Current Drug Targets-CNS & Neurological Disorders - Volume 4, Issue 2, 2005

Stroke is the third leading cause of death and the leading cause of long-term disability in the United States: 25 % of sufferers die from a stroke or its complications and 50 % have health problems and long-term disabilities following a stroke. Additionally, stroke is one of the most costly diseases, with estimated annual healthcare expenditures exceeding $40 billion in the United States alone. Approximately 80 % of strokes are ischemic in nature, caused by a transient or permanent reduction in cerebral blood flow. This reduction in blood flow is typically caused by either an embolic or thrombotic blockade of a blood vessel. A narrowing of a blood vessel can also cause an ischemic stroke. The remaining 20 % of strokes are hemorrhagic in nature, caused by rupture of a blood vessel and resulting plasma leakage into the brain. Despite decades of research and the large number of compounds that have been shown to reduce ischemic damage in preclinical animals models, clinical trials with many of these compounds have yielded disappointing results. To date, the only FDAapproved treatment for acute ischemic stroke is tissue plasminogen activator (tPA), which restores blood flow by dissolving clots. However, its efficacy and utility are limited by its short therapeutic window and potentially devastating side effects, in particular the possibility of inducing intracerebral hemorrhage. The review articles in this hot topic issue of Current Drug Targets-CNS and Neurological Disorders highlight a gamut of neuroprotective therapeutic agents and strategies that are in various stages of development for stroke. Green and Ashwood review free radical trapping as a therapeutic approach to neuroprotection in stroke, concentrating on experimental and clinical studies with Cerovive (NXY-059) and other free radical scavengers. Next, Lutsep summarizes the neuroprotective effects of serotonin agonists in pre-clinical models of stroke and early clinical data for Repinotan (BAY x 3702). Ren and Finklestein discuss the potential utility of select growth factors as treatments for stroke and clinical data for two of these factors, bFGF and EPO. Asano and colleagues focus on the calcium binding protein S100B and the effects of arundic acid (ONO-2506) in preclinical stroke studies. Wang and Shuaib discuss the utility of NR2B selective NMDA receptor antagonists while Weiser discusses AMPA receptor antagonists for the treatment of stroke, since glutamate toxicity remains a hallmark of stroke. The pro-inflammatory agent tumor necrosis factor-α (TNF- α) has been shown to be involved in the neuropathology following stroke. Lovering and Zhang review the therapeutic potential of tumor necrosis factor-alpha-converting enzyme (TACE, which generates soluble, mature TNF- α) inhibitors in stroke. Yang and colleagues summarize the evidence supporting estrogens as protective agents against stroke. Finally, Komjati and colleagues focus on poly (ADP-ribose) polymerase inhibitors as potential therapeutic agents in treating stroke and neurotrauma. Taken together, these reviews provide an overview of the diverse approaches being employed to tackle acute ischemic stroke: they are a testament to the unmet medical needs of stroke patients, and also to the complexity of the major pathogenic mechanisms believed to be important in this disease.

There is substantial experimental evidence that free radicals are produced in the brain during ischemia, during reperfusion and during intracranial hemorrhage. Removal of pathologically produced free radicals is therefore a viable approach to neuroprotection. There is substantial experimental evidence that free radicals are produced in the brain during ischemia, during reperfusion and during intracranial hemorrhage. Removal of pathologically produced free radicals is therefore a viable approach to neuroprotection. Ebselen was a modestly effective neuroprotectant in a rat transient middle cerebral artery occlusion (MCAO) model when given before the start of ischemia, but not when the insult was severe. Data from the permanent MCAO model and an embolic stroke model suggested a bell shaped dose-response curve. The weak preclinical profile may explain the lack of success in clinical trials. Preclinical data on tirilazad in animal models of acute ischemic stroke are neither comprehensive nor consistent. There was little evidence of efficacy in permanent MCAO or when the drug was given several hours post-occlusion. This may explain the negative clinical trials as these did not target patients likely to reperfuse and treatment started several hours after stroke onset. While preclinical data on subarachnoid hemorrhage demonstrated an attenuation of vasospasm the clinical data were inconsistent. There is very limited published preclinical data on edaravone but it has been approved in Japan as a neuroprotectant for the treatment of stroke. Evidence is based on a single placebo controlled trial in a relatively small number of patients. The status of possible development of edaravone outside of Japan is not known. NXY-059 has been found to be a very effective agent in transient and permanent MCAO and thromboembolic models of acute ischemic stroke. Its preclinical development has been governed by adherence with the recommendations of the Stroke Therapy Academic Industry Roundtable (STAIR) group and is now being investigated in Phase III clinical trials using a therapeutic time window and plasma concentrations that are effective in rat and primate models of stroke.

