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.

Pentoxifylline Enhances Antioxidative Capability and Promotes Mitochondrial Biogenesis in D‐Galactose‐Induced Aging Mice by Increasing Nrf2 and PGC‐1α through the cAMP‐CREB Pathway

“…The main pharmacological activities of PDE inhibitor can be explained by inhibition of PDEs, which is responsible for the breakdown of the intracellular second messengers, cAMP or cGMP. Consistent with the effects of PTX, several synthetic or natural molecules inhibiting various PDE subtypes such as cilostazol, milrinone, rolipram, sildenafil, tadalafil, BAY 73-6691, and caffeine have been reported showing encouraging results for the treatment of neurodegenerative disorders, which might be closely related to increase mitochondrial biogenesis and antioxidant activities [ 60 – 66 ]. Our previous research on the antiaging effects of PTX suggested that PTX administration increased the cAMP content in aged rats by preventing the inactivation of cAMP [ 22 ].…”

The Conflicting Role of Caffeine Supplementation on Hyperoxia-Induced Injury on the Cerebellar Granular Cell Neurogenesis of Newborn Rats

“…Apart from caffeine-driven direct or indirect mechanisms, primarily the Nrf2/Nf κ B pathway seems to be important for intracellular transduction. Oxidative stress-associated genes, oxidative stress per se but also neuronal signal transduction, transcriptional regulation, and thus neuronal functions may be affected by methylxanthines [ 100 ].…”

Theophylline Induces Remyelination and Functional Recovery in a Mouse Model of Peripheral Neuropathy

“…In recent years, methylxanthines such as Theophylline have been reported in various studies to have potential beneficial effects to counteract neurodegenerative diseases including Parkinson’s diseases, Alzheimer’s disease and multiple sclerosis [ 14 , 55 ]. In particular, we have shown that Theophylline promotes remyelination in the lysolecithin-induced mouse model of multiple sclerosis lesion, through activating and upregulating HDAC2 [ 14 ], warranting future clinical trials to test the efficiency of Theophylline in remyelinating lesions of multiple sclerosis patients.…”