Hippocampal structure and the action of cholinomimetic drugs

Abstract

Cholinomimetic drugs have become the clinical standard for the treatment of patients with dementia of the Alzheimer type (DAT). However, uncertainty remains as to the proportion of patients that respond to such drugs, and how one might predict the capacity for response before treatment is begun. The thesis of the present review is that the neuroanatomical integrity of the hippocampus determines, at least in part, the capacity of DAT patients to respond to cholinomimetic drugs. Neuroimaging studies suggest that volume losses and other neuroanatomical deformities of the hippocampus are common in patients with even mild DAT. Moreover, more severe neuroanatomical deformities of the hippocampus are associated with more severe dementia symptoms and more rapid clinical decline. Animal research, including studies of cholinergic antagonists, glutamatergic antagonists, hippocampal lesions, and animals with mutant amyloid precursor protein genes, demonstrate that behavioral abnormalities similar to those found in DAT patients, especially those related to memory, are associated with hippocampal pathology. Cholinomimetic drugs, in particular, the cholinesterase inhibitors, have been shown to reverse some but not all of these behavioral abnormalities. More research is needed in DAT patients to determine whether an analysis of hippocampal structure or function can reliably predict the outcome of treatment with cholinomimetic drugs. Further work in animals is also needed to determine the limitations of cholinomimetic drugs for reversing various types of cognitive deficits, and to develop and test other pharmacological strategies for the treatment of DAT. Drug Dev. Res. 56:531-540, 2002.

Effects of donepezil on amyloid-β and synapse density in the Tg2576 mouse model of Alzheimer's disease

“…Findings of reduced cholinergic activity and loss of cholinergic neurons in the brains of individuals with Alzheimer's disease (AD) formed the rationale for the development of acetylcholinesterase inhibitors as drugs to ameliorate the dementia associated with AD (Davis et al, 1992; Rogers et al, 1998; Francis et al, 1999; Tariot et al, 2000; Csernansky et al, 2002). Donepezil, an acetylcholinesterase inhibitor, is one of the most popular approved therapies for AD.…”

Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse model of Alzheimer’s disease

“…Loss of cholinergic neurons and reduced activity of choline acetyltransferase in the cerebral cortex and hippocampus, have also been consistent findings in AD (Cummings et al 1998, Francis et al 1999, West and Gundersen 1990, Mullan 2000. In fact, reduced cholinergic activity in the brains of individuals with AD formed the rationale for the development of acetylcholinesterse inhibitors as drugs to ameliorate the dementia associated with AD (Davis et al 1992, Rogers et al 1998, Tariot et al 2000, Csernansky, et al, 2002. Commonly prescribed cholinesterase inhibitors include donepezil, rivastigmine and galantamine (Moghul andWilkinson, 2001, Shigeta andHomma, 2001).…”

Neuroanatomical Predictors of Response to Donepezil Therapy in Patients With Dementia

“…This hypothesis was based on the premise that cholinergic circuits in the hippocampus are an important pharmacological target for AChE inhibitors. 9 Cholinergic fibers project from the nucleus basalis of Meynert to the hippocampus, and muscarinic and nicotinic cholinergic receptors are densely expressed throughout the hippocampus. 10 In addition, Riekkinen et al 11 previously reported a relationship between hippocampal volume and the clinical response to the AChE inhibitor tacrine.…”