Serotonin agonists can reduce glutamate-induced excitotoxicity in cerebral ischemia. The potent 5- HT1A agonist BAY x 3702, or repinotan, has reduced cortical infarct volume in pre-clinical models even when given 5 hours after injury. Early clinical trials showed that the drug was safe, and displayed primarily serotonergic side effects such as nausea and vomiting. A phase IIb trial in moderate to moderately severe strokes completed enrollment in June 2004.

This review discusses the potential usefulness of several selected polypeptide growth factors as treatments for stroke. Distinctions between global vs. focal cerebral ischemia, permanent vs. temporary focal ischemia, and acute stroke vs. stroke recovery are first discussed. Potential routes of administration of growth factors are also considered. The growth factors basic fibroblast growth factor (bFGF), osteogenic protein-1 (OP- 1), vascular endothelial growth factor (Veg-f), erythropoietin (EPO), and granulocyte colony stimulating factor (G-CSF) all show potential usefulness in animal models of acute stroke and stroke recovery. Two of these factors, bFGF and EPO, have reached human clinical trials for acute stroke, and the data are discussed. Future directions in this field are also discussed.

After focal cerebral ischemia, the infarct volume increases rapidly within acute infarct expansion (initial 12 to 24 h) and continues slowly during delayed infarct expansion (25 to 168 h). While acute infarct expansion represents progressive necrosis within the ischemic core, delayed infarct expansion starts as disseminated apoptotic cell death in a narrow rim surrounding the infarct border, which gradually coalesces to form a larger infarct. Discovery of a distinct correlation between reactive astrogliosis along the infarct border and delayed infarct expansion in the rodent ischemia model led us to investigate the possible causal relationship between the two events. Specifically, the calcium binding protein S100B exerts detrimental effects on cell survival through activation of various intracellular signaling pathways, resulting in altered protein expression. Arundic acid [(R)-(-)-2-propyloctanoic acid, ONO-2506] is a novel agent that inhibits S100B synthesis in cultured astrocytes. In the rodent ischemia model, this agent was shown to inhibit both the astrocytic overexpression of S100B and the subsequent activation of signaling pathways in the peri-infarct area. Concurrently, delayed infarct expansion was prevented, and neurologic deficits were promptly ameliorated. The results of subsequent studies suggest that the efficacy of arundic acid is mediated by restoring the activity of astroglial glutamate transporters via enhanced genetic expression.

Glutamate is the main excitatory neurotransmitter in the central nervous system and it plays a significant role not only in synaptic transmission but also in acute and chronic neuropathologies including stroke. Presently, four receptors for glutamate have been identified and the NMDA receptor family is the most intensively studied. A number of NMDA receptor antagonists have been developed and used for treatment of neurological diseases in patients. However, all of these drugs have been failed in clinical trials either because of intolerable side effects or lack of medical efficacy. Recently, the understanding of molecular structure of NMDA receptors has been advanced and this finding thus provides information for designing subtypeselective antagonists. Using NR2B subunit selective antagonists, ifenprodil and eliprodil, as basic structure models, second and third generation congeners have been developed. Several NR2B-selective compounds showed neuroprotective actions at doses that did not produce measurable side effects in preclinical studies. Some of NR2B subunit selective antagonists have also been tested for the treatment of ischemic brain injury. The present review describes the role of glutamate in ischemic brain injury with an emphasis on the NR2B containing NMDA receptors.

