Figure 1.

Interaction of central glutamate activity in anxiety and depression alterations, characteristic of Multiple Sclerosis (MS).(A) Peripheral and central pathogenic mechanisms in MS. Individuals with MS have a high prevalence of obesity, which is associated with insulin resistance. Obesity is directly linked to the characteristic functional disability of the disease and with increased central inflammation. This inflammation is primarily mediated in MS by an increase in IL-1β and its receptor (IL-1R), as well as an increase in IL-6, which stimulates T-cell activation and promotes IL-17A production, specifically related to functional disability. Disability, as well as inflammation in the CNS mediated primarily by these three interleukins, is associated with glutamate activity. Increased levels of glutamate are observed in areas of greater demyelination and axonal degeneration in MS. Finally, dysregulation of glutamate is associated with increased depression and anxiety, as the increased activity of IL-1β, IL-6, and IL-17A reduces glutamate uptake by astrocytes and stimulates its release at the extrasynaptic level. (B) Proposed mechanisms of action of a ketogenic diet (KD) in improving the perception of anxiety and depression in subjects with MS. The production of ketone bodies resulting from KD intake reduces obesity and improves insulin resistance, thereby enhancing functional capacity. This activity, along with the ability of ketone bodies to cross the BBB, may explain central glutamate activity, particularly at the extrasynaptic level, and through the reduction of IL-1β, IL-6, and IL-17A levels. Ultimately, these changes have an emotional impact, leading to a decrease in the perception of anxiety and depression characteristic of this pathology.