Published Paper Details:

Methylxanthines, particularly 1,3,7-trimethylxanthine (caffeine) and its primary in vivo metabolites (theobromine, theophylline, and paraxanthine), represent some of the most ubiquitously consumed psychoactive substances worldwide. Beyond their historical classification as dietary stimulants, modern molecular pharmacology has uncovered an intricate landscape of bioactivities that extend deep into therapeutic and neuroprotective territories. This extensive review outlines the comprehensive pharmacological mechanisms of methylxanthines, focusing heavily on their multi-targeted interactions within the central nervous system (CNS). We dissect the competitive antagonism of adenosine A1 and A2A receptors, the downstream modulation of neurotransmitter cascades (including dopamine, acetylcholine, serotonin, and gamma-aminobutyric acid), and the inhibition of cyclic nucleotide phosphodiesterases (PDEs). Furtherm examine the potent intracellular calcium mobilization and the epigenetic modifications orchestrated via histone deacetylase activation. In the context of neurodegenerative pathology, we present exhaustive evidence supporting caffeine's therapeutic efficacy against Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis, highlighting its capacity to mitigate neuroinflammation, suppress microglial overactivation, neutralize reactive oxygen species (ROS), and prevent mitochondrial collapse. Despite these profound medicinal attributes, the clinical translation of methylxanthines remains severely bottlenecked by complex pharmacokinetic challenges, including rapid systemic clearance, low metabolic bioavailability, and the restrictive stringency of the blood-brain barrier (BBB). To address these limitations, we comprehensively evaluate cutting-edge nanotechnological intervention strategies. This includes a critical analysis of lipid-based nanoparticles (SLNs and NLCs), polymeric nanoparticles, nanoemulsions, and functionalized carbon nanotubes designed for targeted, sustained, and brain-specific delivery. Ultimately, this review bridges the gap between classic xanthine chemistry and advanced clinical nanomedicine, providing a definitive framework for utilizing methylxanthines as novel, high-efficacy neurotherapeutics.