Alzheimer's Disease and Chronic Neuropathic Pain: a Structural Neurobiology Perspective

Alzheimer's disease (AD) is thought to be the leading cause in senile dementia, hence the development of an effective therapeutic treatment of this disease is of primary importance and would have a great social impact. It has been shown that, associated with AD, is a loss of the cholinergic response due to reduced activity of choline acetyltransferase, the enzyme responsible for the synthesis of acetylcholine (ACh) as well as reduced levels of nicotinic ACh receptors. Hence the rationale behind the current approach of cholinergic therapeutics used in the treatment of AD aims at targeting the inhibition of acetylcholinesterase (AChE) in the brain. Many years after the approval of symptomatic drugs, the improvement of old, and the development of new drugs targeting the cholinergic system is still pursued. In collaboration with pharmaceutical companies as well as academic research groups, we contributed to the screening process for new drugs showing a better pharmacokinetic as well as a pharmaco-dynamic profile, through the determination of the X-ray crystal structure of complexes with derivatives carefully selected among several others. The results obtained clearly pinpointed that in order to help to direct the rational design of new inhibitors and to elucidate the molecular determinants in enzyme inhibition, the crystallographic structure determination of molecular complexes at certain milestones along the elucidation of an enzymatic process or the development of interacting inhibitory drugs based on molecular modeling appeared to be a tool of choice. Chronic neuropathic pain presents a huge economic and social burden, with existing treatments largely unable to satisfy medical needs. The Nerve Growth Factor (NGF) though originally discovered as a trophic factor for sympathetic and sensory neurons during development, it now appears that in adults, levels of NGF are elevated in many acute and chronic pain conditions. Furthermore, preclinical animal models of inflammatory and neuropathic pain also show increased NGF levels, while the sequestration of NGF alleviates the associated hyperalgesia. Current options being explored include the development of humanized monoclonal antibodies to NGF or its tyrosine kinase receptor TrkA (also known as neurotrophic tyrosine kinase receptor, type 1). Administration of either antibodies has been shown to be effective in a number of preclinical models of pain, including interstitial cystitis, non-bacterial prostatitis and osteoarthritis. The monoclonal antibodies MNAC13 (anti-TrkA) and aD11 (anti NGF) are potent antagonists that prevent the NGF-TrkA interaction in vivo systems. In order to gain deeper insights into the molecular basis of their observed high affinities a structural and functional characterization of these antibodies and of their complexes with TrkA and NGF are actively being pursued. A detailed structural information on their antigenic recognition is expected to aid in the development of analogs as antagonists or agonists of neurotrophins that may have greater affinity or specificity for further experimental and therapeutic applications.