Ebselen: prospective therapy for cerebral ischaemia

Stroke occurs due to haemorrhage or occlusive injury and results in ischaemia and reperfusion injury. A variety of destructive mechanisms are involved including oxygen radical generation, calcium overload, cytotoxicity and apoptosis as well as the generation of inflammatory mediators. Ebselen, 2-phenyl-1,2-benzisoselenazol-3(2H)-one (PZ 51, DR3305), is a mimic of GSH peroxidase which also reacts with peroxynitrite and can inhibit enzymes such as lipoxygenases, NO synthases, NADPH oxidase, protein kinase C and H⁺/K⁺-ATPase. Ebselen is in a late stage of development for the treatment of stroke. The molecular actions of ebselen contribute to its anti-inflammatory and anti-oxidant properties, which have been demonstrated in a variety of in vivo models. Numerous in vitro experiments using isolated LDL, liposomes, microsomes, isolated cells and organs have established that ebselen protects against oxidative challenge. Unlike many inorganic and aliphatic selenium compounds, ebselen has low toxicity as metabolism of the compound does not liberate the selenium moiety, which remains within the ring structure. Subsequent metabolism involves methylation, glucuronidation and hydroxylation. Experimental studies in rats and dogs have revealed that ebselen is able to inhibit both vasospasm and tissue damage in stroke models, which correlates with its inhibitory effects on oxidative processes. Results from randomised, placebo-controlled, double-blind clinical studies on the neurological consequences of acute ischaemic stroke, subarachnoid haemorrhage and acute middle cerebral artery occlusion, have revealed that ebselen significantly enhances outcome in patients who have experienced occlusive cerebral ischaemia of limited duration. The benefit achieved with ebselen is closely related to the rapidity with which the treatment is initiated, following the onset of the stroke attack. Safety and tolerability are good and no adverse effects have become apparent. Ebselen is currently at the pre-registration stage for subarachnoid haemorrhage and stroke in Japan.     

Metabotropic glutamate receptors: targets for therapy of cerebral ischaemia

Several pathophysiological processes are involved in the progression of the cerebral ischaemic injury, among which are inflammation, peri-infarct depolarisation, apoptosis and excitotoxicity. Overactivation of glutamate receptors, both ionotropic and metabotropic, constitutes the central step in the excitotoxic cascade of events leading to neuronal cell death following acute brain ischaemia. Owing to their peculiar characteristics of modulatory receptors and due to their wide molecular and biological diversity, metabotropic glutamate receptors constitute an attractive target for the development of potential neuroprotective agents. Recent achievements in developing novel chemical entities and in the characterisation of the physiological and pathological role of individual metabotropic glutamate receptors in postischaemic degeneration will be reviewed.     

Metabotropic glutamate receptors: targets for therapy of cerebral ischaemia

Several pathophysiological processes are involved in the progression of the cerebral ischaemic injury, among which are inflammation, peri-infarct depolarisation, apoptosis and excitotoxicity. Overactivation of glutamate receptors, both ionotropic and metabotropic, constitutes the central step in the excitotoxic cascade of events leading to neuronal cell death following acute brain ischaemia. Owing to their peculiar characteristics of modulatory receptors and due to their wide molecular and biological diversity, metabotropic glutamate receptors constitute an attractive target for the development of potential neuroprotective agents. Recent achievements in developing novel chemical entities and in the characterisation of the physiological and pathological role of individual metabotropic glutamate receptors in postischaemic degeneration will be reviewed.     

