CNS & Neurological Disorders - Drug Targets - Volume 7, Issue 1, 2008

Neurons are typically post-mitotic cells. This means that they are expected to have a life span comparable to that of their carriers. Unfortunately, sometimes, they die prematurely as a result of complex processes known as “neurodegeneration”. Neurodegenerative diseases are now generally considered a group of disorders that seriously and progressively impair the functions of the nervous system through causing the selective neuronal vulnerability of specific brain regions. Neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer Disease (AD), Multiple Sclerosis (MS), and prion disease represent several distinct categories of disease and each manifests its own unique symptoms. However, the diseases share several common features, particularly the aggregation and deposition of abnormal proteins. Neurodegenerative disorders are associated with high morbidity, and few or no effective treatments have been available until now. Neurodegenerative diseases represent a threat to mankind in a variety of guises and induce chronic suffering and debilitation in about 2% of the worldwide population. Moreover, the increase in lifespan of western populations will mean that these neurodegenerative diseases will become more common. Consequently, it is estimated that the number of PD patients will double to between 8.7 and 9.3 million by 2030. As a group, these disorders are a major burden on health care systems compared with other causes of death and the costs of treatment are expected to rise sharply. Despite the enormous amount of progress we have made in terms of understanding the aetiologies of these diseases in the last few years, important questions remain unanswered. This special number deals with this hot topic and is produced by leading groups in the neuroscience field with the aim of summarizing recent advances in genetic, epideniological, molecular and cellular biology research that have increased our knowledge of the mechanisms that give rise to degenerative processes and, in general, to alterations of the structure and function of the nervous system. These contributions give insight into new pharmacological therapies for their treatment and review new and old drugs aimed at interrupting or at attenuating different pathogenic pathways of neurodegeneration and/or at ameliorating symptoms. The pharmaceutical industry faces arguably its most difficult challenge in attempting to develop therapeutics for neurodegenerative disease. The development of disease-modifying therapeutics that addresses the principal causes of neurodegenerative disease is still in its infancy. Moreira et al. review the role played by oxidative stress in the development and progression of AD and show how ROSmediated oxidative damages proteins, lipids, nucleic acids and sugars in AD and how this damage results from extensive mitochondrial and metal abnormalities. They present data supporting the notion that the oxidative modifications that occur in AD may elicit compensatory mechanisms, such as Aβ deposition and hyperphosphorylated tau that try to restore the redox balance in an attempt to avoid neuronal death. However, with the progression of AD and the consequent increase of reactive species, efficient removal of Aβ-metal complexes and hyperphosphorylated tau would be overtaken by their disproportionately high generation, resulting in an uncontrollable growth of plaques and NFTs and, consequently, an increase in reactive species generation. Amyotrophic lateral sclerosis (ALS) is the disorder reviewed by Tripathi and Al-Chalabi. This is a neurodegenerative disease of motor neurons resulting in progressive paralysis and respiratory failure. About 1 in 250,000 people suffer from ALS. The causes of ALS are largely unknown, but the only disease-modifying therapy, riluzole, was designed based on one hypothesis of disease causation, the excitotoxic hypothesis. In this paper they review the current situation regarding ALS and new therapeutic opportunities. The last two papers are about PD. Ali Qureshi et al. review the relation between vitamin B12 deficiency and neurotoxicity of homocysteine and nitrite (a metabolite of nitric oxide) in PD patients treated with levodopa (L-Dopa). A linear relationship between the CSF levels of nitrite with Glutamic acid and homocysteine exists and suggests that the production of nitrite is interrelated with the neurotoxic level of homocysteine. The levels of nitrite and homocysteine resulting in the deficiency of vitamin B12 are some of the factors promoting degeneration in PD through neurotoxic effects. Therefore, higher dietary intakes of folate, vitamin B12, and vitamin B6 might decrease the risk of PD through decreasing plasma homocysteine. Finally, Di Giovanni tries to answer the difficult question of the possibility of preventing PD in the future. Indeed, PD is still fatal, there is at present no cure for it and there are no proven therapies for prevention. Although there is evidence of the existence of risk and protective factors, these are not strong enough to warrant specific measures in an attempt to diminish risk or enhance protection. In the first part of his review new neuroprotective and neurorestorative therapies with their advantages and disadvantages are discussed. In the latter section, various dietary recommendations, lifestyle, environmental and other factors in reducing the risk of PD are analysed. The scenario that results from this special issue is that, despite the enormous research focused on neurodegenerative disorders, the underlying pathophysiology is not yet understood in sufficient detail. The situation is certainly a consequence of the complex interplay of genes, environment and their myriad interactions. There is not as yet a clear means of establishing efficacy in slowly progressing, late-onset disorders. Given the nature of these diseases, future therapeutics will need to be paired with tests for biomarkers indicating onset of brain pathology that precedes overt clinical symptoms. Therefore, it is of paramount importance to reveal those who are at high risk of developing these neurological disorders and allow them start an early program of prevention. This might involve a brain-healthy diet, very similar to a heart-healthy diet, and moderate physical activity with the aim of avoiding the other risk factors known so far.

