Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the alteration of oligodendrocytes in comparison with that of astrocytes and microglia in the mouse striatum after MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropridine) treatment under the same conditions using Western blot analysis and Immunohistochemistry. In our Western blot analysis, four administrations of MPTP at 2-h intervals to mice produced the remarkable loss of TH (tyrosine hydroxylase) protein levels in the striatum after 3 and 7 days. In contrast, GFAP (glial fibrillary acidic protein) and Iba-1 protein in the striatum showed a significant increase of GFAP and Iba-1 protein levels 3 and 7 days after MPTP treatment. On the other hand, the levels of CNPase (2', 3'-cyclic nucleotide 3'-phosphodiesterase) protein were decreased significantly in the striatum 3 and 7 days after MPTP treatment. In our immunohistochemical study, a significant decrease in the area of expression of CNPase-positive profiles was observed in the striatum 3 and 7 days after MPTP treatment. These results demonstrate that oligodendrocytes in the striatum are damaged after MPTP treatment. Thus our present findings provide valuable information for the pathogenesis of Parkinson's disease.
 ...
PMID:Damage to oligodendrocytes in the striatum after MPTP neurotoxicity in mice. 1767 28

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.
 ...
PMID:Evaluation of neuroprotective and anti-fatigue effects of sildenafil. 1782 48

Rolipram, a specific inhibitor of the phosphodiesterase IV (PDE IV), has recently been shown to exert neuroprotective effects in an Alzheimer transgenic mouse model and in hypoxic-ischemic damage in the rat brain. It activates the cAMP-dependent protein kinase (PKA)/cAMP regulatory element-binding protein (CREB) signaling pathway and it inhibits inflammation. We tested the neuroprotective effects of the specific PDE IV inhibitor rolipram in C57BL/6 mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We found that rolipram administered at 1.25 mg/kg or 2.5 mg/kg doses significantly attenuated MPTP-induced dopamine depletion in the striatum, and reduced the loss of tyrosine hydroxylase-positive neurons in the substantia nigra. There was a bell-shaped dose effect with greater efficacy at the 1.25 mg/kg dose than 2.5 mg/kg and a higher dose of rolipram, 5 mg/kg, had no protective effect and even increased the mortality of animals when co-administered with MPTP. Rolipram did not interact with MPTP in its absorption into the brain and in its metabolism to 1-methyl-4-phenylpyridinium (MPP(+)). Our data show a neuroprotective effect of the PDE IV specific inhibitor rolipram against dopaminergic neuron degeneration, suggesting that PDE IV inhibitors might be a potential treatment for Parkinson's disease.
 ...
PMID:Attenuation of MPTP neurotoxicity by rolipram, a specific inhibitor of phosphodiesterase IV. 1832 79

The cyclic nucleotide phosphodiesterases (PDEs) are intracellular enzymes that catalyze the hydrolysis of 3,'5'-cyclic nucleotides, such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), to their corresponding 5'nucleotide monophosphates. These enzymes play an important role in controlling cellular concentrations of cyclic nucleotides and thus regulate a variety of cellular signaling events. PDEs are emerging as drug targets for several diseases, including asthma, cardiovascular disease, attention-deficit hyperactivity disorder, Parkinson's disease, and Alzheimer's disease. Although biochemical assays with purified recombinant PDE enzymes and cAMP or cGMP substrate are commonly used for compound screening, cell-based assays would provide a better assessment of compound activity in a more physiological context. The authors report the development and validation of a new cell-based PDE4 assay using a constitutively active G-protein-coupled receptor as a driving force for cAMP production and a cyclic nucleotide-gated cation channel as a biosensor in 1536-well plates.
 ...
PMID:A cell-based PDE4 assay in 1536-well plate format for high-throughput screening. 1859 13

