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PubMedDate not supplied

Experimental neuroprotective agents: nursing challenge.

Neuroprotective agents are investigational drugs that can potentially suppress the development of secondary brain injury following cerebral traumatic injury. Currently, critical care nurses in research centers are challenged to care for these patients during the clinical trial phase of these drugs. Soon, if these drugs pass the trial phase and are approved, critical care nurses in all settings may be administering neuroprotective agents to brain injury patients, identifying side effects, and evaluating their effects on secondary brain injury.

Brain Injuries↗
PubMed2004

A review of neuroprotective agents.

The brain remains an area where little corrective surgery can be performed and the reversal of damage is almost impossible. Recently, reports of agents offering neuroprotection have begun to appear in the literature. The concept of neuroprotection is the administration of some agent, which should reverse some of the damage or prevent further damage. Some agents offer protection against cell degeneration to the neuronal cells. Still other agents specifically protect the dopamine neurons and the retina. The majority of neuroprotective agents are antioxidants. An immunosuppressive calcineurin inhibitor, NOS inhibitor, sigma-1 modulator, AMPA antagonist and Ca2+ channel blocker have all shown neuroprotective activity. An estrogen agonist and two glycoprotein IIb/IIIa antagonists also exhibit neuroprotective activity. Most of the synthetic compounds presented were not originally designed as neuroprotective agents but were found to possess neuroprotective activity in later studies. Many of these compounds are biologically active natural products, either plant extracts or endogenous peptides/proteins. This review will present the most recent reports on these agents.

Brain Injuries↗
PubMed2003

Nitrones as neuroprotective agents in cerebral ischemia, with particular reference to NXY-059.

Stroke is a major clinical problem, and acute pharmacological intervention with neuroprotective agents has so far been unsuccessful. Recently, there has been considerable interest in the potential therapeutic benefit of nitrone-derived free radical trapping agents as neuroprotective agents. Nitrone compounds have been shown to be beneficial in animal models of various diseases, and the prototypic compound alpha-phenyl-N-tert-butylnitrone (PBN) has been extensively demonstrated to be neuroprotective in rat models of transient and permanent focal ischemia. The nitrone radical trapping agent disodium 2,4-disulfophenyl-N-tert-butylnitrone (NXY-059) has also been shown to be neuroprotective in these models. Furthermore, it has recently been shown to improve neurological function and reduce infarct volume in a primate model of permanent focal ischemia even when given 4 hr postocclusion. While radical trapping activity is demonstrable with NXY-059 and other nitrone compounds such as PBN, this activity is weak. Arguments for and against ascribing radical trapping as the therapeutic mechanism of action are discussed. This compound is well tolerated in human stroke patients and can be administered to produce plasma concentrations exceeding those effective in animal models; crucially, at the same time, it has also been shown to be effective in animal models. NXY-059 may thus be the first compound to be examined in stroke patients using drug exposure and time to treatment that have been shown to be effective in animal models of stroke.

Aged↗
PubMed2006

Neuroprotective agents in schizophrenia and affective disorders.

With the exception of dementia, the use of neuroprotective agents in psychiatric disorders is not yet well established. However, recent data from brain imaging studies and clinical trials support the view that neurodegenerative mechanisms may play a role in the pathophysiology of schizophrenia and affective disorders. Further evidence for the use of neuroprotective agents can be drawn from the findings that second-generation antipsychotics, mood stabilizers and antidepressants have been shown to have neuroprotective effects in vitro and in vivo. Neuroprotective agents as add-on therapies (e.g., modafinil, erythropoietin, glycine, D-serine, memantine and celecoxib) are currently being evaluated in schizophrenia and related disorders. This paper reviews the current options for neuroprotective treatment approaches focusing on schizophrenia and affective disorders.

Animals↗
PubMed2002

[Effect of neuroprotectant agent combined with cocktail on expression of anti-apoptotic protein bcl-2 in rats after focal cerebral ischemia].

OBJECTIVE: To investigate whether the protective effect of therapy with different combined neuroprotectant agents was better than that of single agent on focal cerebral ischemia. METHODS: The right middle cerebral artery in the rats was occluded with suture occlusion technique. The rats were divided into five groups treated with FDP (50 mg/kg, n = 10), MK-801 (1 mg/kg, n = 10) and NAC (150 mg/kg, n = 10) singly, or in combination, respectively, by intraperitoneal infusion 30 minutes after vessel occlusion. The rats were weighed and assessed neurologically, based on a 5-point scale, six and 24 hours after focal cerebral ischemia. The expression of anti-apoptotic protein bcl-2 was observed with SDS-PAGE protein electrophoresis and Western blot technique. RESULT: The optical density of bcl-2 increased more distinctly in the rats treated with combined neuroprotective agents than that with any single agent six and 24 hours after cerebral ischemia, with a statistically significant difference (P < 0.05). CONCLUSIONS: Treatment with combined neuroprotectant agents could un-regulate the anti-apoptotic protein bcl-2 more distinctly than that with any single agents. Combined use of neuroprotectants might be more effective than that of single agent in protecting rats' brain from ischemia.

Acetylcysteine↗
PubMed1996

Issues in accelerating the pace of development for neuroprotective agents.

Accelerating the pace of development for neuroprotective agents requires a number of advances in the therapeutics of Alzheimer disease. Identification of patients who are presymptomatic, by discovering early markers of Alzheimer disease will be essential. Clinical trials methodology must be devised to accommodate atypical outcome measures, prolonged trials, and large sample sizes without posing serious ethical considerations regarding placebo administration. Finally, regulatory issues that discourage development of drugs that will be in complicated, expensive and lengthy clinical trials need to be addressed. This paper reviews these issues, and offers some suggestions.