Oxidative stress occurs early in the progression of Alzheimer disease, significantly before the development of the pathologic hallmarks, neurofibrillary tangles and senile plaques. All classes of macromolecules (sugar, lipids, proteins, and nucleic acids) are affected by oxidative stress leading, inevitably, to neuronal dysfunction. Extensive data from the literature support the notion that mitochondrial and metal abnormalities are key sources of oxidative stress in Alzheimer disease. Furthermore, it has been suggested that in the initial stages of the development of Alzheimer disease, amyloid-β deposition and hyperphosphorylated tau function as compensatory responses to ensure that neuronal cells do not succumb to oxidative damage. However, during the progression of the disease, the antioxidant activity of both agents is either overwhelmed or, according to others, evolves into pro-oxidant activity resulting in the exacerbation of reactive species production.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons resulting in progressive paralysis and respiratory failure. About 1 in every 400 people dies of ALS, usually within 3 to 5 years of symptom onset. The lack of effective therapy means that although the incidence is comparable to that of multiple sclerosis, the prevalence is low. The causes of ALS are largely unknown, but the only disease-modifying therapy, riluzole, was designed based on one hypothesis of disease causation, the excitotoxic hypothesis. In this paper we will review current ideas about the causes of ALS and the therapeutic opportunities they suggest.

This review deals with the results showing the relation between vitamin B12 deficiency and neurotoxicity of homocysteine and nitrite (a metabolite of nitric oxide) in Parkinson's patients treated with levodopa (L-Dopa). We have already reported a linear relationship between the CSF levels of nitrite with glutamic acid and homocysteine suggesting that the production of nitrite is interrelated with the neurotoxic level of homocysteine. The levels of nitrite and homocysteine resulting in the deficiency of vitamin B12 are some of the factors promoting degeneration in Parkinson's disease. This review emphasizes the importance of these parameters in designing suitable drug therapy for Parkinson disease. Additionally, there is evidence that increased homocysteine levels might accelerate dopaminergic cell death in Parkinson disease (PD), through neurotoxic effects. Furthermore, levodopa (L-Dopa) treatment of PD results in hyperhomocysteinemia as a consequence of L-Dopa methylation by catechol-O-methyltransferase (COMT). Therefore, higher dietary intakes of folate, vitamin B12, and vitamin B6 might decrease the risk of PD through decreasing plasma homocysteine.

Parkinson's disease (PD) is the second leading age-related degenerative brain disease in the world affecting millions of people. This neurological disorder disrupts the quality of life of patients and their families, exerts an enormous emotional and physical strain on caregivers, and has a large cost for society. Moreover, the increasing numbers of elderly people in the population will result in a sharp increase in the prevalence of PD. The understanding of its pathophysiology and treatment has advanced at a very impressive rate during past decades. Nevertheless, PD is still fatal and there is at present no cure for it. Furthermore, there are no proven therapies for prevention of PD and although evidence exists of risk and protective factors, this is not strong enough to warrant specific measures in an attempt to diminish risk or enhance protection. Drug development programmes are engaged in finding neuroprotective and neurorestorative therapies or, even better, discovering drugs able to rejuvenate the dopaminergic neurons. The latest developments in this promising field will be discussed with reference to the current literature together with the advantages and pitfalls of suggested drugs. Finally, an analysis of the role of various dietary recommendations, lifestyle, environmental and other factors in reducing the risk of PD is carried out.

