Current Neuropharmacology - Volume 2, Issue 3, 2004

Ischemic brain damage develops at a pace slower than previously believed. In the penumbral area of the ischemic territory after focal ischemia, or in selectively vulnerable regions following transient global ischemia, cell death occurs hours or days following the acute insult. The process is the result of a complex cascade of pathogenic events, in which local and systemic factors play a role. Early and late excitotoxicity, apoptosis and inflammation have been found to contribute to the maturation of the damage. Mechanisms include calcium overload, oxidative stress, mitochondrial dysfunction, as well as damage to DNA, structural proteins and enzymes. Ischemic brain injury can be counteracted, totally or in part, by appropriate therapeutic interventions, resulting in varying degrees of neuroprotection in animal models. Although clinical trials based on neuroprotective agents have been disappointing, therapeutic strategies targeting recently identified pathogenic processes offer new hope. These approaches, alone or in combination with therapies based on early reperfusion of the ischemic brain, are likely to provide powerful tools for the treatment of human stroke.

Ischemic stroke is responsible for about one third of all deaths in industrialized countries and is the major cause of serious, long-term disability in adults over the age of 45. It stands to reason that there is a need for pharmacotherapy to treat acute ischemic stroke. In over two decades of research, the hope of developing a neuroprotective drug that effectively reduces the severity of damage after stroke has not been realized. However, considerable insights have been gained into the mechanisms and cascade of events that occurs following stroke as well as an improved understanding of neuronal injury and cell death. Recent studies in humans indicate many parallels with animal studies not only in the nature of events following ischemia, but also in their time course. Multiple pathways are known to be involved and yet the majority of treatments are still being designed to target a single effector in these pathways. Combinations of drugs, or drugs, which have multiple actions, targeting several pathways may prove to be a more successful strategy.

Alzheimer's Disease (AD) is a progressive and devastating neurodegenerative disorder affecting the brain. It is the most common form of late-life dementia and is one of the leading causes of death in the developed world. Due to the ageing population and improvement in diagnosis it is expected that the number of diagnosed AD patients will increase from the current level of ∼5 million to ∼22 million by 2025. Acetylcholine-based therapies, currently the only treatment regimes approved for AD, will also be the basis for treatment in the near future. However, progression of the disease is not affected by acetylcholinesterase inhibitors; rather it is a symptomatic treatment which can delay deterioration of cognitive symptoms for up to six months. Pharmaceutical companies are now investing their efforts in the development of diseasemodifying treatments for AD. The rationale for new drug design is based on the amyloid cascade hypothesis, which proposes that accumulation of amyloid beta peptide is the key event that triggers the pathological events in AD. The most promising, emerging approaches for the treatment of AD, targeting the release, the aggregation and the clearance of Abeta will be discussed.

The discovery of a neuroprotective treatment is a high priority for research in Parkinson's disease. Substantial progress has been made towards this goal in recent years, but at the present there is still no treatment which can be said to have proven neuroprotective effects. There is no single unifying model to account for the disease; indeed it seems likely that the etiology is a convergence of several causes. This multiplicity may prove helpful, because mitigation of only one or a few of the factors may produce clinically important benefit. This review emphasizes the strategies for discovery of new treatments. Current approaches to the development of neuroprotective treatments can be broadly characterized into three groups: 1) approaches based on the existing understanding of the mechanism of cell injury and death in PD; 2) approaches based on clues from the emerging knowledge of genetics of PD; and 3) approaches based on clues from the epidemiology and role of environmental factors in the etiology of PD. Some specific compounds and approaches are discussed to illustrate these strategies.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder of unknown aetiology. Progressive motor weakness and bulbar dysfunction lead to premature death, usually from respiratory failure. To date, riluzole is the only disease-modifying drug approved for the treatment of ALS, but this has only a minor impact on the clinical outcome. The clinical development of new drugs for ALS is entirely dependent on the understanding of the aetiology and pathophysiology of the disease, which is still far from being fully elucidated. ALS is a multisystem disorder and can be viewed as the consequence of a complex neurodegenerative process involving neuron-glia interactions. Excitotoxicity, oxidative stress, mitochondrial dysfunction, cytoskeletal defects and apoptosis are all putative mechanisms which seem to operate in ALS and might be amenable of pharmacological intervention. Since the pathogenesis of ALS seems to involve multiple factors, future treatments may target different molecular pathways by a combined multi-drug therapy.

Huntington's disease (HD) is a fatal hereditary neurodegenerative disorder for which there is no known cure. In the years since the discovery of a trinucleotide CAG repeat in the gene encoding huntingtin as the disease's causative genetic lesion, there has been an explosion of research attempting to elucidate the mechanisms of neurodegeneration in HD, with the ultimate goal being the development of effective neuroprotective therapy. Development of genetic models of the disorder has been instrumental in these advances, and combination of these with established toxic models has made significant headway in delineating mechanisms of neuronal dysfunction and death in HD. Established theories of pathogenesis, such as mitochondrial dysfunction and glutamate excitotoxicity have been linked with more recently explored mechanisms of damage, such as abnormal programmed cell death, transcriptional dysregulation, and protein aggregation to develop a more unified theory of HD pathogenesis. These investigations have revealed a complex web of pathways that may trigger and shape neuronal death in HD. Discovery of this neuronal death machinery has afforded a great opportunity to intervene to prevent neuronal death at many potential targets that have synergistic mechanisms of action. Continued aggressive research should eventually develop a cure for this devastating disease.