beyond reason
케톤체(베타-하이드록시뷰티레이트)로 파킨슨병의 복합병리를 개선해는 기전에 관한 2019년 논문
norwitz2019.pdf
The Mechanisms by Which the Ketone Body D-b-Hydroxybutyrate May Improve the Multiple Cellular Pathologies of Parkinson’s Disease
Parkinson’s disease, a progressive neurodegenerative disorder characterized by motor
and non-motor symptoms, is strongly associated with the death of dopaminergic
neurons in the brain’s substantia nigra. Although dopamine replacement therapy
temporarily helps patients manage their motor symptoms, this current standard of care
fails to address the underlying network of pathologies that contribute to the persistent
death of dopaminergic neurons. Thus, new treatment approaches are needed that
address the underlying pathologies and, thereby, slow or halt the progression of the
actual disease. D-b -hydroxybutyrate – a ketone body produced by the liver to support
brain function during periods of starvation – may provide an option. Lifestyle interventions
that induce endogenous D-b -hydroxybutyrate production, such as caloric restriction and
ketogenic diets, are known to increase healthspan and lifespan in animal models and are
used to treat neurological disorders. The efficacy of these ketosis-inducing interventions,
along with the recent development of commercially available D-b -hydroxybutyrate-based
nutritional supplements, should inspire interest in the possibility that D-b -hydroxybutyrate
itself exerts neuroprotective effects. This review provides a molecular model to
justify the further exploration of such a possibility. Herein, we explore the cellular
mechanisms by which the ketone body, D-b -hydroxybutyrate, acting both as ametabolite
and as a signaling molecule, could help to prevent the development, or slow the
progression of, Parkinson’s disease. Specifically, the metabolism of D-b -hydroxybutyrate
may help neurons replenish their depleted ATP stores and protect neurons against
oxidative damage. As a G-protein-coupled receptor ligand and histone deacetylase
inhibitor, D-b -hydroxybutyrate may further protect neurons against energy deficit
and oxidative stress, while also decreasing damaging neuroinflammation and death
by apoptosis. Restricted to the available evidence, our model relies largely upon the interpretation of data from the separate literatures on the cellular effects of
D-b -hydroxybutyrate and on the pathogenesis of Parkinson’s disease. Future studies
are needed to reveal whether D-b -hydroxybutyrate actually has the potential to serve as
an adjunctive nutritional therapy for Parkinson’s disease.
Keywords: apoptosis, dopamine, D-b-hydroxybutyrate, energy metabolism, inflammation, oxidative stress, Parkinson’s disease