Methylxanthines and Neurodegenerative Diseases: An Update

Abstract

Methylxanthines (MTX) are purine derived xanthine derivatives. Whereas naturally occurring methylxanthines like caffeine, theophylline or theobromine are widely consumed in food, several synthetic but also non-synthetic methylxanthines are used as pharmaceuticals, in particular in treating airway constrictions. Besides the well-established bronchoprotective effects, methylxanthines are also known to have anti-inflammatory and anti-oxidative properties, mediate changes in lipid homeostasis and have neuroprotective effects. Known molecular mechanisms include adenosine receptor antagonism, phosphodiesterase inhibition, effects on the cholinergic system, wnt signaling, histone deacetylase activation and gene regulation. By affecting several pathways associated with neurodegenerative diseases via different pleiotropic mechanisms and due to its moderate side effects, intake of methylxanthines have been suggested to be an interesting approach in dealing with neurodegeneration. Especially in the past years, the impact of methylxanthines in neurodegenerative diseases has been extensively studied and several new aspects have been elucidated. In this review we summarize the findings of methylxanthines linked to Alzheimer´s disease, Parkinson's disease and Multiple Sclerosis since 2017, focusing on epidemiological and clinical studies and addressing the underlying molecular mechanisms in cell culture experiments and animal studies in order to assess the neuroprotective potential of methylxanthines in these diseases.

Keywords: Alzheimer´s disease; Multiple Sclerosis; Parkinson´s disease; caffeine; istradefylline; methylxanthines; pentoxifylline; propentofylline; theobromine; theophylline.

Figure 1

Summary of the molecular mechanisms reported in recent literature potentially mediating the beneficial effects of methylxanthines in respect to Alzheimer´s disease.

Figure 2

Summary of the molecular mechanisms reported in recent literature potentially mediating the beneficial effects of methylxanthines in respect to Parkinson´s disease.

Figure 3

Summary of the molecular mechanisms reported in recent literature potentially mediating the beneficial effects of methylxanthines in respect to multiple sclerosis. Ac = Acetylation, eEF1A1 = eukaryotic translation elongation factor 1 alpha 1, HDAC2 = histone deacetylase 2, SOX10 = SRY-box transcription factor 10, MBP = myelin basic protein, ROS = reactive oxygen species, SOD1 = superoxide dismutase 1, c-Rel = proto-oncogene c-Rel, NSC = neuronal stem cells, PI3Kδ = phosphatidylinositol-3-kinase delta.