**6. Concluding remarks from a systems biology perspective**

The dynamic interactions between environmental factors and epigenetic mechanisms that involve multiple pathways and processes suggest the need for a system-based approach to understand MS physiopathology and to implement new pharmacological therapies.

Targeting neuroprotection is always ambitious, not only in MS, but in neurology in general, mostly because of a poor understanding of the complexity of interconnections between different cellular and molecular processes. In complex diseases such as MS there is a milieu of dynamical interplay between networks of genes and signaling proteins, lipids, carbohydrate molecules that can have concomitant roles in inflammation, immune systems reactivity, demyelination, neurodegeneration, neuroprotection, remyelination. For example, the network of p38 mitogen-activated protein kinase (MAPK) signaling pathway can trigger both inflam‐ mation and neuroprotection. MAPK is activated by cell stress, playing a key role in immune responses and has been intensively investigated in relation with EAE pathogenesis [102]. Taking in account this multitude of interactions, the currently trend is to inhibit/potentiate selectively a single molecular pathway, for example, acting only on p38α MAPK and not also on p38β MAPK [103].

However, over-selective interventions have an important disadvantage. Imbalances in complex systems always affect concomitant different subsystems between which there is a significant cross-talk. This leads to several pathological outcomes, for example, to inflamma‐ tion, demyelination, and neurodegeneration which potentiate each other, so targeting a single pathway seems senseless. Additionally, some of these processes occur as compensatory mechanisms and become maladaptive and trigger the emergence and expansion of vicious circles due to the alteration of modulatory mechanisms. For example, in a demyelinated axon, homeostatic plasticity that involves the redistribution of ion channels occurs, and this redis‐ tribution contributes to the failure of AP conduction and finally generates a metabolic crisis. Intercorrelation between the molecular mechanisms that underlie inflammation, apoptosis, oxidative stress, increased Ca2+ load, mitochondrial dysfunction, microglial activation, and blood–brain barrier dysfunction is responsible for the expansion of vicious circles that generate a nonlinear pattern of clinical evolution. From this perspective, the traditional idea of a "magic bullet" seems too simplistic to achieve sufficient neuroprotection.

An interesting explanation of these mechanisms derives from the theory of complex biological systems, which are characterized by criticality and degeneracy. Degeneracy describes the ability of structurally and functionally distinct pathways to produce the same output. This characteristic supports the existence of multifunctional components that can perform similar functions under certain conditions. A direct consequence of degeneracy is the assurance of quick compensation if one of these mechanisms fails. However, in pathological conditions, degeneracy can lead to a chronic, robust state in which a unimodal therapeutic approach that targets a single pathway will fail to ensure the sustainable irreversibility of the pathological process. According to this idea, the combination of therapies that utilize pharmacological compounds with synergic effects but different mechanisms of action or individual multimodal, pleiotropic therapies, with modulatory properties that can target as many pathways as possible offer a feasible therapeutic approach.

Last, but not least, it is very important to take in account that everyone has a different genetic polymorphism that leads to different phenotypes which can have an important influence upon the reactivity of molecular networks. This patient inter-variability may be responsible for both heterogeneity in disease progression and treatment response, leading to an open door to metabolomics [104].

### **Author details**

Dafin F. Muresanu1,2\*, Maria Balea1,2, Olivia Rosu1 , Anca Buzoianu3 and Dana Slavoaca1,2

\*Address all correspondence to: dafinm@ssnn.ro

1 Department of Clinical Neurosciences, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania

2 "RoNeuro" Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania

3 Department of Clinical Pharmacology and Toxicology, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania

## **References**

mechanisms and become maladaptive and trigger the emergence and expansion of vicious circles due to the alteration of modulatory mechanisms. For example, in a demyelinated axon, homeostatic plasticity that involves the redistribution of ion channels occurs, and this redis‐ tribution contributes to the failure of AP conduction and finally generates a metabolic crisis. Intercorrelation between the molecular mechanisms that underlie inflammation, apoptosis, oxidative stress, increased Ca2+ load, mitochondrial dysfunction, microglial activation, and blood–brain barrier dysfunction is responsible for the expansion of vicious circles that generate a nonlinear pattern of clinical evolution. From this perspective, the traditional idea of a "magic

An interesting explanation of these mechanisms derives from the theory of complex biological systems, which are characterized by criticality and degeneracy. Degeneracy describes the ability of structurally and functionally distinct pathways to produce the same output. This characteristic supports the existence of multifunctional components that can perform similar functions under certain conditions. A direct consequence of degeneracy is the assurance of quick compensation if one of these mechanisms fails. However, in pathological conditions, degeneracy can lead to a chronic, robust state in which a unimodal therapeutic approach that targets a single pathway will fail to ensure the sustainable irreversibility of the pathological process. According to this idea, the combination of therapies that utilize pharmacological compounds with synergic effects but different mechanisms of action or individual multimodal, pleiotropic therapies, with modulatory properties that can target as many pathways as possible

Last, but not least, it is very important to take in account that everyone has a different genetic polymorphism that leads to different phenotypes which can have an important influence upon the reactivity of molecular networks. This patient inter-variability may be responsible for both heterogeneity in disease progression and treatment response, leading to an open door to

1 Department of Clinical Neurosciences, "Iuliu Hatieganu" University of Medicine and

2 "RoNeuro" Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania

3 Department of Clinical Pharmacology and Toxicology, "Iuliu Hatieganu" University of

, Anca Buzoianu3

and Dana Slavoaca1,2

bullet" seems too simplistic to achieve sufficient neuroprotection.

offer a feasible therapeutic approach.

Dafin F. Muresanu1,2\*, Maria Balea1,2, Olivia Rosu1

\*Address all correspondence to: dafinm@ssnn.ro

Medicine and Pharmacy, Cluj-Napoca, Romania

Pharmacy, Cluj-Napoca, Romania

metabolomics [104].

296 Trending Topics in Multiple Sclerosis

**Author details**


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