Inhibition of Glycolysis as a Treatment for Neurodegeneration

Researchers here discuss a program of drug discovery that led to inhibitors of glycolysis as a potential approach to treatment for neurodegenerative conditions. The researchers note that elevated glycolysis is a characteristic of Alzheimer's disease, for example. There are always many, many mechanisms and altered aspects of cell metabolism one can investigate in aging and age-related disease. The question to ask when looking at any one specific mechanism in isolation is how much of the pathology of the condition lies downstream of this mechanism. It is all to easy to find oneself targeting a side-effect, or a minor mechanism that is not close to the root causes of the condition, which is why it is important to test in animals to observe the degree to which health is improved.

Although it is widely agreed that proteotoxicity drives impairments in Alzheimer's disease (AD) and other neurological diseases, many preclinical and case-report studies indicate that increased microglial production of pro-inflammatory cytokines such as TNF-a mediate proteotoxicity in AD and other neurological conditions. We developed parallel high-throughput phenotypic screens to discover small molecules which inhibit age-related proteotoxicity in a C. elegans model of AD, and microglia inflammation (LPS-induced TNF-a). In the initial screen of 2,560 compounds, the most protective compounds were, in order, phenylbutyrate (HDAC inhibitor), methicillin (beta lactam antibiotic), and quetiapine (tricyclic antipsychotic). These classes of compounds are already robustly implicated as potentially protective in AD and other neurodegenerative diseases.

In addition to quetiapine, other tricyclic antipsychotic drugs also delayed age-related amyloid-beta (Abeta) proteotoxicity and microglial TNF-a. Based on these results we carried out extensive structure-activity relationship studies, leading to the synthesis of a novel congener of quetiapine, #310, which inhibits a wide range of pro-inflammatory cytokines in mouse and human myeloid cells, and delays impairments in animal models of AD, Huntington's, and stroke. #310 is highly concentrated in brain after oral delivery with no apparent toxicity, increases lifespan, and produces molecular responses highly similar to those produced by dietary restriction. Among these molecular responses is inhibition of glycolysis, reversing gene expression profiles and elevated glycolysis associated with AD.

Several lines of investigation strongly supported that the protective effects of #310 are mediated by activating the Sigma-1 receptor, whose protective mechanisms in turn also entail inhibiting glycolysis. Reduced glycolysis has also been implicated in the generally protective effects of dietary restriction, rapamycin, reduced IFG-1 activity, and ketones during aging, suggesting that aging is at least in large part a consequence of glycolysis. In particular, the age-related increase in adiposity, and subsequent pancreatic decompensation leading to diabetes, is plausibly a consequence of age-related increase in beta cell glycolysis. Consistent with these observations, the glycolytic inhibitor 2-DG inhibited microglial TNF-a and other markers of inflammation, delayed Abeta proteotoxicity, and increased lifespan. To our knowledge no other molecule exhibits all these protective effects which makes #310 a uniquely promising candidate to treat AD and other age-related diseases.


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