Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

[3H]Spiperone binding sites and the dopamine-sensitive adenylate cyclase were measured in rat substantia nigra (s. nigra) 7 or 14 days after various lesions. Hemisections, which resulted in a 66% decline in tyrosine hydroxylase and cyclic nucleotide phosphodiesterase and a 73% decrease in glutamate decarboxylase, led to a 50% decrease in [3H]spiperone binding and to the almost complete disappearance of the dopamine-sensitive adenylate cyclase from the s. nigra on the lesioned side. 6-Hydroxydopamine injection into the s. nigra, which depleted tyrosine hydroxylase activity within the s. nigra by 85%, while leaving phosphodiesterase unaffected, resulted in a 40% decrease in [3H]spiperone binding but no change in the dopamine-sensitive adenylate cyclase. Intrastriatal injections of kainic acid did not alter tyrosine hydroxylase activity in the s. nigra, but decreased both glutamate decarboxylase (54%) and phosphodiesterase (68%); [3H]spiperone binding was unaffected by this lesion while the dopamine-sensitive adenylate cyclase was greatly reduced (50-75%). These results suggest that within the s. nigra the dopamine receptor binding sites as defined using [3H]spiperone are located on dopamine neurones while the dopamine-sensitive adenylate cyclase is located presynaptically on striatonigral nerve terminals.
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PMID:Dissociation between the presynaptic dopamine-sensitive adenylate cyclase and [3H]spiperone binding sites in rat substantia nigra. 3 4

Four inhibitors of cyclic AMP phosphodiesterase (PDE), rolipram, Ro 20-1724, ICI 63,197 and CP 76,593, reduced response rates and increased reinforcement rates of rats under a differential reinforcement of low rate 72-sec schedule for water reinforcement in a dose-dependent manner. These actions of the PDE inhibitors are similar to those reported for proven antidepressant drugs. Administration of forskolin, which increases cyclic AMP levels by activation of the catalytic subunit of adenylyl cyclase, either i.p. or i.c.v. did not mimic the effects of the PDE inhibitors. The behavioral effects of the PDE inhibitors were not antagonized by the beta adrenergic antagonist propranolol, suggesting that these drugs were not altering behavior via an increase in norepinephrine release and an indirect stimulation of beta adrenergic receptors. 6-Hydroxydopamine-induced lesions of noradrenergic neurons increased sensitivity to rolipram. This suggests that alterations in PDE activity with a concomitant increase in sensitivity to PDE inhibitors may occur subsequent to functional denervation.
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PMID:Antidepressant-like effects of rolipram and other inhibitors of cyclic adenosine monophosphate phosphodiesterase on behavior maintained by differential reinforcement of low response rate. 838 40

1. The present study investigates whether chemical sympathectomy compromises the relaxation of the rabbit femoral artery precontracted with serotonin. The vasodilating agents promoted cyclic adenosine monophosphate (cAMP) accumulation or opening of the potassium channels. The effect of denervation on the adenylyl cyclase transduction pathway was also studied. 2. 6-Hydroxydopamine treatment did not impair the relaxation to adenosine, 8-bromoadenosine-cAMP (a membrane-permeable analog of cAMP) and 3-isobutyl-1-methylxanthine (a cAMP phosphodiesterase inhibitor). Moreover, denervation enhanced the relaxation to forskolin (a direct Gs-type protein activator) and pinacidil (a potassium channel opener). 3. Denervation modified neither adenosine diphosphate ribosylation of Gs- and Gi-proteins nor adenylyl cyclase activity.
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PMID:Denervation-induced supersensitivity to forskolin and pinacidil is not related to changes in the adenylate cyclase transduction pathway in the rabbit femoral artery. 937 48

The effects of antidepressant treatment on the high- and low-affinity rolipram binding sites on type 4 phosphodiesterase (PDE4) were determined; previous work had shown that repeated antidepressant treatment increases the overall expression of PDE4. Rats were administered different doses of the antidepressant drugs desipramine or fluoxetine, or saline, for 1, 7, or 14 days. [3H]Rolipram and [3H]piclamilast were used to assess the high-affinity rolipram binding sites (HARBS) and low-affinity rolipram binding sites (LARBS) on PDE4 in the hippocampus and cerebral cortex. Repeated, but not acute, treatment with the antidepressants increased [3H]rolipram binding to membrane fractions in a dose-dependent manner; the HARBS component of [3H]piclamilast binding also was increased by these treatments. By contrast, the LARBS component of [3H]piclamilast binding was not altered. [3H]Rolipram and [3H]piclamilast binding to the cytosolic fractions of rat cerebral cortex and hippocampus was not altered by the antidepressant treatments. 6-Hydroxydopamine (6-OHDA; 300 microg i.c.v.) and 5,7-dihydroxytryptamine (5,7-DHT; 200 microg i.c.v.) were used to lesion noradrenergic and serotonergic neurons, respectively. The effects of desipramine, but not fluoxetine, on [3H]rolipram and [3H]piclamilast binding to rat hippocampal membranes were blocked by the 6-OHDA-induced lesion. By contrast, the effects of fluoxetine, but not desipramine, were reduced by the 5,7-DHT-induced lesion. This indicates that the up-regulation of the HARBS by desipramine and fluoxetine requires the integrity of noradrenergic and serotonergic neurons, respectively. Collectively, these results suggest that antidepressants, although acting through different pathways, may eventually lead to the regulation of components of the cAMP signal transduction system.
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PMID:Antidepressant-induced increase in high-affinity rolipram binding sites in rat brain: dependence on noradrenergic and serotonergic function. 1295 19

Sildenafil, a phosphodiesterase-5 inhibitor is widely used for the treatment of erectile dysfunction. Recently, the FDA approved the use of sildenafil in the therapeutic treatment of pulmonary arterial hypertension. Sildenafil crosses the blood-brain barrier and has been shown to enhance memory. Tremor, rigidity and akinesia are the most common symptoms seen in Parkinson's disease. Fatigue and sexual dysfunction are the other prominent features seen in Parkinson's disease. Interestingly, sildenafil is used therapeutically to treat sexual dysfunction in Parkinson's disease patients. Currently research on Parkinson's disease focuses on developing novel drug therapies for retarding the nigral dopaminergic neurodegeneration. Hence, we investigated the anti-fatigue and neuroprotective effects of sildenafil. In this study, the effect of sildenafil on fatigue was evaluated using forced swim test in mice. Sildenafil had no effect on fatigue as seen by the swim time. With regard to neuroprotective effects, we investigated the effects of sildenafil using two animal models of Parkinson's disease. In this study, 6-hydroxydopamine-lesioned (unilateral) rats and MPTP-treated mice were used as the animal models of Parkinson's disease. 6-Hydroxydopamine-lesioned rats were used to determine the effect of sildenafil on rotational behavior. Ipsilateral or contralateral rotational behavior can indicate the amphetamine-like activity or apomorphine-like activity of sildenafil. Sildenafil did not induce contralateral or ipsilateral rotations in 6-hydroxydopamine-lesioned rats. Sildenafil did not protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine depletion in the striatum.
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PMID:Evaluation of neuroprotective and anti-fatigue effects of sildenafil. 1782 48