Dysregulation of dopamine receptors is thought to underlie levodopa-induced dyskinesias in experimental models of Parkinson's disease. It is unknown whether an imbalance of the second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), is involved in the alterations of levodopa/dopamine signal transduction. We examined cAMP and cGMP signalling in the interconnected cortico-striatal-pallidal loop at the peak of levodopa-induced dyskinesias in rats with 6-hydroxydopamine lesions in the substantia nigra. In addition, we examined the role of phosphodiesterase (PDE) and the rate of cAMP and cGMP degradation on the severity of levodopa-induced dyskinesias in animals pretreated with PDE inhibitor, zaprinast. Unilateral lesion of substantia nigra led to an increase in cAMP but a decrease in cGMP levels in the ipsilateral basal ganglia. After chronic levodopa treatment, cAMP and cGMP were differentially regulated in eukinetic animals: the cAMP level increased in the cortex and striatum but decreased in the globus pallidus of both hemispheres, whereas the cGMP decreased below baseline levels in the contralateral cortico-striatal-pallidal regions. In dyskinetic animals chronic levodopa treatment led to an absolute decrease in cAMP and cGMP levels in cortico-striatal-pallidal regions of both hemispheres. Pretreatment with zaprinast reduced the severity of levodopa-induced dyskinesias, and partly prevented the decrease in cyclic nucleotides compared with pretreatment with saline-levodopa. In conclusion, using a rat model of hemiparkinsonism, we observed a significant reduction in the levels of cyclic nucleotides in both hemispheres at the peak of levodopa-induced dyskinesias. We propose that such a decrease in cyclic nucleotides may partly result from increased catabolism through PDE overactivity.
 ...
PMID:Lowered cAMP and cGMP signalling in the brain during levodopa-induced dyskinesias in hemiparkinsonian rats: new aspects in the pathogenetic mechanisms. 1871 35

The objective of this study was to determine if the phosphodiesterase 5 (PDE-5) inhibitor, sildenafil, could be used as a neuroprotective agent in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of Parkinson's disease. The underlying hypothesis of these studies is that blockade of PDE-5 catabolism of cGMP will attenuate the loss of nigrostriatal dopamine (NSDA) neurons following chronic neurotoxin exposure. Chronic MPTP-treated mice were administered sildenafil using three different regimens. Animals were: 1) treated with sildenafil and then exposed to chronic MPTP; 2) treated concurrently with sildenafil and MPTP; and 3) first exposed to MPTP and subsequently treated with sildenafil. End points of neurotoxicity included dopamine (DA) and tyrosine hydroxylase (TH) concentrations in NSDA axon terminals in the striatum, and stereological cell counts of TH immunoreactive neurons in the substantia nigra. Results reveal that sildenafil did not prevent neurotoxicity produced by chronic MPTP exposure regardless of the treatment paradigms employed. On the other hand, sildenafil did not produce any deleterious effect on NSDA neuron function nor did it potentiate the neurotoxic effects of MPTP. These results suggest that sildenafil would not accelerate DA cell loss when used as a treatment for erectile dysfunction in men diagnosed with Parkinson's disease.
 ...
PMID:Effects of sildenafil on nigrostriatal dopamine neurons in a murine model of Parkinson's disease. 1878 Sep 70

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.
 ...
PMID:Role of sildenafil in neurological disorders. 1905 Apr 13

Vasoactive neuropeptides (VNs) such as pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) have critical roles as neurotransmitters, vasodilators including perfusion and hypoxia regulators, as well as immune and nociception modulators. They have key roles in blood vessels in the central nervous system (CNS) including maintaining functional integrity of the blood brain barrier (BBB) and blood spinal barrier (BSB). VNs are potent activators of adenylate cyclase and thus also have a key role in cyclic AMP production affecting regulatory T cell and other immune functions. Virchow-Robin spaces (VRSs) are perivascular compartments surrounding small vessels within the CNS and contain VNs. Autoimmunity of VNs or VN receptors may affect BBB and VRS function and, therefore, may contribute to the aetiology of neurological-related conditions including multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. VN autoimmunity will likely affect CNS and immunological homeostasis. Various pharmacological and immunological treatments including phosphodiesterase inhibitors and plasmapheresis may be indicated.
 ...
PMID:Postulated role of vasoactive neuropeptide-related immunopathology of the blood brain barrier and Virchow-Robin spaces in the aetiology of neurological-related conditions. 1922 45

