No abstract

The cholinergic hypothesis of decline in dementia, whereby deficits in learning, memory and behavior are caused, at least in part, by decreased levels of acetylcholine (ACh) in the brain, first emerged more than 20 years ago. The role for acetylcholinesterase (AChE) and its inhibition in this scheme has long been accepted, but findings from preclinical experiments and clinical trials have placed butyrylcholinesterase (BuChE) alongside AChE as an important contributor to the occurrence, symptoms, progression and responses to treatment in dementia. A number of new lines of evidence suggest that both cholinesterase inhibitors (ChEs) may have broader functions in the CNS than previously thought, which relate to both 'classical' esterase activities of the enzymes as well as non-classical actions unrelated to their enzymatic function. Data suggest involvement of the ChEs in modulating glial activation, cerebral blood flow, the amyloid cascade, and tau phosphorylation. It has therefore been speculated that some actions of the ChEs could affect the underlying disease processes in Alzheimer's disease (AD), and that pharmacological manipulation with ChE inhibitors may affect long-term disease progression. Focusing on new findings relating to BuChE, we review recent evidence that has extended knowledge into the roles of ChEs in health, disease and aging.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) hydrolyze the neurotransmitter acetylcholine and, thereby, function as coregulators of cholinergic neurotransmission. Although closely related, these enzymes display very different substrate specificities that only partially overlap. This disparity is largely due to differences in the number of aromatic residues lining the active site gorge, which leads to large differences in the shape of the gorge and potentially to distinct interactions with an individual ligand. Considerable structural information is available for the binding of a wide diversity of ligands to AChE. In contrast, structural data on the binding of reversible ligands to BChE are lacking. In a recent effort, an inhibitor competition approach was used to probe the overlap of ligand binding sites in BChE. Here, we extend this study by solving the crystal structures of human BChE in complex with five reversible ligands, namely, decamethonium, thioflavin T, propidium, huprine, and ethopropazine. We compare these structures to equivalent AChE complexes when available in the protein data bank and supplement this comparison with kinetic data and observations from isothermal titration calorimetry. This new information now allows us to define the binding mode of various ligand families and will be of importance in designing specific reversible ligands of BChE that behave as inhibitors or reactivators.

The main neural transplantation strategy in Parkinson disease (PD) has been focused on reinnervating the striatum. The clinical results reported in patients who receive transplants have been limited and do not justify the use of neural transplantation as a routine therapeutic procedure for PD. Identifying the optimal target for transplantation may be one of the critical factors for optimizing clinical outcomes. Evidence from preclinical studies indicates that simultaneous intrastriatal and intranigral grafts (double grafts) may produce a more complete functional recovery. The authors report the clinical and positron emission tomography (PET) scanning results in three patients enrolled in a safety and feasibility pilot study who received double grafts and who have been followed for up to 13 months posttransplantation. Patients included in the study had idiopathic PD. All patients underwent detailed assessments before and after surgery, in accordance with the Core Assessment Program for Intracerebral Transplantation. The patients received implants of fetal mesencephalic cell suspensions in the putamen and substantia nigra (SN) bilaterally. There were no intraoperative or perioperative complications. Follow-up PET scans demonstrated an increase in the mean fluorodopa uptake constant values in the putamen and SN 12 months postsurgery. Improvements were also noted in the total Unified Parkinson's Disease Rating Scale, Hoehn and Yahr, Schwab and England, and pronation/supination scores after transplantation. The authors demonstrate the feasibility of reinnervating the SN and striatum by using a double transplant strategy in humans.