The role of microglia in neuroprogressive disorders: mechanisms and possible neurotherapeutic effects of induced ketosis

A comprehensive review of molecular mechanisms involved in the promotion and maintenance of distinct microglia phenotypes is provided. The acquisition and perpetuation of predominantly pro-inflammatory microglial phenotypes have been implicated in the pathophysiology of several neuroprogressive diseases and is associated with reduced ATP production via oxidative phosphorylation, increased ATP generation by glycolysis, elevated oxidative and nitrosative stress and other metabolic, inflammatory and hormonal insults. Microglia can also adopt a predominantly anti-inflammatory phenotypes with neuroprotective properties. Strategies that promote and maintain a predominantly anti-inflammatory phenotype may hold promise as novel therapeutic opportunities for neuroprogressive illness. Induced ketosis may promote a transition towards predominantly anti-inflammatory microglial states/phenotypes by several mechanisms, including inhibition of glycolysis and increased NAD+ production; engagement of microglial GPR109A receptors; histone deacetylase inhibition; and elevated n-3 polyunsaturated fatty acids levels. Since microglia activation can now be assessed in vivo, these data provide a clear rationale for the design of transdiagnostic randomized controlled trials of the ketogenic diet and other ketosis-inducing strategies for neuroprogressive diseases, which may also provide mechanistic insights through the assessment of “target engagement”.