cyclic-gmp and Parkinson-Disease

Neurodegenerative illness develops as a result of genetic defects that cause changes at numerous levels, including genomic products and biological processes. It entails the degradation of cyclic nucleotides, cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP). PDE7 modulates intracellular cAMP signalling, which is involved in numerous essential physiological and pathological processes. For the therapy of neurodegenerative illnesses, the normalization of cyclic nucleotide signalling through PDE inhibition remains intriguing. In this article, we shall examine the role of PDEs in neurodegenerative diseases. Alzheimer's disease, Multiple sclerosis, Huntington's disease, Parkinson's disease, Stroke, and Epilepsy are related to alterations in PDE7 expression in the brain. Earlier, animal models of neurological illnesses including Alzheimer's disease, Parkinson's disease, and multiple sclerosis have had significant results to PDE7 inhibitors, i.e., VP3.15; VP1.14. In addition, modulation of CAMP/CREB/GSK/PKA signalling pathways involving PDE7 in neurodegenerative diseases has been addressed. To understand the etiology, treatment options of these disorders mediated by PDE7 and its subtypes can be the focus of future research.

Topics: Alzheimer Disease; Animals; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 7; Multiple Sclerosis; Neurodegenerative Diseases; Parkinson Disease

Cyclic nucleotide phosphodiesterase (PDE) enzymes catalyze the hydrolysis and inactivation of the cyclic nucleotides cyclic adenosine monophosphate and cyclic guanosine monophosphate, which act as intracellular second messengers for many signal transduction pathways in the central nervous system. Several classes of PDE enzymes with specific tissue distributions and cyclic nucleotide selectivity are highly expressed in brain regions involved in cognitive and motor functions, which are known to be implicated in neurodegenerative diseases, such as Parkinson's disease and Huntington's disease. The indication that PDEs are intimately involved in the pathophysiology of different movement disorders further stems from recent discoveries that mutations in genes encoding different PDEs, including PDE2A, PDE8B, and PDE10A, are responsible for rare forms of monogenic parkinsonism and chorea. We here aim to provide a translational overview of the preclinical and clinical data on PDEs, the role of which is emerging in the field of movement disorders, offering a novel venue for a better understanding of their pathophysiology. Modulating cyclic nucleotide signaling, by either acting on their synthesis or on their degradation, represents a promising area for development of novel therapeutic approaches. The study of PDE mutations linked to monogenic movement disorders offers the opportunity of better understanding the role of PDEs in disease pathogenesis, a necessary step to successfully benefit the treatment of both hyperkinetic and hypokinetic movement disorders. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 2; Humans; Parkinson Disease; Phosphoric Diester Hydrolases

Cyclic nucleotide phosphodiesterase (PDE) enzymes catalyze the hydrolysis and inactivation of cyclic nucleotides (cAMP/cGMP) in the brain. Several classes of PDE enzymes with distinct tissue distributions, cyclic nucleotide selectivity, and regulatory factors are highly expressed in brain regions subserving cognitive and motor processes known to be disrupted in neurodegenerative diseases such as Parkinson's disease (PD). Furthermore, small-molecule inhibitors of several different PDE family members alter cyclic nucleotide levels and favorably enhance motor performance and cognition in animal disease models. This chapter will explore the roles and therapeutic potential of non-selective and selective PDE inhibitors on neural processing in fronto-striatal circuits in normal animals and models of DOPA-induced dyskinesias (LIDs) associated with PD. The impact of selective PDE inhibitors and augmentation of cAMP and cGMP signaling on the membrane excitability of striatal medium-sized spiny projection neurons (MSNs) will be discussed. The effects of cyclic nucleotide signaling and PDE inhibitors on synaptic plasticity of striatonigral and striatopallidal MSNs will be also be reviewed. New data on the efficacy of PDE10A inhibitors for reversing behavioral and electrophysiological correlates of L-DOPA-induced dyskinesias in a rat model of PD will also be presented. Together, these data will highlight the potential of novel PDE inhibitors for treatment of movement disorders such as PD which are associated with abnormal corticostriatal transmission.

