidate the role that has been adopted during evolution by the endogenous cell modulator adenosine. This nucleoside exerts a homeostatic effect on reactive glial cell functions by a sophisticated control of the second messenger interplay, counteracting a pathologically induced dysbalance of the Ca2+- and cAMP-dependent signaling. A strengthening of the cAMP-dependent signaling chains was found to counteract the proliferation rate, the formation of free oxygen radicals, and the stimulated release of TNF-alpha and IL-1beta in cultivated microglia. It also helped proliferative astrocytes to regain their differentiated state and a mature ion channel pattern. The cAMP-linked homeostatic adenosine effects could be reinforced or mimicked by propentofylline, a pharmacon that raises the effective extracellular concentration of adenosine by inhibiting its cellular reuptake and increases the cellular cyclic nucleotide content by selective phosphodiesterase inhibition. We conclude that a pharmacologically reinforced homeostatic control of the pathologically altered Ca2+/cAMP crosstalk may prevent glia-related neuronal damage, providing a potential option for the treatment of dementia.
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PMID:Interfering with the pathologic activation of microglial cells and astrocytes in dementia. 976 26

Propentofylline (Karsivan, Hoechst Roussel Vet) is a selective inhibitor of adenosine transport and phosphodiesterase. For several years it has been well established in the geriatric therapy of the dog improving hemodynamics in cerebral and peripheral compartments. In human medicine clinical development of this pharmaceutical has already entered an advanced stage for the long-term therapy of patients with Alzheimer's disease and vascular dementia. In the brains of senile dogs and in human patients suffering from Alzheimer's disease comparable neuropathological findings can be made. In senile dogs a distinctive correlation exists between the quantity of beta-amyloid accumulation and the degree of dementia. The extension of knowledge by clinical studies in humans and by experimental studies in animals may contribute to a deeper understanding of therapeutical approaches of cognitive dysfunction in the old dog. The xanthine derivative propentofylline [1-(5'-oxohexyl)-3-methyl-7-propylxanthine] directly interfers with the neurodegenerative process and reduces the extent of damage to brain structures. In experimental models of vascular dementia and/or Alzheimer's disease it improves cognitive functions, inhibits inflammatory processes as well as excessive activation of microglia, formation of free radicals, cytocines and abnormal amyloid precursor proteins (APP). It stimulates synthesis and liberation of nerve growth factor (NGF) and reduces ischemic damage to the brain. In clinical studies in humans it improved cognitive functions as well as global functions and the ability to cope with tasks of routine daily life in patients suffering from Alzheimer's disease and vascular dementia.
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PMID:[New pharmacologic aspects in the neurologic profile of propentofylline (Karsivan ad us. vet.)]. 993 90

The biological roles of nitric oxide (NO) and cGMP as inter- and intracellular messengers have been intensively investigated during the last decade. NO and cGMP both mediate physiological effects in the cardiovascular, endocrinological, and immunological systems as well as in central nervous system (CNS). In the CNS, activation of the N-methyl-D-aspartic acid (NMDA) type of glutamatergic receptor induces Ca(2+)-dependent NOS and NO release, which then activates soluble guanylate cyclase for the synthesis of cGMP. Both compounds appear to be important mediators in long-term potentiation and long-term depression, and thus may play important roles in the mechanisms of learning and memory. Aging and the accumulation of amyloid beta (A beta) peptides are important risk factors for the impairment of memory and development of dementia. In these studies, the mechanism of basal- and NMDA receptor-mediated cGMP formation in different parts of adult and aged brains was evaluated. The relative activity of the NO cascade was determined by assay of NOS and guanylate cyclase activities. In addition, the effect of the neurotoxic fragment 25-35 of A beta (A beta) peptide on basal and NMDA receptor-mediated NOS activity was investigated. The studies were carried out using slices of hippocampus, brain cortex, and cerebellum from 3- and 28-mo-old rats. Aging coincided with a decrease in the basal level of cGMP as a consequence of a more active degradation of cGMP by a phosphodiesterase in the aged brain as compared to the adult brain. Moreover, a loss of the NMDA receptor-stimulated enhancement of the cGMP level determined in the presence of cGMP-phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) was observed in hippocampus and cerebellum of aged rats. However, this NMDA receptor response was preserved in aged brain cerebral cortex. A significant enhancement of the basal activity of NOS by about 175 and 160% in hippocampus and cerebellum, respectively, of aged brain may be involved in the alteration of the NMDA receptor response. The neurotoxic fragment of A beta, peptide 25-35, decreased significantly the NMDA receptor-mediated calcium, and calmodulim-dependent NO synthesis that may then be responsible for disturbances of the NO and cGMP signaling pathway. We concluded that cGMP-dependent signal transduction in hippocampus and cerebellum may become insufficient in senescent brain and may have functional consequences in disturbances of learning and memory processes. A beta peptide accumulated during brain aging and in Alzheimer disease may be an important factor in decreasing the NO-dependent signal transduction mediated by NMDA receptors.
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PMID:Aging modulates nitric oxide synthesis and cGMP levels in hippocampus and cerebellum. Effects of amyloid beta peptide. 1034 72