The increasing life expectancy in our population makes Parkinson's disease (PD) a growing public health problem. There is a great need to find a way to prevent and delay the disease. It was shown that selective phosphodiesterase 1 (PDE1) inhibitors and anti-inflammatory agents might be effective in treating PD. Therefore, a novel 1,2,9,11-tetrasubstituted-7H-thieno[2',3':4,5]pyrimido[6,1-b]-quinazolin-7-one (1-15) and 1,3,10,12-tetrasubstituted-8H-pyrido[2',3':4,5]pyrimido[6,1-b]quinazolin-8-one (16-36) derivatives were synthesized by reported method and investigated for their ability to inhibit PDE1. Most of the synthesized compounds have shown good activity against PDE1 and were less effective than 3-isobutyl-1-methylxanthine. All the compounds were also tested for their in vitro anti-inflammatory activity by carrageenan-induced oedema in rats. In addition, ulcerogenic activity was determined. The combined anti-inflammatory data from in vitro animal model showed that compounds, 9,11-dibromo-1-(2-furyl)-3-(4-tolyl)-8H-pyrido[2',3':4,5]pyrimido[6,1-b]quinazolin-8-one 23, 9,11-dibromo-1-(4-methoxy-phenyl)-3-phenyl-8H-pyrido[2',3':4,5]pyrimido[6,1-b]quinazolin-8-one 24, 9,11-dibromo-1-(4-chloro-phenyl)-3-(4-tolyl)-8H-pyrido[2',3':4,5]pyrimido[6,1-b]quinazolin-8-one 29 and 9-bromo-1-(4-chloro-phenyl)-3-(4-tolyl)-8H-pyrido[2',3':4,5]pyrimido[6,1-b]quinazolin-8-one 36 exhibited even more potent anti-inflammatory activity and low gastric ulceration incidence compare to reference standard Indomethacin. Since compound 23, 24, 29 and 36 exhibits both anti-inflammatory activity and PDE1 inhibition, it needs further detailed studies.
 ...
PMID:A new therapeutic approach in Parkinson's disease: some novel quinazoline derivatives as dual selective phosphodiesterase 1 inhibitors and anti-inflammatory agents. 1974 61

Non-motor symptoms are increasingly recognized to adversely impact on the quality of life of patients with in Parkinson's disease (PD), particularly as the disease progresses. Autonomic symptom severity in patients with PD seems to correlate with older age, greater disease severity, psychiatric complications, sleep disorders, and higher doses of dopaminergic medication. The following therapeutic strategies are frequently used in the treatment of PD-related dysautonomia: 1. Orthostatic hypotension: fludrocortisone, midodrine, and droxidopa; 2. Sialorrhea: glycopyrrolate and botulinun toxin injections; 3. Constipation: symbiotic yogurt and bulking agents, macrogol, lubiprostone, mosapride citrate and tegaserod, pyridostigmine bromide, botulinum toxin injections and sacral nerve stimulation; 4. Urinary frequency: oxybutynin, tolterodine, solifenacin, darifenacin, botulinum toxin injections; 5. Erectile dysfunction: sildenafil and other phosphodiesterase type 5 inhibitors. More effective symptomatic and pathogenesis-targeted therapies are needed to ameliorate the non-motor symptoms of PD that usually do not respond well to dopaminergic medications.
 ...
PMID:Treatment of dysautonomia associated with Parkinson's disease. 2008 97


<< Previous 1 2 3 4 5 6 Next >>