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)

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

Changes in hippocampal function seem critical for cognitive impairment in Alzheimer's disease (AD). Although there is eventual loss of synapses in both AD and animal models of AD, deficits in spatial memory and inhibition of long-term potentiation (LTP) precede morphological alterations in the models, suggesting earlier biochemical changes in the disease. In the studies reported here we demonstrate that amyloid beta-peptide (Abeta) treatment of cultured hippocampal neurons leads to the inactivation of protein kinase A (PKA) and persistence of its regulatory subunit PKAIIalpha. Consistent with this, CREB phosphorylation in response to glutamate is decreased, and the decrease is reversed by rolipram, a phosphodiesterase inhibitor that raises cAMP and leads to the dissociation of the PKA catalytic and regulatory subunits. It is likely that a similar mechanism underlies Alphabeta inhibition of LTP, because rolipram and forskolin, agents that enhance the cAMP-signaling pathway, can reverse this inhibition. This reversal is blocked by H89, an inhibitor of PKA. These observations suggest that Alphabeta acts directly on the pathways involved in the formation of late LTP and agents that enhance the cAMP/PKA/CREB-signaling pathway have potential for the treatment of AD.
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PMID:Amyloid beta -peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling. 1224 10

Mice carrying a truncated form of cAMP-responsive element binding protein (CREB)-binding protein (CBP) show several developmental abnormalities similar to patients with Rubinstein-Taybi syndrome (RTS). RTS patients suffer from mental retardation, whereas long-term memory formation is defective in mutant CBP mice. A critical role for cAMP signaling during CREB-dependent long-term memory formation appears to be evolutionarily conserved. From this observation, we reasoned that drugs that modulate CREB function by enhancing cAMP signaling might yield an effective treatment for the memory defect(s) of CBP+/- mice. To this end, we designed a cell-based drug screen and discovered inhibitors of phosphodiesterase 4 (PDE4) to be particularly effective enhancers of CREB function. We extend previous behavioral observations by showing that CBP+/- mutants have impaired long-term memory but normal learning and short-term memory in an object recognition task. We demonstrate that the prototypical PDE4 inhibitor, rolipram, and a novel one (HT0712) abolish the long-term memory defect of CBP+/- mice. Importantly, the genetic lesion in CBP acts specifically to shift the dose sensitivity for HT0712 to enhance memory formation, which conveys molecular specificity on the drug's mechanism of action. Our results suggest that PDE4 inhibitors may be used to treat the cognitive dysfunction of RTS patients.
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PMID:A mouse model of Rubinstein-Taybi syndrome: defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4. 1293 Aug 88

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

Long-term potentiation (LTP) is a long-lasting enhancement of synaptic transmission efficacy and is considered the base for some forms of learning and memory. Nitric oxide (NO)-induced formation of cGMP is involved in hippocampal LTP. We have studied in hippocampal slices the effects of application of a tetanus to induce LTP on cGMP metabolism and the mechanisms by which cGMP modulates LTP. Tetanus application induced a transient rise in cGMP, reaching a maximum at 10s and decreasing below basal levels 5 min after the tetanus, remaining below basal levels after 60 min. Soluble guanylate cyclase (sGC) activity increased 5 min after tetanus and returned to basal levels at 60 min. The decrease in cGMP was due to sustained tetanus-induced increase in cGMP-degrading phosphodiesterase activity, which remained activated 60 min after tetanus. Tetanus-induced activation of PDE and decrease of cGMP were prevented by inhibiting protein kinase G (PKG). This indicates that the initial increase in cGMP activates PKG that phosphorylates (and activates) cGMP-degrading PDE, which, in turn, degrades cGMP. Inhibition of sGC, of PKG or of cGMP-degrading phosphodiesterase impairs LTP, indicating that proper induction of LTP involves transient activation of sGC and increase in cGMP, followed by activation of cGMP-dependent protein kinase, which, in turn, activates cGMP-degrading phosphodiesterase, resulting in long-lasting reduction of cGMP content. Hyperammonemia is the main responsible for the neurological alterations found in liver disease and hepatic encephalopathy, including impaired intellectual function. Hyperammonemia impairs LTP in hippocampus by altering the modulation of this sGC-PKG-cGMP-degrading PDE pathway. Exposure of hippocampal slices to 1 mM ammonia completely prevents tetanus-induced decrease of cGMP by impairing PKG-mediated activation of cGMP-degrading phosphodiesterase. This impairment is responsible for the loss of the maintenance of LTP in hyperammonemia, and may be also involved in the cognitive impairment in patients with hyperammonemia and hepatic encephalopathy.
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PMID:Sequential activation of soluble guanylate cyclase, protein kinase G and cGMP-degrading phosphodiesterase is necessary for proper induction of long-term potentiation in CA1 of hippocampus. Alterations in hyperammonemia. 1531 84

