**8. Concluding Remarks**

In this work, we have assessed the use of nutraceuticals such as inositols, which are mostly components of human organisms and are generally acquired through diet. The nutraceutical industry is booming due to the change in the perception of pharmacological drugs and the search for alternatives based on natural compounds. These molecules can be derived from extraction processes in plants or fermentation in bioreactors, which is an advantage over chemical synthesis processes.

Inositols, essentially MI and DCI, are usually a part of membrane structures like phospholipids. As such, the study of inositols has been instrumental in understanding the mechanism of insulin resistance. At a given concentration, inositol stereoisomers can stimulate insulin signaling, preferably as IGs, but also show antioxidant capacity. However, after revising the proposed models for inositols in insulin signaling, it is still uncertain whether inositols per se are capable of displaying these characteristics. In addition to supporting insulin signaling, the importance of inositols in the brain appears to lie in their ability to control neuron and glia responses to external environments. In this regard, psychiatric disorders such as depression and anxiety were associated with imbalances in MI content in brain. Treatment with MI has been shown to improve behavioral outcomes in depression,

anxiety, panic, and obsessive-compulsive disorders in a mechanism of action related to serotonin receptor activation. Albeit not fully elucidated, MI role may imply PI availability, standing out the importance of MI in physiological regulation of serotonin signaling in behavior.

Inositols are solid candidates for developing new approaches for the treatment or improvement of chronic diseases associated with aging, especially those linked to insulin resistance and oxidative stress. Aging of the population is a challenge for developed countries due to the increasing incidence of dementia. Amongst all types of dementia, sporadic AD represents a heavy burden for patients, their families, and society. AD treatment is considered a high risk, high reward market. Different strategies have been approached in an attempt to merge effective therapy when the disease is clinically diagnosable. This process generally renders unsuccessful results due to the complexity and partial lack of knowledge of the progression of AD development. We have approached AD from the point of view of the initial stages of the disease, as the aging process is closely related to the development of metabolic dysregulations leading to insulin resistance, where inositols might have a potential beneficial use.

This exhaustive review of the physiological role of inositols helps us to understand what benefits can result from external administration, either to compensate for their deficiency or as an adjuvant in oxidative stress processes. The specific position of the hydroxyl radicals gives certain stereoisomers such as SI or EI specific characteristic to limit the aggregation of Aβ, one of the main pathophysiological characteristics of AD and cognitive dementia observed in DS.

The different inositols offer complementary strategies for the preventive treatment of AD. Research of inositols, especially those with a remarkable insulin-sensitizing capacity, such as DCI or its derivative DPIN, may offer a different perspective on how insulin resistance develops in the brain and its contribution to improving cognitive outcomes for AD. The fact that clinical studies on neurological disorders with inositols have been carried out in the last decade meets a necessity and opens a way to the expansion in the use of inositols, whose perspective is not that of being a therapeutic replacement, but a bioactive compound that helps to prevent or suppress decline in neurodegenerative diseases.

**Author Contributions:** Conceptualization: C.S. and F.R.d.F.; writing—original draft preparation: A.J.L.-G. and J.S.; writing—review and editing: P.J.S.-C. and F.R.d.F. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the Agencia Estatal de Investigación, Ministerio de Economía y Competitividad or Ministerio de Ciencia e Innovación, and European Regional Development Funds-European Union (ERDF-EU), grant numbers RTC-2016-4983-1 and RTC-2019-007329-1; Instituto de Salud Carlos III (ISCIII) and ERDF-EU, grant numbers DTS16/00115, PI19/00343, and COV20/00157; Consejería de Economía, Conocimiento, Empresas y Universidad and ERDF-EU, grant number P18-TP-5194, and Consejería de Salud y Familia de la Junta de Andalucía (NeuroRECA), grant number RIC-0111-2019. J.S. holds a "Miguel Servet II" research contract from the National System of Health, ISCIII, ERDF-EU, FIMABIS, grant number CPII17/00024. A.J.L.-G. holds an "i-PFIS" predoctoral research contract from the ISCIII, ERDF-EU, grant number IFI18/00042.

**Conflicts of Interest:** Carlos SanJuan declares he receives salary and has share from Euronutra company. The remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
