A few years after the foundation of the British Pharmacological Society, monoamine oxidase (MAO) was recognized as an enzyme of crucial interest to pharmacologists because it catalyzed the major inactivation pathway for the catecholamine neurotransmitters, noradrenaline, adrenaline and dopamine (and, later, 5‐hydroxytryptamine, as well). Within the next decade, the therapeutic value of inhibitors of MAO in the treatment of depressive illness was established. Although this first clinical use exposed serious side effects, pharmacological interest in, and investigation of, MAO continued, resulting in the characterization of two isoforms, MAO‐A and ‐B, and isoform‐selective inhibitors. Selective inhibitors of MAO‐B have found a therapeutic role in the treatment of Parkinson's disease and further developments have provided reversible inhibitors of MAO‐A, which offer antidepressant activity without the serious side effects of the earlier inhibitors. Clinical observation and subsequent pharmacological analysis have also generated the concept of neuroprotection, reflecting the possibility of slowing, halting and maybe reversing, neurodegeneration in Parkinson's or Alzheimer's diseases. Increased levels of oxidative stress in the brain may be critical for the initiation and progress of neurodegeneration and selective inhibition of brain MAO could contribute importantly to lowering such stress. There are complex interactions between free iron levels in brain and MAO, which may have practical outcomes for depressive disorders. These aspects of MAO and its inhibition and some indication of how this important area of pharmacology and therapeutics might develop in the future are summarized in this review.British Journal of Pharmacology (2006) 147, S287–S296. doi:10.1038/sj.bjp.0706464

Accumulating evidence supports the hypothesis that brain iron misregulation and oxidative stress (OS), resulting in reactive oxygen species (ROS) generation from H₂O₂and inflammatory processes, trigger a cascade of events leading to apoptotic/necrotic cell death in neurodegenerative disorders, such as Parkinson's (PD), Alzheimer's (AD) and Huntington's diseases, and amyotrophic lateral sclerosis (ALS). Thus, novel therapeutic approaches aimed at neutralization of OS‐induced neurotoxicity, support the application of ROS scavengers, transition metals (e.g. iron and copper) chelators and non‐vitamin natural antioxidant polyphenols, in monotherapy, or as part of antioxidant cocktail formulation for these diseases. Both experimental and epidemiological evidence demonstrate that flavonoid polyphenols, particularly from green tea and blueberries, improve age‐related cognitive decline and are neuroprotective in models of PD, AD and cerebral ischemia/reperfusion injuries. However, recent studies indicate that the radical scavenger property of green tea polyphenols is unlikely to be the sole explanation for their neuroprotective capacity and in fact, a wide spectrum of cellular signaling events may well account for their biological actions. In this article, the currently established mechanisms involved in the beneficial health action and emerging studies concerning the putative novel molecular neuroprotective activity of green tea and its major polyphenol (‐)‐epigallocatechin‐3‐gallate (EGCG), will be reviewed and discussed.

Green tea extract and its main polyphenol constituent (‐)‐epigallocatechin‐3‐gallate (EGCG) possess potent neuroprotective activity in cell culture and mice model of Parkinson's disease. The central hypothesis guiding this study is that EGCG may play an important role in amyloid precursor protein (APP) secretion and protection against toxicity induced by β‐amyloid (Aβ). The present study shows that EGCG enhances (~6‐fold) the release of the non‐amyloidogenic soluble form of the amyloid precursor protein (sAPPα) into the conditioned media of human SH‐SY5Y neuroblastoma and rat pheochromocytoma PC12 cells. sAPPα release was blocked by the hydroxamic acid‐based metalloprotease inhibitor Ro31–9790, which indicated mediation via α‐secretase activity. Inhibition of protein kinase C (PKC) with the inhibitor GF109203X, or by down‐regulation of PKC, blocked the EGCG‐induced sAPPα secretion, suggesting the involvement of PKC. Indeed, EGCG induced the phosphorylation of PKC, thus identifying a novel PKC‐dependent mechanism of EGCG action by activation of the non‐amyloidogenic pathway. EGCG is not only able to protect, but it can rescue PC12 cells against the β‐amyloid (Aβ) toxicity in a dose‐dependent manner. In addition, administration of EGCG (2 mg/kg) to mice for 7 or 14 days significantly decreased membrane‐bound holoprotein APP levels, with a concomitant increase in sAPPα levels in the hippocampus. Consistently, EGCG markedly increased PKCα and PKCε in the membrane and the cytosolic fractions of mice hippocampus. Thus, EGCG has protective effects against Aβ‐induced neurotoxicity and regulates secretory processing of non‐amyloidogenic APP via PKC pathway.