Topics: Animals; Brain; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Globus Pallidus; Humans; Neostriatum; Neurons; Parkinson Disease; Phosphodiesterase Inhibitors; Substantia Nigra

Ergotamine and dihydroergotamine show a higher blocking effect towards the dopamine-induced stimulation of adenylate cyclase activity than to the apomorphine-induced stimulation. This could reflect a possible specificity of the compound to dopaminergic receptor. Bromocriptine blocks in a more competitive way the activation of adenylate cyclase induced in vitro by dopamine, but increases the levels of cAMP in rat striatum in vivo. This effect is blocked by haloperidol and reserpine when given together with bromocriptine. On the base of the biochemical observation and various behavioral data the drug has been used in the treatment of parkinsonism with contrasting results and of Huntington's chorea. Moreover, bromocriptine induces a marked decrease of cGMP levels in cerebellum such as haloperidol and chloropromazine while apomorphine and other dopaminergic drugs increase the levels of cGMP. At the dose of 1 mg/kg, bromocriptine as well as DH-ergotoxine markedly reduces the levels of striatal DOPAC.

Topics: Adenylyl Cyclases; Animals; Brain; Cattle; Corpus Striatum; Cyclic AMP; Cyclic GMP; Ergot Alkaloids; Humans; Huntington Disease; Nucleotides, Cyclic; Parkinson Disease; Rats; Receptors, Dopamine

To understand the events underlying the clinical efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN), electrophysiological recordings and microdialysis evaluations were carried out in the substantia nigra pars reticulata (SNr), one of the two basal ganglia (BG) nuclei targeted by STN output, in patients with Parkinson's disease (PD). Clinically effective STN-DBS caused a significant increase of the SNr firing rate. The poststimulus histogram (PSTH) showed an excitation peak at 1.92-3.85 ms after the STN stimulus. The spontaneous discharge of SNr neurons was driven at the frequency of the stimulation (130 Hz), as shown in the autocorrelograms (AutoCrl). The fast Fourier transform (FFT) analysis showed a peak at 130 Hz, and a less pronounced second one at 260 Hz. Accordingly, in the distribution of the interspike intervals (ISIs), the mode was earlier, and skewness more asymmetric. Biochemically, the increased excitatory driving from the STN was reflected by a clear-cut increase in cyclic guanosine 3',5'-monophosphate (cGMP) levels in the SNr. These results indicate that the beneficial effect of DBS in PD patients is paralleled with a stimulus-synchronized activation of the STN target, SNr. Our findings suggest that, during STN-DBS, a critical change towards a high-frequency oscillatory discharge occurs.

Topics: Action Potentials; Aged; Analysis of Variance; Brain Chemistry; Cyclic GMP; Deep Brain Stimulation; Female; Fourier Analysis; Humans; Male; Microdialysis; Middle Aged; Parkinson Disease; Substantia Nigra; Subthalamic Nucleus; Time Factors

Parkinson's disease patients benefit from deep brain stimulation (DBS) in subthalamic nucleus (STN), but the basis for this effect is still disputed. In this intraoperative microdialysis study, we found elevated cGMP extracellular concentrations in the internal segment of the globus pallidus, despite negligible changes in glutamate levels, during a clinically effective STN-DBS. This supports the view that a clinically beneficial effect of STN-DBS is paralleled by an augmentation (and not an inactivation) of the STN output onto the GPi.

Topics: Aged; Analysis of Variance; Case-Control Studies; Cyclic GMP; Deep Brain Stimulation; Dialysis; Female; Globus Pallidus; Humans; Male; Middle Aged; Parkinson Disease; Subthalamic Nucleus

