cyclic-gmp and Multiple-Sclerosis

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

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) characterized by heterogeneous clinical symptoms including gradual muscle weakness, fatigue, and cognitive impairment. The disease course of MS can be classified into a relapsing-remitting (RR) phase defined by periods of neurological disabilities, and a progressive phase where neurological decline is persistent. Pathologically, MS is defined by a destructive immunological and neuro-degenerative interplay. Current treatments largely target the inflammatory processes and slow disease progression at best. Therefore, there is an urgent need to develop next-generation therapeutic strategies that target both neuroinflammatory and degenerative processes. It has been shown that elevating second messengers (cAMP and cGMP) is important for controlling inflammatory damage and inducing CNS repair. Phosphodiesterases (PDEs) have been studied extensively in a wide range of disorders as they breakdown these second messengers, rendering them crucial regulators. In this review, we provide an overview of the role of PDE inhibition in limiting pathological inflammation and stimulating regenerative processes in MS.

Topics: Cyclic AMP; Cyclic GMP; Humans; Multiple Sclerosis; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Second Messenger Systems

During multiple sclerosis (MS), a close link has been demonstrated to occur between inflammation and neuro-axonal degeneration, leading to the hypothesis that immune mechanisms may promote neurodegeneration, leading to irreversible disease progression. Energy deficits and inflammation-driven mitochondrial dysfunction seem to be involved in this process. In this work we investigated, by the use of striatal electrophysiological field-potential recordings, if the inflammatory process associated with experimental autoimmune encephalomyelitis (EAE) is able to influence neuronal vulnerability to the blockade of mitochondrial complex IV, a crucial component for mitochondrial activity responsible of about 90% of total cellular oxygen consumption. We showed that during the acute relapsing phase of EAE, neuronal susceptibility to mitochondrial complex IV inhibition is markedly enhanced. This detrimental effect was counteracted by the pharmacological inhibition of microglia, of nitric oxide (NO) synthesis and its intracellular pathway (involving soluble guanylyl cyclase, sGC, and protein kinase G, PKG). The obtained results suggest that mitochondrial complex IV exerts an important role in maintaining neuronal energetic homeostasis during EAE. The pathological processes associated with experimental MS, and in particular the activation of microglia and of the NO pathway, lead to an increased neuronal vulnerability to mitochondrial complex IV inhibition, representing promising pharmacological targets.

Topics: Animals; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Encephalomyelitis, Autoimmune, Experimental; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Mitochondria; Multiple Sclerosis; Neurons; Nitric Oxide; Organ Culture Techniques; Signal Transduction; Sodium Azide

A recent controlled trial has established that high-dose biotin supplementation - 100 mg, three times daily - has a stabilizing effect on progression of multiple sclerosis (MS). Although this effect has been attributed to an optimization of biotin's essential cofactor role in the brain, a case can be made that direct stimulation of soluble guanylate cyclase (sGC) by pharmacological concentrations of biotin plays a key role in this regard. The utility of high-dose biotin in MS might reflect an anti-inflammatory effect of cGMP on the cerebral microvasculature, as well on oligodendrocyte differentiation and on Schwann cell production of neurotrophic factors thought to have potential for managing MS. But biotin's ability to boost cGMP synthesis in the brain may have broader neuroprotective potential. In many types of neurons and neural cells, cGMP exerts neurotrophic-mimetic effects - entailing activation of the PI3K-Akt and Ras-ERK pathways - that promote neuron survival and plasticity. Hippocampal long term potentiation requires nitric oxide synthesis, which in turn promotes an activating phosphorylation of CREB via a pathway involving cGMP and protein kinase G (PKG). In Alzheimer's disease (AD), amyloid beta suppresses this mechanism by inhibiting sGC activity; agents which exert a countervailing effect by boosting cGMP levels tend to restore effective long-term potentiation in rodent models of AD. Moreover, NO/cGMP suppresses amyloid beta production within the brain by inhibiting expression of amyloid precursor protein and BACE1. In conjunction with cGMP's ability to oppose neuron apoptosis, these effects suggest that high-dose biotin might have potential for the prevention and management of AD. cGMP also promotes neurogenesis, and may lessen stroke risk by impeding atherogenesis and hypertrophic remodeling in the cerebral vasculature. The neuroprotective potential of high-dose biotin likely could be boosted by concurrent administration of brain-permeable phosphodiesterase-5 inhibitors.

