Current Drug Targets-CNS & Neurological Disorders - Volume 4, Issue 1, 2005

Neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease and neurodegenerative conditions such as stroke and traumatic brain injury are leading causes of death in the Western world. Although displaying a diverse range of clinical symptoms, these neuropathologies have a commonality: the abnormal loss of neurons. While current treatments can reduce the symptoms associated with some of these pathologies, they do not stop the loss of neurons and hence do not slow down disease progression. Thus, there is an urgent need for the development of therapeutic drugs that will stop or reduce the loss of neurons in these diseases. Essential to this process of drug development is the identification of disease-related molecules that can be targeted by small molecule compounds and biomolecules. Compelling evidence gathered over the past decade has indicated that pathological neurodegeneration occurs as a result of an inappropriate activation of apoptosis, a cell suicide program. Intensive research has identified a large number of molecules and signal transduction pathways that promote or inhibit apoptosis. Inhibition of many of the molecules that promote apoptosis or stimulation of the activity of molecules that promote cell survival has been found to protect neurons in cell culture and in animal models of neurodegenerative disorders. Understanding the molecular mechanisms underlying apoptosis therefore offers promise of benefit to people suffering from neurodegenerative conditions. The overall aim of the reviews in this issue is to describe the latest and most exciting information on the identification of intracellular molecular targets involved in neurodegenerative conditions, and the development of potential neuroprotective drugs that act on them. D'Mello and Chin provide a description of the molecular mechanisms underlying apoptosis in neurons. A section of the review covers neuroprotective compounds that modulate the activity of specific signaling molecules involved in the regulation of apoptosis. It is well established that caspases, a family of cysteine proteases, play a pivotal role in the apoptotic process in both neurons and non-neuronal cell types. Prunell et al. review the current information on caspases. Focus is placed on ischemic stroke and the role of caspases in this neurological condition. Another family of proteins consisting of both anti- and pro-apoptotic members are the Bcl-2 proteins. Shacka and Roth provide a description of the Bcl-2 proteins. Their involvement in the development of the nervous system and in various neurodegenerative diseases has been reviewed. A separate section covers neuroprotective strategies targeting Bcl-2 proteins. A number of small molecule activators and inhibitors of individual Bcl-2 proteins have recently been identified. The efficacy of some of these small molecule modulators in preventing death of cultured neurons and in animal models of neurodegenerative diseases is described in the review. Among the biological factors that stimulate the activity of anti-apoptotic proteins are estrogens. A separate review by Simpkins et al. describes the neuroprotective effects of estrogen. The protective effect of estrogens is likely to be mediated by supporting mitochondrial function. Compelling evidence for oxidative stress, bioenergetic impairment and mitochondrial failure in the etiology of neurodegenerative diseases has been presented in this review. Besides mitochondrial dysfunction, acetylation and deacetylation of histones within chromatin and of other nuclear and cytoplasmic signaling proteins has been found to regulate neuronal survival. Langley et al. review the evidence that misregulation of histone acetylase transferases and / or histone deacetylases are involved in certain neurological syndromes and in neurodegenerative diseases such as Huntington's disease, Alzheimer's disease and amyotropic lateral sclerosis. The promise of histone deacetylase inhibition by small molecule compounds in the treatment of central nervous system disorders has also been discussed. Another target that is being explored for the treatment of neurodegenerative conditions is the c-Jun N-terminal kinase signaling pathway. CEP-1347, a compound that inhibits this pathway is already in a multi-center phase II / III clinical trial for the treatment of Parkinson's disease. Kuan and Burke review JNK signaling as a therapeutic target. Finally, Freeman and Barone describe the role of the hypoxia-inducible transcription factor (HIF) in neuroprotection. As described in the review, HIF is activated in response to stimuli such as hypoxia leading to the stimulation of cell survival genes. Several compounds which increase HIF activity have been developed and the utility of such compounds in the treatment of neurological disorders associated with hypoxia is being seriously considered.

Neurological diseases disrupt the quality of the lives of patients and often leads to their premature deaths. A common feature of most neurological diseases is the degeneration of neurons. It is generally accepted that neuronal loss, in these diseases, occurs by the inappropriate activation of a cell-suicide process called apoptosis. Drugs that inhibit neuronal apoptosis could thus be candidates for therapeutic intervention in neurodegenerative disorders. In this review we describe advances made in recent years on the molecules and signal transduction pathways that regulate neuronal apoptosis either positively or negatively. Emphasis is on molecules that are being targeted for the potential treatment of neurodegenerative conditions in humans. Furthermore, we will summarize results from studies performed using small-molecule neuroprotective drugs that target specific signaling molecules known to regulate neuronal apoptosis.

The Bcl-2 family of proteins contains both anti and pro-apoptotic members that have been shown to regulate neuronal cell death during development and in many models of acute and chronic neurodegeneration. This family of proteins can be divided into three distinct classes based on structure and function: the antiapoptotic sub-group; the pro-apoptotic, multi-domain sub-group; and the pro-apoptotic, BH3 domain-only sub-group. Alterations in the expression of Bcl-2 family members occur in several animal and human neurodegenerative diseases including Alzheimer's, Huntington's and Parkinson's diseases and Amyotrophic Lateral Sclerosis. Similar changes are seen in in vivo and in vitro models of acute neurodegeneration, including stroke and traumatic brain injury. Methods to increase the overall expression and / or function of anti-apoptotic Bcl-2 family members, and thus promote neuron survival, have been studied extensively in these models. Most treatment efforts focus on either the targeted delivery via viral vectors of anti-apoptotic members of Bcl-2 family members into the affected brain regions of interest, the generation of direct interactions of small molecule inhibitors with Bcl-2 family members, or the induced expression of Bcl-2 family members secondary to pharmacological manipulation. Although many challenges exist in the design of safe and efficacious Bcl-2 family mimetics for the treatment of neurodegeneration, such strategies offer great promise for preserving neuron viability, and hopefully function, in a variety of human neurological diseases.

