Neuroprotective Effect of <i>Phyllanthus acidus</i> L. on Learning and Memory Impairment in Scopolamine-Induced Animal Model of Dementia and Oxidative Stress: Natural Wonder for Regulating the Development and Progression of Alzheimer’s Disease

This review describes the three mammalian glutathione transferase (GST) families, namely cytosolic, mitochondrial, and microsomal GST, the latter now designated MAPEG. Besides detoxifying electrophilic xenobiotics, such as chemical carcinogens, environmental pollutants, and antitumor agents, these transferases inactivate endogenous alpha,beta-unsaturated aldehydes, quinones, epoxides, and hydroperoxides formed as secondary metabolites during oxidative stress. These enzymes are also intimately involved in the biosynthesis of leukotrienes, prostaglandins, testosterone, and progesterone, as well as the degradation of tyrosine. Among their substrates, GSTs conjugate the signaling molecules 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) and 4-hydroxynonenal with glutathione, and consequently they antagonize expression of genes trans-activated by the peroxisome proliferator-activated receptor gamma (PPARgamma) and nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). Through metabolism of 15d-PGJ2, GST may enhance gene expression driven by nuclear factor-kappaB (NF-kappaB). Cytosolic human GST exhibit genetic polymorphisms and this variation can increase susceptibility to carcinogenesis and inflammatory disease. Polymorphisms in human MAPEG are associated with alterations in lung function and increased risk of myocardial infarction and stroke. Targeted disruption of murine genes has demonstrated that cytosolic GST isoenzymes are broadly cytoprotective, whereas MAPEG proteins have proinflammatory activities. Furthermore, knockout of mouse GSTA4 and GSTZ1 leads to overexpression of transferases in the Alpha, Mu, and Pi classes, an observation suggesting they are part of an adaptive mechanism that responds to endogenous chemical cues such as 4-hydroxynonenal and tyrosine degradation products. Consistent with this hypothesis, the promoters of cytosolic GST and MAPEG genes contain antioxidant response elements through which they are transcriptionally activated during exposure to Michael reaction acceptors and oxidative stress.

Oxidative stress (OS) has been implicated in the pathophysiology of many neurological, particularly neurodegenerative diseases. OS can cause cellular damage and subsequent cell death because the reactive oxygen species (ROS) oxidize vital cellular components such as lipids, proteins, and DNA. Moreover, the brain is exposed throughout life to excitatory amino acids (such as glutamate), whose metabolism produces ROS, thereby promoting excitotoxicity. Antioxidant defense mechanisms include removal of O(2), scavenging of reactive oxygen/nitrogen species or their precursors, inhibition of ROS formation, binding of metal ions needed for the catalysis of ROS generation and up-regulation of endogenous antioxidant defenses. However, since our endogenous antioxidant defenses are not always completely effective, and since exposure to damaging environmental factors is increasing, it seems reasonable to propose that exogenous antioxidants could be very effective in diminishing the cumulative effects of oxidative damage. Antioxidants of widely varying chemical structures have been investigated as potential therapeutic agents. However, the therapeutic use of most of these compounds is limited since they do not cross the blood brain barrier (BBB). Although a few of them have shown limited efficiency in animal models or in small clinical studies, none of the currently available antioxidants have proven efficacious in a large-scale controlled study. Therefore, any novel antioxidant molecules designed as potential neuroprotective treatment in acute or chronic neurological disorders should have the mandatory prerequisite that they can cross the BBB after systemic administration.

The cholinesterase inhibitors (ChE-Is) attenuate the cholinergic deficit underlying the cognitive and neuropsychiatric dysfunctions in patients with AD. Inhibition of brain acetylcholinesterase (AChE) has been the major therapeutic target of ChE-I treatment strategies for Alzheimer's disease (AD). AChE-positive neurons project diffusely to the cortex, modulating cortical processing and responses to new and relevant stimuli. Butyrylcholinesterase (BuChE)-positive neurons project specifically to the frontal cortex, and may have roles in attention, executive function, emotional memory and behaviour. Furthermore, BuChE activity progressively increases as the severity of dementia advances, while AChE activity declines. Therefore, inhibition of BuChE may provide additional benefits. The two cholinesterase (ChE) enzymes that metabolize acetylcholine (ACh) differ significantly in substrate specificity, enzyme kinetics, expression and activity in different brain regions, and complexity of gene regulation. In addition, recent evidence suggests that AChE and BuChE may have roles beyond 'classical' co-regulatory esterase functions in terminating ACh-mediated neurotransmission. 'Non-classical' roles in modulating the activity of other proteins, regional cerebral blood flow, tau phosphorylation, and the amyloid cascade may affect rates of AD progression. If these additional mechanisms are demonstrated to underlie clinically meaningful effects, modification of the over-simplistic cholinergic hypothesis in AD that is limited to symptomatic treatment, ignoring the potential of cholinergic therapies to modify the disease process, may be appropriate. The specificity of ChE inhibitory activity, up-regulation of AChE activity and changes in the composition of AChE molecular forms over time, selectivity for AD-relevant ChE molecular forms, brain vs. peripheral selectivity, and pharmacokinetic profile may be important determinants of the acute and long-term efficacy, safety and tolerability profiles of the different ChE-Is. This review focuses on new evidence for the roles of BuChE and AChE in symptom generation and rate of underlying disease progression in dementia, and argues that it may be appropriate to re-evaluate the place of ChE-Is in the treatment of dementia.