Current Medicinal Chemistry - Central Nervous System Agents - Volume 5, Issue 1, 2005

The year 2005 began in the wake of the most catastrophic natural disaster of modern times: the destructive tsunami which has devastated much of coastal Southeast Asia and resulted in enormous loss of life and human suffering. I'm sure many readers donated generously to the various relief efforts following this tragedy. To be faced with human suffering on such a scale is feel at times overwhelmed by the enormity of the task of helping the victims of such a disaster. The alleviation of suffering from the degenerative disorders of the nervous system is a long-sought goal for medicinal and pharmaceutical scientists, and the slow progress and severity of the diseases can likewise wear at the dedicated researcher. But progress is being made, surely if more slowly than we would like. It is the intention of Current Medicinal Chemistry-Central Nervous System Agents to pursue the topic of therapeutic approaches to chronic degenerative disorders of the nervous system is several Hot Topic issues. This month, Professor Uri Saragovi of McGill University has guest-edited a collection of articles focused on this topic. The topic of Alzheimer's Disease, discussed in two of these articles, will be reprised in a later Hot Topic issue. The present issue is rounded out by two exceptionally interesting articles: One by Prof. Martyn Wood on 5-HT2c receptors in the action of atypical antipsychotics, and a sweeping review by Prof. Stefan Przyborski and colleagues on the manipulation of neural progenitor pathways as an approach to neural restoration. It is hoped this issue's articles, and those of the future, provide a basis for readers' continued ruminations on how to apply their intellectual gifts and physical energy to bringing hope to those who currently have none.

Alzheimer's disease (AD) is the most common dementia. Its frequency has increased dramatically in the last years due to the extended length of life. It presents cognitive symptoms inherent to the dementias, and a progressive and insidious deterioration. Aside from the cognitive deficits there are psychiatric symptoms related to the neurodegeneration of the different cerebral zones, with alteration of the neurotransmission. The etiologic hypotheses of the Alzheimer's Disease are complex; it is considered that the appearance of the disease is a consequence of the interrelation of genetic and neurobiological processes like colinergic hypothesis, amyloid hypothesis, glutamatergic hypothesis, oxidative hypothesis and inflammatory hypothesis. The diagnosis of the Alzheimer's Disease is by exclusion due to the fact that there are no accurate diagnostic methods in the life of the patient. However, the criteria of the diagnosis by exclusion should be relative considering the AD is one of the most frequent dementia, and we have now some possible orientators. The Mild Cognitive Impairment (MCI) is an entity definy because of the memory impairment without another deficit, and a normal global function. However, some studies had demostrated the MCI has an evolution to Alzheimer's disease 12% per year. The pharmacological treatment in early stages of the disease is useful to improve the cognitive disorders to slow down the advance of the deficits, and to diminish the psychiatric symptoms such as agitation, depression and the psychosis. The colinesterase inhibitors are the most studied for the treatment of the AD: tacrine, rivastigmine, donepezil,and galantamine. Vitamin E, estrogens, antiinfamatory drugs, ginkgo biloba and another strategies has been utilized with different efficacy. The future will show new horizons in relationship with neuronal growth factor, antiamyloid therapies and genetic therapies.

Striking advances have been made in recent years toward potential therapies for Alzheimer's disease. Alzheimer's disease, which is the leading cause of dementia in the elderly, is pathologically defined by the presence of amyloid plaques, composed of the amyloid-beta protein, and neurofibrillary tangles. The amyloid pathology has been associated with decreased synaptic plasticity and neurodegeneration, thereby explaining the visibly decreased cognitive function and evident dementia. Subsequently, a large number of studies have been launched, which attempt to disrupt the progression from Ab aggregation to plaque formation. These studies have involved the use of beta-sheet breakers, secretase inhibition, immunotherapy and anti-inflammatories, the most notable findings of which are discussed in this review.

Neurotrophin proteins bind to p75NTR and Trk receptors to trigger potent biological effects including modulation of neuronal survival, promotion and maintenance of neurite networks, upregulation of neural function and modulation of synaptic plasticity. Factors limiting clinical application include poor stability, restricted nervous system penetration and a wide array of biological activities that may lead to adverse effects. A potential approach for addressing these limitations is the development of synthetic, small molecule, neurotrophin mimetics with favorable profiles of stability, tissue penetration and targeted biological actions. Neurotrophin mimetic strategies include development of agents that act at neurotrophin receptors as agonists, partial agonists, inverse agonists or antagonists to promote, inhibit or modify neurotrophin- related signal transduction. The existence of a two-receptor system for neurotrophins, suggests the possibility that small molecules mimicking p75NTR versus Trk-interacting neurotrophin domains might differentially promote selected neurotrophin functions. Moreover, the principle of differential receptor activation predicts that different mimetics acting at a given neurotrophin receptor might elicit differential signaling patterns and biological effects. For example, prevention of neuronal death in the absence of the neurotrophin effects of upregulation of pain transduction or inflammation might constitute a desired activity profile. Synthesis of active peptide mimetics corresponding to specific neurotrophin domains has established the proof-of-principle that neurotrophin domain mimetics can be created that exhibit antagonist or agonist features and points to the possibility of creating non-peptide, small molecule mimetics with favorable medicinal properties and targeted neurotrophin activities.