The pathophysiology of Alzheimer's disease is complex and involves several different biochemical pathways. These include defective beta-amyloid (Abeta) protein metabolism, abnormalities of glutamatergic, adrenergic, serotonergic and dopaminergic neurotransmission, and the potential involvement of inflammatory, oxidative and hormonal pathways. Consequently, these pathways are all potential targets for Alzheimer's disease treatment and prevention strategies. Currently, the mainstay treatments for Alzheimer's disease are the cholinesterase inhibitors, which increase the availability of acetylcholine at cholinergic synapses. Since the cholinesterase inhibitors confer only modest benefits, additional non-cholinergic Alzheimer's disease therapies are urgently needed. Several non-cholinergic agents are currently under development for the treatment and/or prevention of Alzheimer's disease. These include anti-amyloid strategies (e.g. immunisation, aggregation inhibitors, secretase inhibitors), transition metal chelators (e.g. clioquinol), growth factors, hormones (e.g. estradiol), herbs (e.g. Ginkgo biloba), nonsteroidal anti-inflammatory drugs (NSAIDs, e.g. indomethacin), antioxidants, lipid-lowering agents, antihypertensives, selective phosphodiesterase inhibitors, vitamins (E, B12, B6, folic acid) and agents that target neurotransmitter or neuropeptide alterations. Neurotransmitter receptor-based approaches include agents that modulate certain receptors (e.g. nicotinic, muscarinic, alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid [AMPA], gamma-aminobutyric acid [GABA], N-methyl-D-aspartate [NMDA]) and agents that increase the availability of neurotransmitters (e.g. noradrenergic reuptake inhibitors). Of these strategies, the NMDA receptor antagonist memantine is in the most advanced stage of development in the US and is already approved in Europe as the first treatment for moderately severe to severe Alzheimer's disease. Memantine is proposed to counteract cellular damage due to pathological activation of NMDA receptors by glutamate. Results with Ginkgo biloba have been mixed. Data for neurotrophic therapies and vitamin E (tocopherol) appear promising but require confirmation. NSAIDs and conjugated estrogens have not proven to be of value to date for the treatment of Alzheimer's disease. Statins may have a potential role in reducing the risk or delaying the onset of Alzheimer's disease, although this has yet to be confirmed in randomised trials. There are currently no data to support the use of statins as a treatment for dementia. This article provides an update on the current status of selected agents, focusing primarily on those agents with the most extensive clinical evidence at present.
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PMID:Non-cholinergic strategies for treating and preventing Alzheimer's disease. 1242 Nov 15

