Recent Patents on CNS Drug Discovery (Discontinued) - Volume 4, Issue 3, 2009

Alzheimer's disease is the most common cause of dementia in the elderly. Currently its clinical assessment is based on the exclusion of other forms of dementia and a definitive diagnosis requires a confirmation by examination of post-mortem brains. Therefore, there is a strong need to find easy measurable AD biomarkers that could facilitate the early diagnosis and monitoring the efficacy of the few therapies currently available. This would favor the development of further therapeutic approaches. Recently, dozens of biomarkers altered in peripheral tissues and body fluids have been patented by a variety of approaches, including transcriptomics, proteomics and peptidomics. However, assays for the routine laboratory diagnosis of AD are not available yet. The validation of these biomarkers is hindered by the fact that patient classification relies on clinical diagnosis that is not always accurate and this problem obstacles the enrollment of well characterized large patient cohorts needed for confirmation. This review provides an update of the status of research on AD peripheral biomarkers in the current post-genomic era, including recent patents in the field.

The market for pain treatment is a major segment of nervous system pathologies. Despite this dynamism, the management of some pain conditions remains a clinical challenge. Neuropathic pain arises as a direct consequence of a lesion or disease affecting the somatosensory system. It is generally a chronic and disabling condition which is difficult to treat. Antidepressant drugs are recommended as one of the first line treatments, but they display noticeable side effects and are not effective on all patients. Using a murine model of neuropathy, we demonstrated that the stimulation of β2- adrenergic receptors (β2-AR) is not only necessary for antidepressant drugs to exert their antiallodynic action but that it is in fact sufficient to alleviate neuropathic allodynia. Chronic, but not acute, treatment with β-mimetics such as terbutaline, salbutamol, fenoterol, salmeterol, ritodrine, isoprenaline (isoproterenol), metaproterenol (orciprenaline), procaterol, formoterol, clenbuterol or bambuterol, relieves allodynia. Agonists of β2-ARs, and more generally any molecule stimulating β2-ARs such as β-mimetics, are thus proposed as potential new treatments for neuropathic pain. Clinical studies are now in preparation to confirm this potential in patients with neuropathic pain. This article reviews the findings leading to propose β-mimetics for neuropathic pain treatment and other recent patents on the topic.

Disorders affecting the central nervous system frequently involve programmed neuronal loss. There are wellestablished changes in gene expression that occur in neurodegenerative diseases, and traumatic and ischemic injuries. Yet, we currently lack sufficient knowledge of the underlying mechanisms leading to the altered gene expression profiles affecting cell survival in the brain and spinal cord. The cell loss is accelerated by the induction of pro-cell death gene expression profiles through an altered balance of pro- and anti-apoptotic transcription factors. Dysregulation of these transcription factors constitutes one of the earliest events in these disorders and may offer a therapeutic window of opportunity for intervention across a narrow time period prior to irreversible neuronal death. There has been increasing interest in the modulation of these cell death factors to prevent or mitigate damage to neurons, with the goal of improving the lives of affected individuals. Here we review some of the recent patents that have been developed in the course of this research in the context of five different transcription factors.

Novel approaches in the understanding of the neurodegeneration observed in Alzheimer's disease (AD), involving neurochemical as well as biochemical techniques are being developed, opening up new possibilities in the direction of a metabolic degeneration. Indeed, brain lipids are closely involved in amyloid β-related pathogenic pathways. An important modulator of lipid homeostasis is the pluripotent peptide leptin, which has been shown to reduce amyloid β levels and tau-related pathological pathways, the major pathological hallmarks of AD. These data suggest that leptin holds promise as a novel therapeutic tool for AD. In this article, with some patent literature we will review here some of the most promising approaches involving leptin to cure and prevent, rather than to treat, AD symptoms.

Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disorder. The recent Metal Hypothesis states that the interaction of Amyloid beta (Aβ, the main constituent of senile plaques) with transition metals is at the basis of AD neurodegeneration. This hypothesis is based on in vitro studies demonstrating that metals (copper, zinc) accelerate the aggregation and precipitation into plaques of Aβ, ultimately leading to synaptic dysfunction and accelerated amyloidogenesis. Recently, we have identified in AD patients a specific ‘copper disease’ marker, consisting in a serumincrease of copper not bound to ceruloplasmin, named ‘free’ copper. Several patents have been issued in the recent years and many clinical trials have been attempted in search of an anti-metal effect counteracting AD progression. Some of them have delivered very encouraging results. These anti-metal agents, however, have also shown adverse events. This work is aimed at reviewing ‘old’ and ‘new’ attitudes towards the use of anti-copper complexing agents or biological molecules which induce or maintain a state of copper malabsorption, such as zinc compounds, paying special attention to how such a rethinking of ‘old’ clinical trials might trace new routes in planning ‘modern’ ones.

For over fifteen years, N-methyl-D-aspartate receptor (NMDAR) mediated glutamatergic neurotransmission has generated interest because of its putative role in the pathophysiology of schizophrenia. Thus far, all antipsychotic medications have centered on manipulating the dopamine receptor to treat psychosis. These medications have limited efficacy, especially in treating the cognitive and negative symptoms of schizophrenia, and serious side effects. The NMDAR now provides an entirely new array of targets around which to focus new drug development. This paper first examines components of the glutamatergic synapse and discusses the relationship between decreased NMDAR function and schizophrenia. Then, human trials that have been conducted with agents that enhance NMDAR function, whether by molecules that activate the glycine co-agonist site (GCS), or by positive allosteric modulators (PAMs) that act on non- NMDAR are reviewed. In examining patents granted in the United States for treatment of schizophrenia based on normalizing glutamatergic neurotransmission, it seems academic researchers have focused primarily on GCS agents, and pharmaceutical industries have concentrated on synthesizing PAMs. The 21st century holds promise as the era in which an entirely new type of medication for schizophrenia may be created, one with more success at treating the debilitating negative and cognitive symptoms of this disease.

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