Targeting Phosphodiesterases—Towards a Tailor-Made Approach in Multiple Sclerosis Treatment

Abstract

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.

PDE inhibition in distinct cell types to reclaim the balance of synaptic plasticity

“…This review will focus on AKAP/cAMP complexes. Extensive research has demonstrated that elevating cAMP and cGMP levels can drive the CNS towards a neuroprotective environment to prevent damage 9 - 17 . Achieving this elevation is possible through the anabolic pathway via guanylyl cyclase (GC) or adenylyl cyclase (AC), or by blocking phosphodiesterases (PDEs), which hydrolyze and break down cGMP and cAMP.…”

“…In addition to the modulation of neuroplasticity effects, cyclic nucleotides also affect neuroinflammatory processes 14 , 66 . Through compartmentalization of signaling cascades, generic cAMP and cGMP can selectively influence different processes.…”

“…The involvement of PDEs in astrocytic-mediated synaptic control remains an unstudied topic. PDE inhibition or cAMP elevation within astrocytes seems to regulate distinct neuroinflammatory pathways and could, therefore, influence synaptic integrity in an indirect manner 66 . Treatment of astrocytes with 8-Br-cAMP, a cAMP analog, has been shown to decrease the levels of the pro-inflammatory cytokine TNFα 11 .…”

“…Therefore, oligodendrocyte cell signaling pathways should not be overlooked in the context of synaptogenesis. Cyclic nucleotide signaling has proven to be vital in oligodendrocyte metabolism, implicating them as interesting effector cells 66 . For instance, inhibition of the cGMP-specific PDE5 by sildenafil improves BDNF signaling of oligodendrocytes and thus synaptogenesis 100 .…”

Mitochondria, Oxidative Stress, cAMP Signalling and Apoptosis: A Crossroads in Lymphocytes of Multiple Sclerosis, a Possible Role of Nutraceutics

“…cAMP is the most studied second messenger in the context of T lymphocyte activation and proliferation [ 19 ]. It has been reported that the increase of cAMP level attenuates the T lymphocyte-mediated production of pro-inflammatory cytokines such as IFN-γ and interleukin (IL)-1b (IL-1b) suggesting that a decrease of cAMP level is required for T cell activation [ 14 , 20 , 21 ]. The activation of immune cells, especially T cells, is also related to OS [ 15 ] and the peripheral blood mononuclear cells (PBMCs) of MS patients show an impaired redox status associated with a metabolic reprogramming that includes mitochondrial alterations [ 22 , 23 , 24 , 25 ].…”