Cerebrovascular white matter (WM) lesions, which are frequently observed in vascular cognitive impairment and vascular dementia, can be produced in rats by clipping the common carotid arteries bilaterally. Since TNF-alpha is known to cause the degeneration of myelin, we examined whether these lesions can be ameliorated by ibudilast, a cyclic AMP phosphodiesterase (PDE) inhibitor that suppresses tumor necrosis factor (TNF)-alpha production. After the ligation of both common carotid arteries in 29 rats, 21 rats received a daily oral administration of 10, 30 or 60 mg/kg ibudilast and 8 rats received vehicle for 14 days. The pathological changes in the white matter were quantified in terms of white matter lesions and the emergence of activated microglia immunoreactive for major histocompatibility complex (MHC) antigen. In the vehicle-treated animals, white matter lesions and microglial activation occurred in the optic tract, internal capsule and corpus callosum. A low dose (10 mg/kg) of ibudilast failed to suppress the white matter lesions and microglial activation, whereas a dose of either 30 or 60 mg/kg ibudilast ameliorated these lesions (p<0.001). Without an alterations in laboratory blood data, 60 mg/kg ibudilast exhibited percent reduction of the white matter lesions ranging between 50% and 70%, which was more effective than 30 mg/kg ibudilast (p<0.05). The TNF-alpha immunoreactive glia decreased in number in the 60 mg/kg ibudilast-treated group as compared to the vehicle-treated group (p<0.001). These results indicate a dose-dependent protective effect of ibudilast against cerebrovascular white matter lesions and suggest a potential use for ibudilast in the treatment of vascular dementia.
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PMID:Ibudilast, a phosphodiesterase inhibitor, protects against white matter damage under chronic cerebral hypoperfusion in the rat. 1460 72

The phosphodiesterase inhibitor, ibudilast, has many effects on lymphocytes, endothelial cells, and glial cells. We examined the neuroprotective role of ibudilast in neuron and microglia co-cultures. Ibudilast significantly suppressed neuronal cell death induced by the activation of microglia with lipopolysaccharide (LPS) and interferon (IFN)-gamma. To examine the mechanisms by which ibudilast exerts a neuroprotective role against the activation of microglia, we examined the production of inflammatory and anti-inflammatory mediators and trophic factors following ibudilast treatment. In a dose-dependent manner, ibudilast suppressed the production of nitric oxide (NO), reactive oxygen species, interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha and enhanced the production of the inhibitory cytokine, IL-10, and additional neurotrophic factors, including nerve growth factor (NGF), glia-derived neurotrophic factor (GDNF), and neurotrophin (NT)-4 in activated microglia. Thus, ibudilast-mediated neuroprotection was primarily due to the inhibition of inflammatory mediators and the upregulation of neurotrophic factor. In the CA1 region of hippocampal slices, long-term potentiation (LTP) induced by high frequency stimulation (HFS) could be inhibited with LPS and interferon-gamma stimulation. Ibudilast returned this LTP inhibition to the levels observed in controls. These results suggest that ibudilast may be a useful neuroprotective and anti-dementia agent counteracting neurotoxicity in activated microglia.
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PMID:Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia. 1497 96

The human immunodeficiency virus type-1 (HIV-1) coat glycoprotein gp120 has been proposed as a likely etiologic agent of HIV-associated dementia (HAD). The pathogenic mechanisms underlying HAD have not yet been fully elucidated, but different evidences indicate that glial cells play an essential role in the development and amplification of the disease. The NO/cyclic GMP (cGMP) system is a widespread signal transduction pathway in the CNS involved in numerous physiological and pathological functions. Increased expression of NO synthase has been reported in the brain of AIDS patients and in cultured rodent glial cells exposed to gp120. The aim of this study was to investigate if gp120 could cause alterations in the metabolism of the NO physiological messenger cGMP that could contribute to the pathogenesis of HAD. Here, we show that long-term treatment (more than 24 h) of rat cerebellar astrocyte-enriched cultures with gp120 (10 nM) induces changes in the cultured cells--astrocyte stellation and proliferation of ameboid microglia--compatible with the acquisition of a reactive phenotype and reduces the capacity of the astrocytes to accumulate cGMP in response to NO in a time-dependent manner (maximal after 72 h). Measurements in cell extracts show that gp120 enhances Ca2+-independent cGMP phosphodiesterase activity by 80-100% without significantly affecting soluble guanylyl cyclase (sGC). Experiments in whole cells using specific phosphodiesterase inhibitors indicate that the viral protein increases the activity of cGMP specific phosphodiesterase 5.
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PMID:HIV-1 coat protein gp120 decreases NO-dependent cyclic GMP accumulation in rat brain astroglia by increasing cyclic GMP phosphodiesterase activity. 1531 88

