**4. Materials and Methods**

The PubMed library was searched for journal articles published in English up to 4 May 2022; we used the entry words "pro-resolving mediators", "resolvins", "maresins", "annexins", "lipoxins", "protectins", "neuroinflammation", "central nervous system", "glial cells", and "Alzheimer", "Parkinson", "neurodegenerative", "stroke", "cerebrovascular". We purposefully focused on findings in human studies and on pre-clinical studies which have been implemented in the animal model, as pre-clinical animal studies more closely resemble possible future applications in clinical practice. In vitro studies have not been discussed in this work. However, a concise overview of the main in vitro models currently used in the field of neurological diseases and SPMs research has been provided in Table 4.

**Table 4.** Overview of the main in vitro models currently used in the field of neurological disease and SPMs research.



Aβ40: Amyloid Beta 1–40; Aβ42: Amyloid Beta 1–42; AD: Alzheimer's Disease; ALS: Amyotrophic Lateral Sclerosis; (βAPP)sw: Swedish double mutation APP695sw, K595N-M596L; DA: dopamine; HNG: Human Neuronal-Glial co-culture; LPS: Lipopolysaccharide; MPP+: 1-methyl-4-phenylpyridium; MPTP: 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine; NSC-34: Neuroblastoma spinal cord 34; OGD: oxygen-glucose deprivation; OGD/R: oxygenglucose deprivation/reoxygenation; PBMCs: Peripheral Blood Mononuclear Cells; PD: Parkinson's disease; SOD-1: Superoxide Dismutase-1; STS: Staurosporine; TDP-43: TAR DNA-binding protein 43; TLR: Toll-like receptor.

#### **5. Conclusions**

Inflammation is a reaction to a harmful agent, physiologically self-contained thanks to the intervention of endogenous molecules which promote its resolution. If persistent or dysregulated, inflammation itself becomes noxious for human tissues.

Chronic, low-grade inflammation of the CNS is considered the pathophysiological foundation of many neurological disorders and of the neurodegenerative processes themselves.

In this picture, pro-resolution is a spontaneous collateral biochemical mechanism led by SPMs in the inflamed tissues and the identification of these molecules contributed to the understanding of the inflammation processes; their use in the clinical setting could potentially be an important tool for clinicians.

We have analyzed the bulk of the evidence in this article on the role of SPMs in the control of inflammation processes in several models of the most important neurological disorders. This amount of evidence has moved an interest among patients and physicians for the clinical use of SPMs.

Unfortunately, at the moment, this interest cannot be certainly defined as evidence-based.

A preliminary problem to be explored for future clinical studies relates to the route of administration of SPMs. In fact, regarding the administration of SPMs, there is at present no evidence on whether they can actually cross the BBB, although their characteristic of small lipophilic molecules makes this possibility plausible, similarly to what is known for their precursors DHA and EPA [74].

A second aspect concerns the definition of precise and clinically meaningful outcome measures, specific for the diseases to be treated.

Finally, little is known about the toxicology of SPMs, although no side effects have been reported so far. However, since research on SPMs is relatively new, an effort should be made to conduct future studies on safety, in order to rule out possible harmful effects. This is even more important if we consider that a few, not recent, studies on ω-3 PUFAs,

which are SPMs precursors, have pointed out that they may impact platelet aggregation and reduce the immune response to infections [106–109].

Having in mind these considerations, we believe that the information coming from animal studies should prompt investigators and industry to fill the scientific gap with robust clinical studies on SPMs, which are tremendously needed.

It is likely that the clinical use of SPMs will not be as potent as that of anti-inflammatory drugs, but their action is likely more physiological, and it could probably be better tolerated by patients. In addition, their effects could be potentiated by the synergic action of other "natural" approaches to the control of chronic low-grade inflammation, such as those based on nutrition and lifestyle.

**Author Contributions:** Conceptualization, M.V. and M.D.; methodology, M.D.; validation, G.L.G. and M.V.; resources, M.V. and G.L.G.; writing—original draft preparation, M.D., F.K., F.B.; writing—review and editing, M.D., F.K., F.B., M.V. and G.L.G.; supervision, G.L.G. and M.V.; project administration: M.V. All authors have read and agreed to the published version of the manuscript.

**Funding:** This review received no external funding.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