Peptides are currently the most promising lead molecules. Quorum sensing peptides have a variety of structural features and are regularly exposed to post-translational modifications. Antiparkinsonian drugs lose their efficacy after a long period of use, and patients develop motor problems such as drug-induced dyskinesia (DIDs). The interaction between PDE10A and cAMP is necessary for dopamine neurotransmission and may play a role in Parkinson's disease pathogenesis. cAMP and cGMP are cyclic nucleotides that act as secondary messengers in the signal transduction pathway, influencing a range of CNS activities. PDE enzymes hydrolyze phosphodiester bonds to break down cAMP and cGMP, allowing them to control intracellular levels of these second messengers effectively. PDE expression, and hence cyclic nucleotide levels and their downstream targets, may change with age and in numerous age-related illnesses, including Parkinson's disease, according to mounting evidence. At the peak of dyskinesias, cyclic nucleotide levels were lower, and using phosphodiesterase inhibitors before antiparkinsonian medicines reduced the severity of dyskinesias. In a recent study, PapRIV was found to have the ability to activate BV-2 microglia cells, indicating that this quorum sensing peptide may play a role in gut-brain contact. As a result of the current in silico work, mainly focused on QSPs as a lead molecule for inhibiting PDE10A, the SRNAT QSP sequence has been a potent molecule in molecular docking and molecular dynamics simulations. Furthermore, we can test the efficiency of therapeutic components in vitro and in vivo utilizing this computational approach against PDE10A.

Topics: Cyclic GMP; Dyskinesias; Humans; Molecular Docking Simulation; Parkinson Disease; Peptides; Phosphoric Diester Hydrolases; Quorum Sensing

The cyclic nucleotides cyclic adenosine-3',5'-monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) are important second messengers and are potential biomarkers for Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Creutzfeldt-Jakob disease (CJD).. Here, we investigated by liquid chromatography/tandem mass spectrometry (LC-MS/MS) the cerebrospinal fluid (CSF) concentrations of cAMP and cGMP of 82 patients and evaluated their diagnostic potency as biomarkers. For comparison with a well-accepted biomarker, we measured tau concentrations in CSF of CJD and control patients. CJD patients (n = 15) had lower cAMP (-70%) and cGMP (-55%) concentrations in CSF compared with controls (n = 11). There was no difference in PD, PD dementia (PDD) and ALS cases. Receiver operating characteristic (ROC) curve analyses confirmed cAMP and cGMP as valuable diagnostic markers for CJD indicated by the area under the curve (AUC) of 0.86 (cAMP) and 0.85 (cGMP). We calculated a sensitivity of 100% and specificity of 64% for cAMP and a sensitivity of 67% and specificity of 100% for cGMP. The combination of both nucleotides increased the sensitivity to 80% and specificity to 91% for the term cAMPxcGMP (AUC 0.92) and to 93% and 100% for the ratio tau/cAMP (AUC 0.99).. We conclude that the CSF determination of cAMP and cGMP may easily be included in the diagnosis of CJD and could be helpful in monitoring disease progression as well as in therapy control.

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Area Under Curve; Biomarkers; Brain; Creutzfeldt-Jakob Syndrome; Cyclic AMP; Cyclic GMP; Female; Humans; Male; Middle Aged; Parkinson Disease; Predictive Value of Tests; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization; tau Proteins

At odd with traditional views, effective sub-thalamic nucleus (STN) deep brain stimulation (DBS), in Parkinson's disease (PD) patients, may increase the discharge rate of the substantia nigra pars reticulata and the internal globus pallidus (GPi), in combination with increased cyclic guanosine monophosphate (cGMP) levels. How these changes affect the basal ganglia (BG) output to the motor thalamus, the crucial structure conveying motor information to cortex, is critical. Here, we determined the extracellular GABA concentration in the ventral anterior nucleus (VA) during the first delivery of STN-DBS (n=10) or following levodopa (LD) (n=8). Both DBS and subdyskinetic LD reversibly reduced (-30%) VA GABA levels. A significant correlation occurred between clinical score and GABA concentration. By contrast, only STN-DBS increased GPi cGMP levels. Hence, STN-ON and MED-ON involve partially different action mechanisms but share a common target in the VA. These findings suggest that the standard BG circuitry, in PD, needs revision as relief from akinesia may take place, during DBS, even in absence of reduced GPi excitability. However, clinical amelioration requires fast change of thalamic GABA, confirming, in line with the old model, that VA is the core player in determining thalamo-cortical transmission.