Increasing clinical and experimental evidence implicate cerebral hypoperfusion during increased ageing and points to chronic cerebrovascular ischemia as a vital component of the neuropathological progression of dementia. In vivo cerebral perfusion animal models can greatly contribute to the evaluation of drugs and to the screening of drug interactions. This study describes a baboon Papio ursinus model under anaesthesia, for in vivo cerebral blood flow (CBF) determinations, using Single Photon Emission Computed Tomography (SPECT) following the split-dose method with 99mTc-hexamethylpropylene amine oxime (99mTc-HMPAO). Perfusion studies with acetazolamide as intervention clearly showed that the non-human primate model under aneasthesia is sufficiently sensitive to serve in the evaluation of other cerebrovasoactive drugs for induced perfusion changes with significant increases of the R-value (+40%) for comparative measurement when compared to the control value (2.53+/-0.15 vs. 1.79+/-0.13). These findings stimulated investigations of several drugs, i.e. pentifylline (phosphodiesterase inhibitor); nimodipine (calcium channel blocker); sumatriptan (serotonin receptor agonist) and nicotinic acid (vasodilator) for CBF effects. Increases in the cerebral perfusion in some cases more than +30% for nimodipine (2.51+/-0.14 vs. 1.79+/-0.13), acetazolamide and +29% for the combination of pentifylline and nicotinic acid (2.31+/-0.19 vs. 1.79+/-0.13) were observed. Drug interaction studies revealed an attenuation of increased CBF due to nimodipine, with sumatriptan (-25%) and acetazolamide (+22%) in combination with nimodipine. Drug interactions with clinical implications may result during simultaneous use of cerebrovasoactive drugs in managing patients with cerebrovascular disorders. This study further showed that the CBF non-human primate model under anaesthesia is useful for the investigation of vasoactive drugs acting via various pharmacological modes of action.
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PMID:Non-human primate SPECT model for determining cerebral perfusion effects of cerebrovasoactive drugs acting via multiple modes of pharmacological action. 1576 Jun 48

Sildenafil, a phosphodiesterase-5 inhibitor commonly used for erectile dysfunction, may also have a beneficial therapeutic effect in the treatment of stroke, subarachnoid hemorrhage, dementia, learning, and neurodegenerative disorders by enhancing angiogenesis and neurogenesis. It also favorably influences the nitric oxide-cyclic guanosine monophosphate pathways, which are involved in the pathogenesis of a number of neurological diseases. Its potential therapeutic role in the treatment of the neurological disorders mentioned above is still under preclinical investigation. Sildenafil is currently being used to treat erectile dysfunction in patients with multiple sclerosis, Parkinson disease, multisystem atrophy, and spinal cord injury by improving their neurologically related erectile dysfunction. Conversely, it has been implicated in a number of neurological problems, such as intracerebral hemorrhage, migraine, seizure, transient global amnesia, nonarteritic anterior ischemic optic neuropathy, macular degeneration, branch retinal artery occlusion, and ocular muscle palsies. Thus, preclinical and very limited clinical data suggest that sildenafil may have therapeutic potential in selected neurological disorders. However, numerous reports are available regarding neurological adverse events ascribed to the drug. Although sildenafil shows some promise as a therapeutic agent in selected neurological disorders, well-designed clinical trials are needed before the agent can be recommended for use in any neurological disorder.
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PMID:Role of sildenafil in neurological disorders. 1905 Apr 13


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