Physiological processes underpinning the ubiquitous benefits and interactions of melatonin, butyrate and green tea in neurodegenerative conditions

Abstract

There is a growing dissatisfaction at the lack of progress in treating neurodegenerative conditions, such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. No current pharmaceuticals have any significant impact on the pathophysiological changes occurring in such neurodegenerative conditions. More promising has been the utilization of nutraceuticals, a number of which show preventative and treatment benefits. This article reviews the beneficial effects of melatonin, sodium butyrate and epigallocatechin gallate (EGCG) in the management of the pathophysiological changes underpinning neurodegenerative conditions. It is proposed that all three nutraceuticals upregulate the tryptophan-melatonin pathway, which may be particularly important in astrocytes given astrocyte regulation of neuronal energy supply and antioxidants, including released melatonin. Alterations in the tryptophan-melatonin pathway are intimately intertwined with changes in the kynurenine pathway and its neuroregulatory products, including kynurenic acid and quinolinic acid. This article places these changes in the tryptophan-melatonin pathways within a novel circadian-systemic interaction, involving the regulation of the night-time rise in cortisol culminating in the morning cortisol awakening response that mediates effects via glucocorticoid receptor (GR) activation. The night-time and morning GR activation is suppressed by melatonin, gut microbiome derived butyrate and bcl2-associated athanogene (BAG)-1. As melatonin, butyrate and BAG-1 decrease over age, there is a heightened level of GR nuclear translocation with age at night and early morning. This is exemplified by the 10-fold decrease in pineal melatonin in people in their 9th, versus 2nd, decade of life. The ‘battle’ of melatonin/butyrate/EGCG versus cortisol/GR for influence on cellular function, microenvironment homeostasis and systemic system (immune) regulation at night and early morning shapes how the body and brain are prepared for the coming day and drives the emergence of aging associated neurodegenerative conditions. It is upon such processes that melatonin, butyrate and EGCG have their impacts.