Glaucoma is a neurodegenerative disorder that affects the optic nerve and the inner layers of the retina. Increased intraocular pressure is a major risk factor in the disease. Chronic elevation of intraocular pressure specifically induces the death of retinal ganglion cells. By developing animal models of the disease, the scientific community has been able to make progress in understanding the mechanisms leading to the death of retinal ganglion cells, the molecular mechanisms of the pathology, and developing new pharmacological interventions. In this report, we review and compare animal models of glaucoma. We find that the episcleral cauterization model offers many advantages over other in vivo models. Its feasibility and lack of frequent complications make it the most extensively used animal model of glaucoma. Furthermore, we discuss features related to the pathogenesis of the disease and compare it with other models of retinal ganglion cell damage (e.g. optic nerve axotomy and excitotoxicity). In the last section, we focus on drug candidates for neuroprotective treatment of glaucoma, and discuss their likely mechanisms of action.

Despite the controversial discussion about amyloid-β as a cause or consequence of Alzheimer disease pathophysiology, one of the most devastating neurodegenerative disorders, all researchers working in this field agree that oxidative stress is intimately associated with Alzheimer disease. This review will focus primarily on oxidative stress associated to disturbances in energy metabolism, with special emphasis on the role of mitochondrial dysfunction and the overproduction of reactive oxygen and nitrogen species. These free radical species attack neuronal lipids, proteins and nucleic acids inevitably leading to neuronal dysfunction. These neuronal alterations can be measured using several markers such as protein carbonyls and 3-nitrotyrosine (protein oxidation markers), malondialdehyde, thiobarbituric acid-reactive substances, 4-hydroxynonenal and acrolein (lipid oxidation markers), 8-hydroxyguanosine and 8-hydroxy-2'-deoxyguanosine (nucleic acid oxidation markers) and advanced glycation end products (glyco-oxidation marker). The prompt identification of early signs of oxidative stress and its potential neuronal targets can open a window for the development of new therapeutic strategies envisaged to prevent or, at least, ameliorate the symptoms of Alzheimer disease. In this line, and since oxidative damage occurs due to an imbalance between reactive species production and cell antioxidant defenses, we will discuss in brief the use of antioxidant-based therapies and their effects in the fight against the oxidative stress occurring in Alzheimer disease.

The atypical antipsychotic drugs (APD) are characterised by an interaction with the 5-hydroxytryptamine (5- HT)2 receptor. Following the identification of the 5-HT2A, 5-HT2B and 5-HT2C receptor subtypes and the development of more selective compounds for these receptors, the role of these receptors in the pharmacological profile of APD has been studied. Although initial interest focussed on the 5-HT2A receptor, recent evidence has suggested that an interaction with the 5-HT2C could be more important. This has been limited by suggestions that 5-HT2C receptor antagonism in APD may be associated with the severe side-effect of weight gain. This review highlights the evidence suggesting that 5-HT2C receptor antagonism could have important benefits in APD profile and that 5-HT2C receptor antagonism does not directly contribute to weight gain.

Progress over the last decade has confirmed the occurrence of de novo neurogenesis within discrete regions of the adult brain. It has been demonstrated that under certain conditions neurogenesis can be stimulated above basal levels in the adult, and that resident pools of adult progenitors can be manipulated to generate new neurons in situ. Undoubtedly, these reports prelude possibilities for applications in regenerative medicine. Much attention is now being focused on the elucidation of the discrete mechanisms that are involved in the induction of the neurogenic response in the adult brain and whether these pathways can be pharmacologically manipulated to endogenously replace lost cells and alleviate neuropathy. There is evidence that the re-expression of many key molecular components of the various pathways controlling cellular proliferation, migration and differentiation during development can be re-induced within the mature brain. Recent reports show that the expression of a number of these developmentally-associated molecules occurs in close association with adult progenitor proliferation and neurogenesis, signifying an additional role for these systems in eliciting the adult neurogenic response. Here we review the literature regarding this phenomenon, with reference to the main candidate pathways involved including bone morphogenetic protein, sonic hedgehog and Wnt signalling pathways, and discuss the progress which has been made in the use of small molecules to manipulate these pathways and affect adult neurogenesis in situ.