Topics: Aged; Antiparkinson Agents; Cyclic GMP; Deep Brain Stimulation; gamma-Aminobutyric Acid; Humans; Levodopa; Middle Aged; Parkinson Disease; Statistics, Nonparametric; Subthalamic Nucleus; Thalamus

We have previously found that average serum cGMP level in unselected patients with Parkinson's disease (PD), particularly in patients treated with a combination of l-DOPA and the dopamine agonist pergolide mesylate, is markedly higher than that in healthy controls. Here we compared serum cGMP and total testosterone levels between l-DOPA/pergolide mesylate-treated male idiopathic PD patients without and with cardiovascular disease (iPD, n = 10, and iPD-CVD, n = 10, respectively) and age-matched healthy volunteers (n = 10). There was no difference in PD-related disability between the two patient groups as assessed by UPDRS motor score and Hoehn-Yahr staging. Whereas none of the patients showed hypoandrogenemia, PD patients compared to controls revealed significantly lower serum testosterone levels, and iPD-CVD patients showed significantly lower levels than iPD patients. Serum cGMP levels were but moderately while significantly higher in the two groups of PD patients than in the controls, and were the highest in the iPD-CVD group. For all study groups combined, there was a high negative correlation between total testosterone level and cGMP level. Our data indicate that blood total testosterone level is negatively correlated with general health status in PD patients, whereas the reverse is true for blood cGMP level.

Topics: Aged; Cardiovascular Diseases; Cyclic GMP; Humans; Male; Middle Aged; Parkinson Disease; Pilot Projects; Testosterone

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) patients augments STN-driven excitation of the internal globus pallidus (GPi). However, other DBS-induced changes are largely unknown. Here we report the biochemical effects of STN-DBS in two basal ganglia stations (putamen--PUT--and GPi) and in a thalamic relay nucleus, the anteroventral thalamus (VA). In six advanced PD patients undergoing surgery, microdialysis samples were collected from GPi, PUT and VA before, during and after one hour of STN-DBS. cGMP was measured in the GPi and PUT as an index of glutamatergic transmission, whereas GABA was measured in the VA. During clinically effective STN-DBS, we found a significant decrease in GABA extracellular concentrations in the VA (-25%). Simultaneously, cGMP extracellular concentrations were enhanced in the PUT (+200%) and GPi (+481%). DBS differentially affects fibers crossing the STN area: it activates the STN-GPi pathway while inhibiting the GPi-VA one. These findings support a thalamic dis-inhibition, as the main responsible for the clinical effect of STN-DBS. This, in turn, re-establishes a more physiological level of PUT activity.

Topics: Aged; Biomarkers; Cyclic GMP; Deep Brain Stimulation; Extracellular Space; Female; gamma-Aminobutyric Acid; Globus Pallidus; Humans; Male; Microdialysis; Middle Aged; Parkinson Disease; Thalamus

The aim of our study was to investigate the expression and the activity of soluble guanylyl cyclase (GC) and phosphodiesterase (PDE) activities that regulate cGMP level in the striatum, hippocampus, and brain cortex in an animal model of PD, induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We observed the increase of total activity and protein level of GC in striatum after MPTP injection. It was accompanied by an enhancement of both mRNA expression and protein level of GCbeta1 subunit. MPTP induces mRNA expression and elevates protein concentration of GCbeta1 in striatum up to 14 days after its injection, which in turn causes a marked enhancement of cGMP formation. Furthermore, the activation of GC occurs through change of maximal enzyme activity (V(max)). Simultaneously, no change in PDE activity has been detected in all investigated regions of the brain after MPTP. MPTP injection caused the elevation of GCbeta1 protein level in both the membrane and cytosol fractions being significantly higher in cytosol. Western blot analysis demonstrated about 45-67% decrease of tyrosine hydroxylase protein content in striatum. These data suggest that NO/cGMP signaling pathway may at least partially contribute to dopaminergic fiber degeneration in the striatum, the damage attributed to PD.