Neurotrophic factors were originally identified based on their ability to prevent naturally occurring cell death in the developing nervous system. Many of these proteins also promote survival after injury or protect neurons in toxin-disease models in animals. In addition to neuroprotective effects, these factors exert trophic effects on neurons, stimulating increases in neuronal metabolism, cell size, and process outgrowth. These properties underlie expectations for neurorestoration, in which growth of new axons and synapses could lead to functional improvement, which is of great interest for those patients who are already significantly disabled by disease. In spite of such encouraging experimental findings, clinical studies have proven largely disappointing. Although these proteins are natural products, they cannot be given orally, present uncertain pharmacokinetic behaviour, and large-scale production is labour and cost-intensive. For CNS diseases, the advantages of small molecule mimetics over proteins are evident. Small organic molecules can be modified to penetrate freely into the brain parenchyma and can be designed for oral administration. A detailed understanding of neurotrophic factor-receptor structure and interactions and intracellular signalling has been crucial in the design of peptidyl and non-peptidyl small molecule neurotrophin mimetics which interact directly with the receptor, or which potentiate neurotrophin activation of its cognate receptor. Another example of how such knowledge has been exploited is that of the low-affinity pan-neurotrophin receptor p75NTR, which can promote cell survival in the absence of Trk receptors. A pharmacophore designed to capture selected structural and physico-chemical features of a neurotrophin domain known to interact with p75NTR was applied to in silico screening of small molecule libraries to select neurotrophic compounds. Other strategies include intracellular effector-targeting approaches, which capitalise on knowledge of signalling pathways involved in neuronal cell survival and demise, and which can be agonised or antagonised to promote neuroprotection. This issue will begin with a brief overview on the biology neurotrophic proteins, followed by articles describing strategies taken towards the development of small molecule mimetics for neurotrophic factors and the emerging drug candidates, and will encompass both receptor-directed as well as intracellular signalling approaches. Moreover, exciting recent data describing G-protein-coupled receptor transactivation of Trk receptors and their downstream signalling pathways raise the possibility of using small molecule G-protein-coupled receptor ligands as a new strategy for promoting trophic effects during neurodegeneration. While many challenges lie ahead, the development of neurotrophic compounds is potentially very rewarding and appears to offer real promise for disease modification. Neurotrophic drug development, however, has historically been a high-risk approach. Nonetheless, novel emerging targets and technological improvements, as well as the development of biomarkers that can act as surrogates to assess drug activity at the defined molecular target together with a more focused effort on translational medicine approaches may facilitate the development of neurotrophic small molecules with lower associated attrition rates.

The neurotrophins are a family of closely related proteins that were first identified as survival factors for sympathetic and sensory neurons, and have since been shown to control a number of aspects of survival, development and function of neurons in both the central and peripheral nervous systems. Limiting quantities of neurotrophins during development control the numbers of surviving neurons to ensure a match between neurons and the requirement for a suitable density of target innervation. Biological effects of each of the four mammalian neurotrophins are mediated through activation of one or more of the three members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB and TrkC). In addition, all neurotrophins activate the p75 neurotrophin receptor (p75NTR), a member of the tumour necrosis factor receptor superfamily. Nerve growth factor (NGF), the best characterised member of the neurotrophin family, sends its survival signals through activation of TrkA and can induce death by binding to p75NTR. Neurotrophin engagement of Trk receptors leads to activation of Ras, phosphatidylinositol 3-kinase, phospholipase C-γ1 and signalling pathways controlled through these proteins, including the mitogen-activated protein kinases. Neurotrophin availability is required into adulthood, where they control synaptic function and plasticity, and sustain neuronal cell survival, morphology and differentiation. Preclinical studies point to the therapeutic potential of neurotrophic factors in preventing or slowing the progression of neurodegenerative conditions. Given the difficulties inherent with a protein therapeutic approach to treating central nervous system disorders, increasing attention has turned to the development of alternative strategies and, in particular, small molecule mimetics. This article will provide an overview of neurotrophin biology, their receptors, and signalling pathways, followed by a description of functional mimetics of neurotrophins acting at Trk receptors. Moreover, exciting recent data describing G-protein-coupled receptor transactivation of Trk receptors and their downstream signalling pathways raise the possibility of using small molecules to elicit neuroprotective effects.