An effective treatment for age-related cognitive deficits remains an unmet medical need. Currently available drugs for the symptomatic treatment of Alzheimer's disease or other dementias have limited efficacy. This may be due to their action at only one of the many neurotransmitter systems involved in the complex mechanisms that underlie cognition. An alternative approach would be to target second messenger systems that are utilized by multiple neurotransmitters. Cyclic adenosine monophosphate (cAMP) is a second messenger that plays a key role in biochemical processes that regulate the cognitive process of memory consolidation. Prolongation of cAMP signals can be accomplished by inhibiting phosphodiesterases (PDEs). Eleven PDE families, comprised of more than 50 distinct members, are currently known. This review summarizes the evidence demonstrating that rolipram, a selective inhibitor of cAMP-selective PDE4 enzymes, has positive effects on learning and memory in animal models. These data provide support for the general approach of second messenger modulation as a potential therapy for cognitive dysfunction, and specifically suggest that PDE4 inhibitors may have utility for improving the symptoms of cognitive decline associated with neurodegenerative and psychiatric diseases.
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PMID:Phosphodiesterase inhibitors for cognitive enhancement. 1625 Aug 39

The nitric oxide/guanylyl cyclase, cyclic guanosine monophosphate/phosphodiesterase 5 (NO/cGMP/PDE5) pathways play a key role in physiological and pathological situations, such as synaptic plasticity, learning and memory formation, diabetic gastropathy and neuropathy, long-term potentiation (LTP), epilepsy, cerebral ischemia, and neurodegenerative diseases. Several studies have demonstrated the alteration of NO-cGMP pathway in cognitive impairment. The present study was aimed to study the effect of sildenafil, a PDE5 inhibitor on diabetes and electroconvulsive shock (ECS)-induced cognitive dysfunction in rat using one-trial step-through type of passive avoidance and elevated plus-maze task. Diabetic and ECS-treated rats showed poor learning performance in step-through passive avoidance and plus-maze task. Acute administration of sildenafil significantly reversed the diabetes and ECS-induced retention deficits in both the test paradigms. Sildenafil also significantly improved the cognitive performance in young rats in both the paradigms. Furthermore, L-NAME, a non-selective NOS inhibitor and methylene blue, a guanylate cyclase inhibitor blocked the effect of sildenafil. The results thus suggest that cognitive impairment might be due to the modulatory effect of nNOS or PDE5 enzyme on cGMP levels. Moreover, sildenafil-induced reversal of cognitive impairment suggests the protective role of PDE5 inhibitors in neurodegenerative disorders.
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PMID:Modulatory effect of sildenafil in diabetes and electroconvulsive shock-induced cognitive dysfunction in rats. 1684 11