Signal transduction via ionotropic glutamate receptors is found in many life forms, from protozoa to mammals. Glutamate is the main excitatory neurotransmitter in the mammalian CNS, were fast postsynaptic depolarisation is induced by the activation of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors. In addition to their important physiological role, excessive AMPA receptor stimulation is also a hallmark of excitotoxicity-related diseases, like ischaemic stroke. Conversely, AMPA receptor inhibitors were proposed to be useful neuroprotective drugs. First generation AMPA receptor blockers were competitive antagonists, like NBQX, which showed robust neuroprotection in a variety of disease-related animal models. Its clinical use, however, was restricted by the very low solubility, inducing kidney precipitaton in vivo. Second generation competitive antagonists are available, which do not possess this property. None of those, however, up to now is in clinical use. Competitive AMPA receptor antagonists are not the first choice for neuroprotective drugs, since due to receptor kinetics they preferently suppress the physiological relevant component of the postsynaptic glutamate response. Non-competitive blockers, like 2,3-benzodiazepines or the novel neuroprotectant BIIR 561 should be suited better for the treatment of stroke. The latter compound is also described as blocker of voltage-gated sodium channels. Targetting more than one mechanism in the excitotoxicity cascade might be a fruitful approach for the development of neuroprotective drugs.

Stroke is the third leading cause of death and the leading cause of permanent disability in western countries and the incidence of stroke is expected to increase in the foreseeable future due to the ageing population. The effective treatment of stroke remains challenging due to the complexity and heterogenicity of the disease. Recombinant tissue plasminogen activator (rt-PA) is the only FDA-αpproved therapy for stroke during the first 3 hr after the disease onset. However the risk of hemorrhage and its narrow therapeutic window has limited its use in clinic. Inflammation has been known to play a crucial role in the induction and development of stroke and tumor necrosis factor-α (TNF-α) is a central player in the initiation of multiple inflammatory cascades. The recent success of three anti-TNF biologics in the clinic for the treatment of rheumatoid arthritis as well as other inflammatory diseases has further validated TNF159nflammation. TNF-α has also been shown to be associated with ischemic stroke. Anti-TNF biologics have been shown to be effective in reducing the disease symptoms in various pre-clinical stroke models. Small molecule TNF inhibitors are highly desirable due to the limitations of protein therapeutics. Tumor necrosis factor-alpha-converting enzyme (TACE) is the major sheddase of TNF-α and is essential for the generation of soluble, mature TNF-α. Thus TACE appears to be an attractive target for development of oral small molecule TNF-α inhibitors. This review summarizes the role of TNF-α in stroke and the effect of several TACE/MMP inhibitors in pre-clinical stroke models. The data strongly suggest that TACE/MMP inhibitors have great therapeutic potential and may be valuable alternatives in treating stroke in the clinic.

Estrogens are now recognized as potent neuroprotectants in a variety of in vitro and in vivo model for cerebral ischemia. These protective effects of estrogens are seen in neurons, astrocytes, microglia and vascular endothelial cells and result in a profound protection of the brain during stroke. Herein, we provide a thesis that indicates that the protective effects of estrogens during stroke may be a combined effect on multiple targets of the neurovascular unit (NVU) through a fundamental protective effect of estrogens on the subcellular organelle that defines the fate of cells during insults, the mitochondria. By protecting mitochondria during insult, estrogens are able to reduce or eliminate the signal for cellular necrosis or apoptosis and thereby protect the NVU from ischemia/reperfusion. In this context, estrogens may be unique in their ability to target the cellular site of initiation of damage during stroke and could be a central compound in a multi-drug approach to the prevention and treatment of brain damage from stroke.

