Current Medicinal Chemistry - Central Nervous System Agents - Volume 5, Issue 4, 2005

Alzheimer's disease (AD) is one type of dementing central nervous amyloidosis characterized by two different types of fibrillar deposits, namely senile plaques and neurofibrillary tangles. Amyloid-β-proteins (Aβ) are the major constituents of senile plaques. The aggregation of soluble Aβ into insoluble amyloid fibrils is believed to be an important step in the pathogenesis of AD and the prevention of this process therefore seems to be a promising strategy for the treatment of AD. Laminin is an important extracellular matrix (ECM) protein which has been reported to accumulate in the senile plaques. It supports such biological activities as cell adhesion, cell proliferation, neurite outgrowth. Recent reports have revealed that laminin inhibits both Aβ fibril formation and Aβ neurotoxicity in vitro . Laminin-related peptides, which have almost the same biological activities as laminin, have also recently been reported to inhibit Aβ fibril formation and/or Ab neurotoxicity. Finally, Laminin can induce a complete disaggregation of Aβ amyloid fibrils by disassembly into protofibrils and subsequently into an amorphous aggregate. These results thus suggested that laminin or its related peptides may be useful as an effective therapeutic agent for the treatment of AD.

A broad overview of neurotoxins is presented based on electron transfer, reactive oxygen species, and oxidative stress. Although mode of action is complex, these aspects evidently play an important role in many cases. It is relevant that metabolites from toxins generally possess electron transfer functionalities which can participate in redox cycling. Much evidence exists in support of the theoretical framework. Toxic effects at the molecular level include lipid peroxidation, DNA attack, adduction, enzyme inhibition, oxidative attack on the CNS, and cell signaling. The toxins fall into many categories, including drugs, industrial chemicals, abused drugs, reproductive toxins, metal compounds, pesticides, and herbicides. Beneficial effects of antioxidants are documented, which may prove clinically useful. Knowledge of mechanisms operating in CNS insults should prove useful in drug design.

Currently, a handful of FDA approved drugs are commercially available to treat Alzheimer's disease (AD). Among these, Tacrine (Cognex), Donepezil (Aricept), Rivastigmine (Exelon), Galantamine (Reminyl) and Memantine (Nemenda; Forest) are either acetylcholinesterase or N-methyl-D-aspartate antagonists. These are only palliative solutions, however, and side effects remain an important concern. Clearly, the search for more potent and effacious drugs for the treatment of AD is one of the most pressing pharmacological goals, and many more drugs are either in clinical trials or are being tested in laboratories around the world, both in academia and industry. In this review, we will compare the aforementioned five drugs with several other molecules that are currently in clinical trials or are ready to go into clinical trials. These will include antioxidants, metal chelators, monoamine oxidase inhibitors, anti-inflammatory drugs, as well as other AChE and NMDA inhibitors. In addition, medicinal chemistry approaches toward designing better pharmaceuticals will be discussed.

Alzheimer's disease (AD) is triggered by the pathophysiological cleavage of a single transmembrane glycoprotein denominated amyloid β-protein precursor (AβPP) rendering amyloid β-peptide (Aβ) that aggregates in β- sheets forming the neuritic plaques. Since AbPP is playing a key role in AD development, this review will be focused in the structure, proteolytic processing, related secretases, mutations, localization and physiological role of AβPP protein. AβPP is present in several tissues and can be spliced at different exons rendering up to ten AβPP isoforms. The most abundant isoforms are AβPP770, AβPP751 and AβPP695, being the last one the predominant isoform in neurons. Mutations in the AβPP sequence or in the secretases that cleavage AβPP determinate an early onset of AD. AβPP and the secretase activities involve in the non amyloidogenic and the amyloidogenic pathways are putative therapeutic targets in AD, but their relationships with other physiological functions can produce controversial results.

The life cycle of a protein consists of highly regulated stages of synthesis, maturation, activity, and degradation. The last stage of this cycle frequently occurs through the ubiquitin-proteasome system, which tags and destroys proteins in the cell. Work in recent years regarding the ubiquitin-proteasome system has extended into the field of neurobiology, where the system is critical for proper neuronal function. In this review, we summarize existing knowledge regarding the ubiquitin-proteasome pathway and recount recent studies that frame its importance in neuronal development and synaptic plasticity. Furthermore, we discuss the evidence for protein degradation in neuropathologies, concentrating on neurodegenerative disorders characterized by ubiquitin-rich protein aggregates. We conclude by surveying ongoing drug discovery efforts directed at the ubiquitin-proteasome pathway. Although the current focus of potential proteasomal drugs is on cancer, the prevalence of this pathway in neuronal function makes it a tantalizing target for future central nervous system therapeutics.

Several lines of evidence suggest a role for oxidative cascades of events leading to neurodegeneration associated with Parkinson's, Alzheimer, Huntington diseases, and amyotrophic lateral sclerosis. In agreement with the notion of oxidative/nitrosative involvement in these chronic diseases, in vivo models of disease as well as biochemical and epidemiological evidence suggest a neuroprotective role for natural antioxidant polyphenols in neurodegenerative diseases. However, the molecular mechanisms for neuroprotection do not merely rely on a direct radical scavenging/antioxidant activity. Rather, polyphenols may function at several cellular levels, including direct interaction and modulation of enzymatic activities and the regulation of signaling pathways with implications for cell survival and death. Nitric oxide is a paradigmatic example. In view of the wide collection of activities of nitric oxide in the brain, ranging from synaptic plasticity to excitotoxicity, the regulation of its rate and pattern of production and decay in tissues by polyphenols is of obvious physiological relevance. Thus, the elucidation of polyphenol activities at the molecular level may lay the foundations for new pharmacological approaches in relation to neurodegeneration. In this review, the molecular mechanisms underlying the potential health promoting effects of natural polyphenols in connection with neurodegenerative diseases are discussed. Additionally, we provide evidence for a modulatory effect of hydroxycinnamic phenol caffeic acid on glutamate NMDA receptor/nitric oxide pathway in hippocampal slices.