It has long been known that
It has long been known that native BChE is a major factor in the inactivation of cocaine, an ester-type drug of abuse . But recently some researchers conceived the idea that BChE mutations could improve that function to a point that would favorably impact cocaine overdose. Rapid progress was made in different laboratories approaching this goal, assisted by computer-based models of cocaine docking in the enzyme’s active site, which led to successful predictions to improve drug binding and hydrolysis . At present, near-optimal BChE versions that enhance the rate of cocaine inactivation by more than a thousand-fold have been generated . Efficacy with exogenous administration of such cocaine-hydrolyzing BChE variants can also suffer because they are more rapidly cleared from the circulation than native BChE. However, site-directed mutagenesis introducing disulfide bonds between two mutant BChE subunits led to an approximate doubling of circulatory zilpaterol in rats . In our hands, mice and rats treated with a cocaine hydrolase showed no reaction whatsoever to doses of cocaine that would ordinarily have been lethal within 1–2 min. In contrast, they merely continued normal cage-side activities, eating and grooming, just like vehicle-controls .
Several studies on the safety of BChE as an OP bioscavenger or cocaine hydrolase have reported no overt signs of toxicity, even with massive increases in circulating BChE activity. While the severity of either nerve agent intoxication or cocaine abuse may warrant taking the risk for possible side effects of large increases in circulating BChE levels for extended periods, the emerging role of BChE in the metabolism of ghrelin could be of concern. Long-term studies should be conducted to evaluate more subtle physiological changes that may accompany prolonged BChE elevation. Of special note, altered affective behaviors in mice with high levels of genetically-modified BChE were disconcerting at first, but they led to highly positive effects such as reductions in aggression and stress-induced fear , , .
Acknowledgements This work was primarily supported by grants from the Defense Threat Reduction Agency (HDTRA1-13-1-0042, CP), National Institute for Environmental Health Sciences (ES008739, CP) and a Translational Avant-Garde Award from the National Institute on Drug Abuse (DA42492, SB).
Introduction Alzheimer’s disease (AD) is an age-related chronic neurodegenerative disorder occurring in middle or late life , , , . The disease is associated with progressive dementia leading to severe disability in performing the daily life activities . Memory deterioration, loss of cognitive function and privation of personality are common symptoms of the disease . AD is progressive and irreversible leading to abnormal changes in the brain that interferes with many aspects of brain functions and worsens over time . AD progresses in stages ranging from mild forgetfulness and cognitive impairment to great loss of mental abilities. In highly advanced stages of AD, the patient becomes helpless and dependant on others for aspects of everyday life activities . A family history may play a role in increasing one’s risk of developing AD . Postmortem brain tissue samples from AD patients revealed progressive accumulation of β-amyloid proteins (Aβ) together with tau (τ)-protein aggregation leading to shrinkage and death of neurons , . Several theories have been proposed to explain the mechanism of AD development , , among which the cholinergic hypothesis has become the most leading theory to explain the etiology of the disease. This was based on the observation of cholinergic neurons loss in the brain area involved in cognitive and behavioral functions of AD patients. Furthermore, several centrally active anticholinergic drugs were found to induce dose-related cognitive deficits in humans . Accordingly, increasing levels of acetylcholine (ACh) in cholinergic synapses in the brain of AD patients would be expected to relieve symptoms associated with the disease , , , . Consequently, inhibition of acetyl cholinesterase (AChE), the enzyme responsible for the hydrolysis of acetylcholine, has become the most targeted approach for the development of agents active against AD , , , , , . However, it is well established that the use of acetyl cholinesterase inhibitors (AChEIs) for the treatment of AD can only alleviate the symptoms. Unfortunately no clinically approved drug has been discovered that can reverse the progress of the disease.