Ligand-independent and/or proNGF-induced p75NTR signaling has emerged as a potential major contributor to a number of pathological states, including axotomy-induced death, motor neuron degeneration, neuronal degeneration in Alzheimer's disease and oligodendrocyte death following spinal cord injury. A long standing goal in the neurotrophin field has been the development of non-peptide, small molecules capable of functioning as specific ligands at neurotrophin receptors such as p75NTR to promote desired biological outcomes. Synthetic peptides modeled on neurotrophin protein domains have been found to bind to and activate various neurotrophin receptors, raising the possibility that active, nonpeptide, small molecule ligands might also be identified; however, traditional high-throughput screening approaches have been largely ineffective in identifying such compounds. Using pharmacophores derived from the structure of loop 1 of nerve growth factor, non-peptide, small molecules that function as p75NTR ligands to promote survival and block proNGFinduced death have recently been identified. Small molecule p75NTR ligands, with high potency and specificity, may provide novel therapeutic approaches for neurodegenerative diseases, neurotrauma and other pathologic states.

Neurotrophic factors, and in particular the neurotrophins, restore the function of damaged neurons and prevent apoptosis in adults. The potential therapeutic property of the neurotrophins is however, complicated by the peptidergic structure of these trophic factors, which impairs their penetration into the brain parenchyma, and therefore makes their pharmaco-therapeutic properties difficult to evaluate. In this article we will focus on the neurotrophin Brain-derived neurotrophic factor (BDNF) and its receptors to address various therapeutic strategies that may overcome this problem. We will call this strategy “small molecule approach” because it relies on increasing the function of endogenous neurotrophins by pharmacological compounds that induce synthesis and release of neurotrophins in relevant brain areas or by small synthetic molecules that bind and activate specific neurotrophin receptors. The ability of small molecules to mimic BDNF has a potential therapeutic importance in preventing neuronal damage in several chronic neurodegenerative diseases including Parkinson's Disease, Alzheimer's Disease, and AIDS dementia.

The signaling pathways which contribute to neuronal death during development, aging and disease have been extensively studied. While initial efforts focused on developmental death, increasing evidence suggests that mitogenactivated protein kinase pathways play a role in human pathology. In particular, the c-Jun N-terminal kinases (JNKs), mitogen- activated protein kinases activated by extracellular stimuli including stress, are a major focus. Knock-out mouse studies have demonstrated that removing particular JNK genes can reduce the severity in various disease scenarios, including those which are used to model Parkinson's disease and cerebral ischemia. In addition, activation of JNKs can be seen in human disease tissue. In this review we bring together the evidence for JNK being an important regulator of neuronal loss and outline the advancement of small molecule inhibitors for future therapeutic intervention.

Embryonic stem cells (ESC) are a source of renewable cells, which possess a phenomenal potential to differentiate into a myriad of cell types. Thus, ESCs offer a potentially unlimited supply of cells, which can be deployed in developing cell-based therapies. The in vitro differentiation capacity of ESC into derivatives of the neuronal lineage has been demonstrated and the functionality of the ESC derived neuroprogenitors, upon transplantation into in vivo models has been substantiated. In this review, we discuss various approaches to directing ESC towards neural lineages and protocols for sorting and selection of differentiated progenies. We examine in particular in vitro differentiation of ESC to mid-brain dopaminergic (DA) neurons and glial cells and the potential issues related to the transition to the clinic.

Neurotrophic factors comprise a broad family of secreted proteins that have growth promoting, survival promoting and differentiation inducing activities. Disruption of neurotrophic factor signalling is a characteristic of many central and peripheral nervous system disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, and peripheral neuropathy and pain. It follows that treating patients with neurotrophic factors might be beneficial in a range of neurological diseases. However, the promising results seen in animal models of disease have not translated well into clinical trials due to the poor pharmacokinetics associated with the intact proteins, in particular, their short in vivo half-life, low blood brain barrier permeability, limited diffusion, and undesirable effects through multiple receptor interactions. This has been the main motivation for the design of small molecule modulators of the neurotrophic factor pathways. The review gives a brief survey of the various strategies to design mimetics that have been reported in the literature with special emphasis on the tandem repeat peptide agonist approach for BDNF/NT-4/5 and N-cadherin mimetics.