Critical role for PDE4 subfamilies in the development of experimental autoimmune encephalomyelitis

Sanabra, Cristina; Johansson, Emily M.; Mengod, Guadalupe

doi:10.1016/j.jchemneu.2012.12.005

Cited by 16 publications

(21 citation statements)

References 48 publications

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“…EAE was actively induced using myelin oligodendrocyte glycoprotein (MOG) 35–55 peptide as previously described (Martin‐Alvarez et al., ; Sanabra, Johansson, & Mengod, ). MOG 35–55 (100 μg, EspiKem S.r.l., Italy) was thoroughly emulsified with 100 μl complete Freund's adjuvant (CFA, Sigma‐Aldrich) containing Mycobacterium tuberculosis (H37Ra strain, Difco, Detroit, MI, USA).…”

Section: Methodsmentioning

confidence: 99%

Comparative study of the expression of cholinergic system components in the CNS of experimental autoimmune encephalomyelitis mice: Acute vs remitting phase

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Martín-Álvarez

et al. 2018

Eur J of Neuroscience

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Acetylcholine (ACh) is involved in the modulation of the inflammatory response. ACh levels are regulated by its synthesizing enzyme, choline acetyltransferase (ChAT), and by its hydrolyzing enzymes, mainly acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). A more comprehensive understanding of the cholinergic system in experimental autoimmune encephalomyelitis (EAE) disease progression could pave the path for the development of therapies to ameliorate multiple sclerosis (MS). In this work, we analyzed possible alterations of the CNS cholinergic system in the neuroinflammation process by using a MOG-induced EAE mice model. MOG- and vehicle-treated animals were studied at acute and remitting phases. We examined neuropathology and analyzed mRNA expression of ChAT, AChE and the α7 subunit of the nicotinic acetylcholine receptor (α7nAChR), as well as AChE and BuChE enzyme activities, in brain and spinal cord sections during disease progression. The mRNA expression and enzyme activities of these cholinergic markers were up- or down-regulated in many cholinergic areas and other brain areas of EAE mice in the acute and remitting phases of the disease. BuChE was present in a higher proportion of astroglia and microglia/macrophage cells in the EAE remitting group. The observed changes in cholinergic markers expression and cellular localization in the CNS during EAE disease progression suggests their potential involvement in the development of the neuroinflammatory process and may lay the ground to consider cholinergic system components as putative anti-inflammatory therapeutic targets for MS.

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Section: Methodsmentioning

confidence: 99%

Comparative study of the expression of cholinergic system components in the CNS of experimental autoimmune encephalomyelitis mice: Acute vs remitting phase

Pinto

Bari

Martín-Álvarez

et al. 2018

Eur J of Neuroscience

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“…Some uncertainties remain, however. Although expression of PDE4B2 is increased in the brainstem and spinal cord in mice with EAE, and the PDE4 inhibitor, rolipram, reduced clinical signs of the disease, PDE4B KO mice unexpectedly developed EAE faster than WT mice (Sanabra et al , ). Furthermore, a small clinical study of effects of rolipram in patients with multiple sclerosis (MS) was prematurely terminated because of side effects (nausea, emesis) and an unexpected increase in brain inflammation in the MS patients, even though rolipram administration reduced inflammation markers in circulating lymphocytes (Bielekova et al , ).…”

Section: Pde Functions: Implications Regarding Pathophysiology Of Dismentioning

confidence: 99%

Cyclic Nucleotide Phosphodiesterases: important signaling modulators and therapeutic targets

et al. 2014

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By catalyzing hydrolysis of cAMP and cGMP, cyclic nucleotide phosphodiesterases are critical regulators of their intracellular concentrations and their biological effects. Since these intracellular second messengers control many cellular homeostatic processes, dysregulation of their signals and signaling pathways initiate or modulate pathophysiological pathways related to various disease states, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication, chronic obstructive pulmonary disease, and psoriasis. Alterations in expression of PDEs and PDE-gene mutations (especially mutations in PDE6, PDE8B, PDE11A and PDE4) have been implicated in various diseases and cancer pathologies. PDEs also play important role in formation and function of multi-molecular signaling/regulatory complexes called signalosomes. At specific intracellular locations, individual PDEs, together with pathway-specific signaling molecules, regulators, and effectors, are incorporated into specific signalosomes, where they facilitate and regulate compartmentalization of cyclic nucleotide signaling pathways and specific cellular functions. Currently, only a limited number of PDE inhibitors (PDE3, PDE4, PDE5 inhibitors) are used in clinical practice. Future paths to novel drug discovery include the crystal structure-based design approach, which has resulted in generation of more effective family-selective inhibitors, as well as burgeoning development of strategies to alter compartmentalized cyclic nucleotide signaling pathways by selectively targeting individual PDEs and their signalosome partners.

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“…GSEA indicated that PDE4B played a positive role in the "inflammatory response" signaling pathway, which closely correlated with IBD progression. In addition, PDE4B was also shown to be related to the level of immune cell infiltration (36,37). Expression of PDE4B was positively correlated with the infiltration of M1 macrophages in our study, suggesting that PDE4B may promote the progression of inflammation.…”

Section: Discussionsupporting

confidence: 64%

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Critical role for PDE4 subfamilies in the development of experimental autoimmune encephalomyelitis

Cited by 16 publications

References 48 publications

Comparative study of the expression of cholinergic system components in the CNS of experimental autoimmune encephalomyelitis mice: Acute vs remitting phase

Comparative study of the expression of cholinergic system components in the CNS of experimental autoimmune encephalomyelitis mice: Acute vs remitting phase

Cyclic Nucleotide Phosphodiesterases: important signaling modulators and therapeutic targets

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