Topics: 1-Methyl-3-isobutylxanthine; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Corpus Striatum; Cyclic GMP; Dopamine Agents; Guanylate Cyclase; Mice; MPTP Poisoning; Nitric Oxide; Parkinson Disease; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Protein Subunits; Signal Transduction; Tyrosine 3-Monooxygenase; Up-Regulation

We measured CSF and plasma levels of cGMP in 22 patients with Parkinson's disease (PD) and in 28 age and sex-matched controls. PD patients had similar plasma cGMP levels than those of controls, although they showed a non-significant trend towards higher CSF cGMP levels (P=0.07). PD patients treated with levodopa showed significantly higher CSF cGMP levels than those not treated with this drug (P<0.01), and controls (P<0.01). However, treatment with dopamine agonists did not influence CSF cGMP levels. Plasma and CSF levels of cGMP did not correlate with age at onset, duration, and severity of PD. These results suggest that changes in the concentration of cGMP in CSF of patients with PD are not related with the disease, but rather with levodopa therapy.

Topics: Aged; Cyclic GMP; Dopamine Agonists; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Selegiline

To investigate whether nitric oxide (NO) plays a role in degenerative neurologic disease (DND), we measured nitrite, nitrate and cyclic GMP in cerebrospinal fluid (CSF) samples from patients with Parkinson's disease (PD), spinocerebellar ataxia (SCA) and amyotrophic lateral sclerosis (ALS). We found no significant change in CSF nitrite, nitrate or cyclic GMP in patients with any DND compared with control values. These results suggest that NO production is preserved in PD, SCA and ALS.

Topics: Aged; Amyotrophic Lateral Sclerosis; Biomarkers; Cyclic GMP; Female; Humans; Male; Middle Aged; Nerve Degeneration; Nervous System Diseases; Nitrates; Nitric Oxide; Nitrites; Parkinson Disease; Spinocerebellar Degenerations

Concentrations of cyclic nucleotides--adenosine-3',5'-monophosphate (c-AMP) and guanosine-3',5'-monophosphate (c-GMP)--were measured in cerebrospinal fluid (CSF) of 17 drug-free Parkinson patients and 12 controls. No significant difference between the cyclic nucleotide contents (p greater than 0.05) in CSF of patients and controls was detected, nor was there a correlation between the content and the degree of neurological disability. Besides, no changes in the cyclic nucleotide contents were detected in the subgroups of patients according to the prominence of tremor or rigidity/akinesia as the main symptoms of the disease.

Topics: Cyclic AMP; Cyclic GMP; Female; Humans; Male; Middle Aged; Movement Disorders; Muscle Rigidity; Parkinson Disease; Tremor

Concentrations of cyclic adenosine 3',5' monophosphate (cAMP) were significantly lower in parkinsonian patients than in controls, but concentrations of guanosine 3',5' monophosphate (cGMP) were not altered. Both cAMP and cGMP levels were lower in patients with more severe symptoms on the left side of the body. Somatostatin-like immunoreactivity (SLI) was similar in parkinsonian patients and controls. Both cAMP and SLI were significantly related to acetylcholinesterase activity.

Topics: Acetylcholinesterase; Aged; Cyclic AMP; Cyclic GMP; Homovanillic Acid; Humans; Male; Middle Aged; Parkinson Disease; Radioimmunoassay; Somatostatin

Human CSF cyclic AMP and cyclic GMP have been measured as possible indicators of activity of central neurotransmitter-sensitive adenylate or guanylate cyclase. In an attempt to help to identify the specific neurotransmitter systems of origin of human CSF cyclic AMP and GMP, we studied Parkinson patients with and without L-dopa therapy and schizophrenic patients before and after propranolol therapy. No effect of L-dopa or propranolol was found on CSF cyclic nucleotides. However, Parkinson patients had a 40-50% reduction of CSF cyclic AMP and a 80-90% reduction of CSF cyclic GMP compared with the schizophrenic patients. Implications of this finding are discussed.

Topics: Adult; Aged; Cyclic AMP; Cyclic GMP; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Propranolol; Schizophrenia

Topics: Adult; Animals; Brain; Chromatography, Ion Exchange; Cyclic AMP; Cyclic GMP; Glioblastoma; Humans; Hydrogen-Ion Concentration; Kinetics; Magnesium; Male; Methods; Middle Aged; Parkinson Disease; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Rabbits; Rats; Resins, Plant; Snakes; Temperature; Theophylline; Time Factors; Tritium; Venoms