The cost of cerebral ischaemia

Cerebral ischaemia is a major cause of disability and death globally and has a profoundly negative impact on the individuals it affects, those that care for them and society as a whole. The most common and familiar manifestation is stroke, 85% of which are ischaemic and which is the second leading cause of death and most common cause of complex chronic disability worldwide. Stroke survivors often suffer from long-term neurological disabilities significantly reducing their ability to integrate effectively in society with all the financial and social consequences that this implies. These difficulties cascade to their next of kin who often become caregivers and are thus indirectly burdened. A more insidious consequence of cerebral ischaemia is progressive cognitive impairment causing dementia which although less abrupt is also associated with a significant long-term disability.Globally cerebrovascular diseases are responsible for 5.4 million deaths every year (1 in 10 of total). Approximately 3% of total healthcare expenditure is attributable to cerebral ischaemia with cerebrovascular diseases costing EU healthcare systems €21 billion in 2003. The cost to the wider economy (including informal care and lost productivity) is even greater with stroke costing the UK £7-8 billion in 2005 and the US$62.7 billion in 2007. Cerebrovascular disease cost the EU €34 billion in 2003. From 2005 to 2050 the anticipated cost of stroke to the US economy is estimated at US$2.2 trillion.Given the global scale of the problem and the enormous associated costs it is clear that there is an urgent need for advances in the prevention of cerebral ischaemia and its consequences. Such developments would result in profound benefits for both individuals and their wider societies and address one of the world's most pre-eminent public health issues.     

Prostaglandin signalling in cerebral ischaemia

The inducible cyclooxygenase COX-2 exerts neurotoxic effects in a wide spectrum of neurological disease models, including models of cerebral ischaemia and chronic neurodegeneration. As COX-1 and COX-2 catalyse the first committed step in prostaglandin synthesis, recent efforts have focused on identifying the downstream prostaglandin signalling pathways responsible for mediating the toxic effect of COX-2. Recent studies in models of in vitro excitotoxicity or hypoxia demonstrate that certain prostaglandin receptors mediate toxic effects, but a large number appear to mediate paradoxically protective effects. In vivo studies have begun to confirm initial in vitro findings, with selected prostaglandin receptors eliciting either neurotoxic or protective effects in models of cerebral ischaemia. In the present issue, Ikeda-Matsuo et al. examine the function of the PGE₂ EP3 receptor in a model of transient focal ischaemia and explore its potential signalling through Rho kinase activation.This article is a commentary on Ikeda-Matsuo et al., pp. 847–859 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2010.00711.x     

Dichloroacetate and cerebral ischaemia therapeutics

Brain ischaemia is a major medical problem which totally lacks meaningful therapeutic options. A drug that reduces morbidity and mortality associated with head injury and stroke would constitute a major medical breakthrough. Although many mechanistic approaches have been evaluated clinically for both stroke and head injury, none have yet to be proven successful. Dichloroacetate (DCA, Ceresine) is a small molecule that activates pyruvate dehydrogenase (PDH) and crosses the blood-brain barrier. PDH activation reduces neurotoxic lactic acidosis which always accompanies brain ischaemia. DCA shows substantial efficacy in a variety of models of stroke, pre-stroke, head or spinal cord injury. Agents that lower cerebral lactic acidosis have not yet been clinically evaluated in head injury and stroke, although DCA has been shown clinically to reduce ambient lactate concentrations in patients with such conditions. DCA has also been shown to be well-tolerated in these patients, and unlike many halogenated molecules, is not mutagenic. Since elevated brain lactate is correlated with poor outcome in both preclinical and clinical studies, an agent such as DCA may prove to reduce the brain injury associated with these disorders. Potential clinical applications of DCA include stroke, head injury, spinal cord injury, and chronic disorders such as congenital lactic acidosis (CLA) and mitochondrial lactic acidosis and stroke-like syndrome (MELAS).     