Acetylation and deacetylation of histone protein plays a critical role in regulating gene expression in a host of biological processes including cellular proliferation, development, and differentiation. Accordingly, aberrant acetylation and deacetylation resulting from the misregulation of histone acetyltransferases (HATs) and / or histone deacetylases (HDACs) has been linked to clinical disorders such as Rubinstein-Taybi syndrome, fragile X syndrome, leukemia, and various cancers. Of significant import has been the development of small molecule HDAC inhibitors that permit pharmacological manipulation of histone acetylation levels and treatment of some of these diseases including cancer. In this Review we discuss evidence that aberrant HAT and HDAC activity may also be a common underlying mechanism contributing to neurodegeneration during acute and chronic neurological diseases, including stroke, Huntington's disease Amyotrophic Lateral Sclerosis and Alzheimer's disease. With this in mind, a number of studies examining the use of HDAC inhibitors as therapy for restoring histone acetylation and transcriptional activation in in vitro and in vivo neurodegenerative models are discussed. These studies demonstrate that pharmacological HDAC inhibition is a promising therapeutic approach for the treatment of a range of central nervous system disorders.

Cerebral ischemia is one of the major causes of morbidity and mortality in the Western world. Despite extensive research, adequate therapies are still elusive. Neuronal degeneration and death are hallmarks of stroke / ischemia. Understanding how the death machinery executes neuronal death in ischemia will provide therapeutic targets. Key to the death machinery are caspases: the family of cell death proteases. While much data has been published regarding caspase involvement in models of ischemia, the pathways have not been thoroughly defined. The specification of the caspases critical for death has been hampered by the use of nonspecific reagents. Thus many conclusions about specificity are unwarranted. In this review we discuss how caspases can be measured and review the existing knowledge of the roles of specific caspases in ischemia. We also discuss approaches to determining the molecules that execute ischemic death.

The c-Jun NH2-terminal Kinase (JNK) signaling pathway is frequently induced by cellular stress and correlated with neuronal death. This unique property makes JNK signaling a promising target for developing pharmacological intervention. Among several neurological disorders, JNK signaling is particularly implicated in ischemic stroke and Parkinson's disease. The inhibitors of the JNK signaling pathway include upstream kinase inhibitors (for example, CEP-1347), small chemical inhibitors of JNK (SP600125 and AS601245), and peptide inhibitors of the interaction between JNK and its substrates (D-JNKI and I-JIP). The mechanisms by which JNK signaling induces apoptosis and evidence of cytoprotective effects of these JNK inhibitors are summarized in the present review.

Oxidative stress, bioenergetic impairment and mitochondrial failure have all been implicated in the etiology of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), as well as retinal degeneration in glaucoma and retinitis pigmentosa. Moreover, at least 75 debilitating, and often lethal, diseases are directly attributable to deletions or mutations in mitochondrial DNA, or in nuclear-encoded proteins destined for delivery to the mitochondria. Such widespread mitochondrial involvement in disease reflects the regulatory position mitochondrial failure plays in both acute necrotic cell death, and in the less catastrophic process of apoptosis. The potent feminizing hormone, 17 β-estradiol (E2), has shown cytoprotective activities in a host of cell and animal models of stroke, myocardial infarct and neurodegenerative diseases. The discovery that 17 α-estradiol, an isomer of E2, is equally as cytoprotective as E2 yet is >200-fold less active as a hormone, has permitted development of novel, more potent analogs where cytoprotection is independent of hormonal potency. Studies of structure-activityrelationships, glutathione interactions and mitochondrial function have led to a mechanistic model in which these steroidal phenols intercalate into cell membranes where they block lipid peroxidation reactions, and are in turn recycled via glutathione. Such a mechanism would be particularly germane in mitochondria where function is directly dependent on the impermeability of the inner membrane, and where glutathione levels are maintained at extraordinarily high 8-10mM concentrations. Indeed, the parental estrogens and novel analogs stabilize mitochondria under Ca2+ loading otherwise sufficient to collapse membrane potential. The cytoprotective and mitoprotective potencies for 14 of these analogs are significantly correlated, suggesting that these compounds prevent cell death in large measure by maintaining functionally intact mitochondria. This therapeutic strategy is germane not only to sudden mitochondrial failure in acute circumstances, such as during a stroke or myocardial infarction, but also to gradual mitochondrial dysfunction associated with chronic degenerative disorders such as AD, PD and HD.

Hypoxia occurs when oxygen availability drops below the levels necessary to maintain normal rates of metabolism. Because of its high metabolic activity, the brain is highly sensitive to hypoxia. Severe or prolonged oxygen deprivation in the brain contributes to the damage associated with stroke and a variety of other neuronal disorders. Conversely, the extreme hypoxic environment found in the core of many brain tumors supports the growth of the tumor and the survival of tumor cells. Normal cells exposed to transient or moderate hypoxia are generally able to adapt to the hypoxic conditions largely through activation of the hypoxia-inducible transcription factor HIF. HIF-regulated genes encode proteins involved in energy metabolism, cell survival, erythropoiesis, angiogenesis, and vasomotor regulation. In many instances of hypoxia or hypoxia and ischemia, the induction of HIF target genes may be beneficial. When these same insults occur in tissues that are normally poorly vascularized, such as the retina and the core of solid tumors, induction of the same HIF target genes can promote disease. Major new insights into the molecular mechanisms that regulate the oxygen-sensitivity of HIF, and in the development of compounds with which to manipulate HIF activity, are forcing serious consideration of HIF as a therapeutic target for diverse CNS disorders associated with hypoxia.