The NMDA type of glutamate receptors modulates learning and memory. Excessive activation of NMDA receptors leads to neuronal degeneration and death. Hyperammonemia and liver failure alter the function of NMDA receptors and of some associated signal transduction pathways. The alterations are different in acute and chronic hyperammonemia and liver failure. Acute intoxication with large doses of ammonia (and probably acute liver failure) leads to excessive NMDA receptors activation, which is responsible for ammonia-induced death. In contrast, chronic hyperammonemia induces adaptive responses resulting in impairment of signal transduction associated to NMDA receptors. The function of the glutamate-nitric oxide-cGMP pathway is impaired in brain in vivo in animal models of chronic liver failure or hyperammonemia and in homogenates from brains of patients died in hepatic encephalopathy. The impairment of this pathway leads to reduced cGMP and contributes to impaired cognitive function in hepatic encephalopathy. Learning ability is reduced in animal models of chronic liver failure and hyperammonemia and is restored by pharmacological manipulation of brain cGMP by administering phosphodiesterase inhibitors (zaprinast or sildenafil) or cGMP itself. NMDA receptors are therefore involved both in death induced by acute ammonia toxicity (and likely by acute liver failure) and in cognitive impairment in hepatic encephalopathy.
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PMID:NMDA receptors in hyperammonemia and hepatic encephalopathy. 1770 32

Recent studies have suggested that currently available antipsychotic medications, while useful in treating some aspects of schizophrenia, still possess considerable limitations. Improving the treatment of negative symptoms and cognitive dysfunction, and decreasing adverse effects remain significant challenges. Many new drug strategies have been proposed in recent years and increasing evidence suggests that members of the phosphodiesterase (PDE) gene family may play a role in the aetiology or treatment of schizophrenia. PDEs are key enzymes responsible for the degradation of the second messengers cAMP (3',5'-cyclic adenosine monophosphate) and cGMP (3',5'-cyclic guanosine monophosphate). Mammalian PDEs are composed of 21 genes and are categorized into 11 families based on sequence homology, enzymatic properties and sensitivity to pharmacological inhibitors. Representatives from most families have been identified in the brain by the presence of protein or RNA, and numerous studies suggest that PDEs play an important role in the regulation of intracellular signalling downstream of receptor activation in neurons. Insights into the multiple brain processes to which PDEs contribute are emerging from the phenotype of genetically engineered mice that lack activity of specific PDEs (knockout mice), as well as from in vitro and in vivo studies with PDE inhibitors.This article provides a brief overview of recent studies implicating PDE inhibition, focusing on PDE4 and PDE10, as targets for treating the positive, negative or cognitive symptoms associated with schizophrenia.
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PMID:The role of phosphodiesterases in schizophrenia : therapeutic implications. 1899 37

Patients with liver diseases (e.g. cirrhosis) may present hepatic encephalopathy (HE), an alteration in cerebral function which is a consequence of previous failure of liver function. Patients with minimal or clinical HE present different levels of cognitive impairment. Hyperammonemia is considered a main contributor to the neurological alterations in HE. Animal models of chronic HE (e.g. rats with portacaval shunts) or of "pure" hyperammonemia also show impaired cognitive function. The studies summarized here show that the impairment of some types of cognitive function in chronic HE is due to the impaired function of the glutamate-nitric oxide-cGMP pathway in brain. Both hyperammonemia and neuroinflammation contribute to the impairment of the pathway and of cognitive function. Treatment of rats with chronic HE or hyperammonemia with inhibitors of phosphodiesterase 5 restores the function of the glutamate-nitric oxide-cGMP pathway and cGMP levels in brain as well as the ability to learn a Y maze conditional discrimination task. The same beneficial effects may be obtained by treating the rats chronically with an anti-inflammatory, ibuprofen. As the function of this pathway is also altered in brain of patients died in HE, this alteration would also contribute to cognitive impairment in patients with HE. Increasing cGMP by using inhibitors of phosphodiesterase 5 (PDE-5) or anti-inflammatories (under safe conditions) would be therefore a new therapeutic approach to improve learning and memory performance in individuals with minimal or clinical HE.
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PMID:Mechanisms of cognitive alterations in hyperammonemia and hepatic encephalopathy: therapeutical implications. 1942 13


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