Calcium channel blockers in cerebral ischaemia

Ischaemic stroke usually results from the obstruction of a major cerebral vessel which leads to a decrease in cerebral blood flow, and a subsequent reduction in ATP. This energy loss leads to impaired cellular function due to reduced ATP-dependent processes and a disruption in ionic gradients across membranes. Under these conditions, there is a significant efflux of K+ from cells producing cellular depolarisation and the movement of extracellular calcium into cells through calcium channels. It is this increase in intracellular calcium that leads to the 'calcium toxicity' that has been associated with cerebral ischaemia. Increased intracellular calcium triggers the break-down of phospholipids, proteins and nucleic acids. This is activated by calcium-dependent phospholipases, proteases and endonucleases, and contributes to structural and functional damage of the cell membrane, which compromises cell function and facilitates cell death. Calcium channel blockers are used routinely to treat cardiovascular disease and hypertension. Although some experimental studies over the last decade suggest efficacy/benefit in the treatment of experimental ischaemic stroke, clinical data do not bear this out. This article discusses the role of voltage-operated calcium channel blockers in stroke, and reviews much of the available experimental and clinical data.     

New models of focal cerebral ischaemia.

1. Studies in animal models of stroke have provided an invaluable contribution to our current understanding of the pathogenesis of cerebral ischaemia. The strengths of stroke research in animals are: 1) the ability to control the severity, duration, location and cause of the ischaemia, variables which confound interpretation of human stroke data; 2) co-existent disease states and variations in cerebrovascular anatomy are avoided; and 3) physiological parameters such as blood pressure, blood gases, temperature and plasma glucose (all of which influence the magnitude of the ischaemic lesion) can be closely monitored and controlled. Taking all these things on board, it is possible to induce a consistent focal ischaemic lesion in animal models of stroke (e.g. the permanent occlusion of the middle cerebral artery (MCA) in the rat). This has resulted in the wide use of animal models for assessment of anti-ischaemic drug efficacy as well as for research into the pathophysiological sequelae of stroke. 2. Traditionally focal ischaemia models involved permanent occlusion of a major cerebral artery such as the MCA. However, since vessel occlusion is seldom permanent in human stroke more recent developments have incorporated reperfusion (following ischaemia) into the design of the animal model. This has been achieved by reversible occlusion of cerebral vessels using 1) intraluminal filaments; 2) microclips; 3) the abluminal application of potent and prolonged vasoconstrictors; or 4) the introduction of emboli into the cerebral circulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neuroprotective role of adenosine in cerebral ischaemia.

Several lines of evidence suggest that adenosine may be an endogenous protective agent in cerebral ischaemia. Adenosine is normally present in the extracellular fluid in most tissues of the body, including the brain, and its level increases dramatically following hypoxia or ischaemia. The rate of adenosine production is enhanced when the energy demand is larger than the rate of energy supply. Adenosine acts on specific receptors that are present in most cells in the body and that produce cellular effects that tend to antagonize a number of pathological events thought to be instrumental for ischaemic nerve cell death. Karl Rudolphi and colleagues review evidence for the neuroprotective potential of adenosine and indicate some targets for drug development.     

Gene therapy for cerebral vascular disease: update 2003

Gene therapy is a promising strategy for cerebrovascular diseases. Several genes that encode vasoactive products have been transferred via cerebrospinal fluid for the prevention of vasospasm after subarachnoid hemorrhage. Transfer of neuroprotective genes, including targeting of proinflammatory mediators, is a current strategy of gene therapy for ischemic stroke. Stimulation of growth of collateral vessels, stabilization of atherosclerotic plaques, inhibition of thrombosis, and prevention of restenosis are important objectives of gene therapy for coronary and limb arteries, but application of these approaches to carotid and intracranial arteries has received little attention. Several fundamental advances, including development of safer vectors, are needed before gene therapy achieves an important role in the treatment of cerebrovascular disease and stroke.     

Nimodipine tested in a human model of cerebral ischaemia

Summary The anti-ischaemic properties of nimodipine 30 mg and 60 mg t.i.d. for 4 days has been tested in a double-blind, placebo-controlled, cross-over study based on the use of hyperventilation to reduce flow velocity in cerebral arteries. Whether the anti-ischaemic properties were due to a vasodilatator action on cerebral blood vessels or to an anti-ischaemic effect on cerebral neurons was studied. There was a slight cardiovascular effect, without any significant change in the EEG at rest. During standardized hyperventilation, there was no difference in the reduction in the blood flow velocity in the nimodipine and placebo groups (namely 56%, 56% and 59%). Both doses of nimodipine, however, significantly attenuated the hyperventilation-induced increase in slow EEG activity in the 1.5–6.0 Hz range. It is concluded that the anti-ischaemic properties of nimodipine are due to an effect on the central nervous system rather than to an effect on cerebral blood flow.     