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Biotin; Brain; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 5; Extracellular Signal-Regulated MAP Kinases; Humans; Long-Term Potentiation; Microcirculation; Multiple Sclerosis; Neurogenesis; Neuroprotective Agents; Phosphatidylinositol 3-Kinases; Phosphodiesterase Inhibitors; Randomized Controlled Trials as Topic; Signal Transduction

Increasing evidence suggests a correlation between cytokine-induced nitric oxide synthase (iNOS) and demyelination in Multiple sclerosis (MS). Inhibition of iNOS may therefore be a novel therapeutic approach in MS. To test an antisense oligodeoxynucleotide (ODN) knockdown strategy for inhibiting iNOS, we used lipopolysaccharide (LPS) together with gamma-interferon (IFN-gamma) to induce iNOS in adult mouse mixed glial cell cultures. We administered an iNOS-derived antisense phosphorothiorate oligodeoxynucleotide (S-ODN) to block the induction. The antisense ODN treatment resulted in significant inhibition of LPS and IFN-gamma induced iNOS mRNA and protein expression. It also inhibited nitric oxide (NO) and cyclic GMP (cGMP) production in a dose dependent fashion. Sense and random S-oligo had no effect in any of these studies. These data indicate the efficacy and specificity of the antisense oligodeoxynucleotide approach in inhibiting iNOS in glial cells.

Topics: Animals; Base Sequence; Cyclic GMP; Interferon-gamma; Lipopolysaccharides; Mice; Molecular Sequence Data; Multiple Sclerosis; Neuroglia; Nitric Oxide; Nitric Oxide Synthase; Oligonucleotides, Antisense

Recent evidence suggests the involvement of nitric oxide (NO) in inflammation and demyelination in the brain. To test this hypothesis, we measured NO markers in the cerebrospinal fluid from patients with bacterial meningitis (BM), aseptic meningitis (AM), multiple sclerosis (MS), and Guillain-Barré syndrome (GBS). Subjects with non-inflammatory neurologic diseases served as the controls. NO markers were cyclic guanosine monophosphate (cGMP) measured with an enzyme immunoassay, and nitrite and nitrate measured with the Griess reaction. Except for BM, cGMP was not increased in AM, MS or GBS compared with the controls. Nitrite and nitrate were unaltered in any of the groups studied. These results do not support the hypothesis that NO is increased in the brain in meningitis, MS or GBS. Otherwise cGMP, nitrite and nitrate in the cerebrospinal fluid do not reflect the increase in NO in the brain.

Topics: Adult; Biomarkers; Brain; Cyclic GMP; Humans; Meningitis; Middle Aged; Multiple Sclerosis; Nitrates; Nitric Oxide; Nitrites; Polyradiculoneuropathy

The concentrations of cyclic AMP and cyclic GMP were estimated in plasma of 26 patients with definite multiple sclerosis (MS) in relapse, and compared to that of 26 sex- and age-matched healthy controls. MS patients had significantly lower levels of both nucleotides. The levels of c-GMP correlated negatively to the Disability Status Scale score.

Topics: Adult; Cyclic AMP; Cyclic GMP; Female; Humans; Male; Middle Aged; Multiple Sclerosis

The authors studied concentrations of cyclic nucleotides (cAMP and cGMP), as well as their ratio in the blood plasma and cerebrospinal fluid (CSF) of 83 patients with disseminated sclerosis of different forms and variants. An elevation in cAMP concentrations in the plasma and CSF detected in all the patients was more expressed in cases of a long standing and disseminated process. Blood levels of cAMP showed greater variability in the period of exacerbation versus remission of the disease.

Topics: Adult; Cyclic AMP; Cyclic GMP; Female; Humans; Male; Multiple Sclerosis; Nucleotides, Cyclic

Cyclic guanosine monophosphate (cGMP) levels have been measured in the cerebrospinal fluid of patients with various neurological diseases. The subjects with epilepsy or cerebrovascular diseases do not show any difference from the controls. Moreover, in the CSF of patients having cerebral tumors the levels of cGMP are markedly increased. This change is in line with previous in vitro studies on the increase of cGMP during cell growth and cell proliferation showing that the role of the nucleotide is important for the control of the life cycle of the cell.

Topics: Adolescent; Adult; Aged; Alzheimer Disease; Brain Neoplasms; Cerebrovascular Disorders; Cyclic GMP; Epilepsy; Female; Humans; Hydrocephalus, Normal Pressure; Male; Middle Aged; Multiple Sclerosis