Poly (ADP-ribose) polymerase-1 (PARP-1) is a DNA-binding protein that is primarily activated by nicks in the DNA molecule. It regulates the activity of various enzymes - including itself- that are involved in the control of DNA metabolism. Upon binding to DNA breaks, activated PARP cleaves NAD+ into nicotinamide and ADP-ribose and polymerizes the latter on nuclear acceptor proteins including histones, transcription factors and PARP itself. Poly(ADP-ribosylation) contributes to DNA repair and to the maintenance of genomic stability. Evidence obtained with pharmacological PARP inhibitors of various structural classes, as well as animals lacking the PARP-1 enzyme indicate that PARP plays an important role in cerebral ischemia/reperfusion, stroke and neurotrauma. Overactivation of PARP consumes NAD+ and ATP culminating in cell dysfunction and necrosis. PARP activation can also act as a signal that initiates cell death programs, for instance through AIF (apoptosis inducing factor) translocation. PARP has also been shown to associate with and regulate the function of several transcription factors. Of special interest is the enhancement by PARP of NF-kB-mediated transcription, which plays a central role in the expression of inflammatory cytokines, chemokines, adhesion molecules and inflammatory mediators. Via this mechanism, PARP is involved in the up-regulation of numerous pro-inflammatory genes that play a pathogenetic role in the later stage of stroke and neurotrauma. Here we review the roles of PARP in DNA damage signaling and cell death, and summarize the pathogenetic role of PARP in stroke and neurotrauma.

Locomotion results from the activity in neural networks in the spinal cord that together with sensory and descending inputs generate coordinated motor outputs. Descending inputs include glutamatergic, monoaminergic, and peptidergic pathways. Spinal injuries interrupt these descending pathways, resulting in the disruption or loss of function. Drugs that target these endogenous transmitter systems have been used to improve function after spinal injury. However, individual drugs can have beneficial or deleterious effects in different studies and thus there is little consensus on optimal pharmacological strategies. The variability may be influenced by changes introduced by the type of lesion (complete or partial), time after injury, or the lack of specific ligands that target specific transmitter systems. It is now recognised that these transmitter systems do not necessarily act in isolation, but can interact to evoke additive, inhibitory, or novel metamodulatory effects. Meta interactions mean that differing chemical environments in lesioned spinal cords could influence drug effects. The spinal cord also exhibits injury-induced changes, which could alter the chemical environment and functional properties over time. While they have not been considered in pharmacological approaches to spinal injury, interactive and adaptive changes could influence the effects of spinal lesions and therapeutic interventions. The properties of endogenous transmitter systems in spinal locomotor networks before and after spinal lesions need to be understood, and pharmacological tools that target specific functional aspects need to be developed.

The L-glutamate (Glu) has been hypothesized as an excitatory amino acid neurotransmitter in the mammalian central nervous system after successful cloning and identification of a number of genes encoding signaling machineries required for the neurocrine at synapses in the brain. These include excitatory amino acid transporters (EAATs) for signal termination and vesicular Glu transporters (VGLUTs) for signal output through exocytotic release, in addition to Glu receptors (GluRs) for signal input. These Glu signaling molecules not only play key roles in mechanisms associated with synaptic plasticity such as learning and memory, but also participate in the etiology and pathology of different neuropsychiatric disorders and neuronal cell death seen in various neurodegenerative diseases. Of the aforementioned Glu signaling molecules, EAATs are essential for the termination of signal transmission mediated by Glu as well as for the prevention of neurotoxicity mediated by this endogenous excitotoxin, while VGLUTs are crucial for the storage of Glu in synaptic vesicles to suffice for the definition of a glutamatergic phenotype. Many early desperate efforts were devoted to the search and development of novel compounds with a therapeutic window toward GluRs, while relatively little attention was paid to either EAATs or VGLUTs in this aspect. In this review, therefore, we will summarize the classification and functionality of EAATs and VGLUTs with a focus on their possibilities as potential therapeutic targets for different neurodegenerative and neuropsychiatric disorders related to malfunction of Glu signaling in human beings.