Helicases as prospective targets for anti-cancer therapy

It has been proposed that selective inactivation of a DNA repair pathway may enhance anti-cancer therapies that eliminate cancerous cells through the cytotoxic effects of DNA damaging agents or radiation. Given the unique and critically important roles of DNA helicases in the DNA damage response, DNA repair, and maintenance of genomic stability, a number of strategies currently being explored or in use to combat cancer may be either mediated or enhanced through the modulation of helicase function. The focus of this review will be to examine the roles of helicases in DNA repair that might be suitably targeted by cancer therapeutic approaches. Treatment of cancers with anti-cancer drugs such as small molecule compounds that modulate helicase expression or function is a viable approach to selectively kill cancer cells through the inactivation of helicase-dependent DNA repair pathways, particularly those associated with DNA recombination, replication restart, and cell cycle checkpoint.     

Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a prospective randomized study

Purpose

Eradication rates following standard triple therapy for Helicobacter pylori infection are declining. Recent studies, conducted in a number of countries, have shown that sequential therapy for H. pylori infection yields high cure rates.

Aim

To compare the efficacy and tolerability of a sequential regimen as a first-line treatment of H. pylori infection with a standard triple treatment regime in Morocco.

Methods

A total of 281 naive H. pylori-infected patients, confirmed by histological examination, were assigned randomly to one of two treatment groups: standard triple therapy [omeprazole (20 mg bid) + amoxicillin (1 g bid) + clarithromycin (500 mg bid) for 7 days] or sequential therapy [omeprazole (20 mg bid) + amoxicillin (1 g bid) for 5 days, followed by omeprazole (20 mg bid) + tinidazole (500 mg bid) + clarithromycin (500 mg bid) for an additional 5 days]. H. pylori eradication was checked 4–6 weeks after treatment initiation by using a ¹³C-urea breath test. Compliance and adverse events were assessed.

Results

The two groups did not differ significantly in gender, age, previous disease history, endoscopic and histological features and smoking. The intention-to-treat and per-protocol eradication rates were 65.9 and 71 % in the standard triple therapy group, and 82.8 and 89.9 % in the sequential therapy group, respectively. The eradication rate was significantly higher in the sequential therapy group than in the standard triple therapy group (p?<?0.001), There was no statistically significant difference in compliance (97.5  vs. 96.3 %) and incidence of side-effects (27.5 vs. 27.9 %) between the two groups.

Conclusions

Based on our results, we conclude that for eradication of H. pylori infection, the 10-day sequential therapy is more effective than the standard triple therapy and is equally tolerated. These results confirm those of other studies in other countries.     

Social olfactory recognition in rodents: deterioration with age, cerebral ischaemia and septal lesion

Social olfactory recognition in rodents has been shown to assess short-term memory and to be sensitive to cholinergic drugs. It is based on the investigation of a juvenile by an adult rat and is measured by a reduction in duration of exploration during the second of two successive exposures lasting 5min. The present experiments further characterize rodent social recognition in pathophysiological models known to impair memory. Social recognition was distrupted by ageing in both rats and mice, by vincristine-induced septal lesion and by damaging the CA1 hippocampal layer after cerebral ischaemia in rats. These memory deficits could be compensated by reducing the time interval between the two presentations of the juvenile and/or by prolonging the juvenile encounter. Similarly, muscarinic agonists (arecoline, SR 46559A) counterbalanced the memory impairment in the three models. The present results indicate that the hippocampus plays a key role in social recognition. They suggest that in the three pathophysiological models, memory ability is still present although it is of very short duration; however, it can still be improved by pharmacological treatments.