Alzheimer Disease↗
PubMed2001

Electrophysiological and neurochemical evidence for voltage-dependent Ca(2+) channel blockade by a novel neuroprotective agent NS-7.

The effects of a neuroprotective agent 4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride (NS-7) on the Ca(2+) currents in rat dorsal root ganglion neurones and on the depolarization-evoked nitric oxide synthesis, which was estimated from cyclic GMP formation in slices of the rat cerebral cortex, were investigated, and its mode of action was compared with those of typical Ca(2+) channel blockers. In rat dorsal root ganglion neurones, NS-7 (0.3-100 microM) inhibited the whole-cell Ba(2+) currents (IBa) in a voltage-dependent manner, in which the compound more potently blocked the IBa elicited from the holding potential of -40 mV than that induced from -80 mV. In slices of rat cerebral cortex, KCl-evoked nitric oxide synthesis was markedly inhibited by omega-conotoxin GVIA and omega-agatoxin IVA, but only slightly attenuated by nifedipine, suggesting that the response is mediated predominantly through activation of N-type and P/Q-type Ca(2+) channels. NS-7 (1-100 microM) inhibited the KCl-stimulated nitric oxide synthesis in a manner dependent on the intensity of the depolarizing stimuli. Moreover, weak but significant inhibitory effect of NS-7 was observed even after wash-out. Similar voltage-dependent inhibition of the KCl response was observed by a limited concentration (10 microM) of verapamil. These findings indicate that NS-7 in several concentrations blocks Ca(2+) channel in a voltage-dependent manner.

Animals↗
PubMed2002

[Current state on development of neuroprotective agents for cerebral ischemia].

The improvement of decreased cerebral blood flow using thrombolytic agents, anti-thrombin drugs, and antiplatelet drugs has been essential for acute ischemic stroke. Edaravone, a free radical scavenger, has been commercially available as a novel neuroprotective agent for ischemic stroke in Japan from 2001. The appearance of a neuroprotective agent implies that therapeutic strategy can be expanded through a combination with thrombolysis. In the previous development, several cases have reported that neuroprotective compounds failed in clinical trials. However, recent studies have clarified that the cerebral ischemia induced the neuronal cell death by mediating multiple mechanisms with necrosis and/or apoptosis. The cytotoxicity derived from the NO/peroxynitrite/free radical generating system, one of intracellular Ca2+ signaling, is a typical event in ischemic injury, which is protected by edaravone. Furthermore, it is suggested that suppression of excessively activated voltage-dependent Na+ and Ca2+ channels is effective as a strategy for neuroprotection, since abnormal excitatory stimuli in the neuronal network result in the cerebral infarction. The development of several compounds having different mechanisms of action for acute stroke is in progress. It is therefore prospected that the various novel neuroprotective agents will be provided for assuring the option of therapeutic strategy, since the reinforcement of medical stroke care including diagnosis contributes to the prolongation of the therapeutic time window.

Brain Ischemia↗
PubMed1997

In vivo and in vitro experiments show that betaxolol is a retinal neuroprotective agent.

The aim of the study was to determine whether betaxolol is a neuroprotective agent and can therefore slow down the changes seen in the retina following ischaemia/reperfusion. Ischaemia was induced in one rat eye by raising the intraocular pressure for 45 min. Three days later electroretinograms were recorded from both eyes and the retinas were examined immunohistochemically for the localisation of calretinin and choline acetyltransferase (ChAT) immunoreactivities. The effect of glutamate agonists, hypoxia or experimental ischaemia was examined on the GABA immunoreactivity, lactate dehydrogenase (LDH) and internal calcium levels ([Ca2+]i) of the isolated rabbit retina, rat cortical cultures and chick retinal cell cultures respectively. Betaxolol was tested to see whether it can attenuate the influence of the glutamate agonists, hypoxia or experimental ischaemia. Ischaemia for 45 min causes a change in the nature of the normal calretinin immunoreactivity, an obliteration of the ChAT immunoreactivity and a drastic reduction in the b-wave of the electroretinogram after 3 days of reperfusion. When betaxolol was injected i.p. into the rats before ischaemia and on the days of reperfusion the changes to the calretinin and ChAT immunoreactivities were reduced and the reduction of the b-wave was prevented. Rabbit retinas incubated in vitro in physiological solution lacking oxygen/glucose or containing the glutamate agonists kainate or NMDA caused a change in the nature of the GABA immunoreactivity. Inclusion of betaxolol partially prevented the changes caused by NMDA and lack of oxygen/glucose. Rat cortical cultures exposed to glutamate or hypoxia/reoxygenation resulted in a release of LDH. The release of the enzyme was almost completely attenuated when betaxolol was included in the culture medium. Kainate increased the [Ca2+]i in chick retinal cultures, as measured with Indo-1. In a medium with sodium, this kainate-induced elevation of [Ca2+]i was significantly reduced by betaxolol. The combined data show that betaxolol is a neuroprotective agent and attenuates the effects on the retina induced by raising the intraocular pressure to simulate an ischaemic insult as may occur in glaucoma.

Animals↗
PubMed2001

Current status of neuroprotective agents in the treatment of acute ischemic stroke.

To keep ischemic brain cells alive, neuroprotective agents target events in the ischemic cascade that might be injurious to the cells. They can be divided broadly into groups that restore ion balance, block receptors, prevent reperfusion injury, or promote neuronal healing. To date, neuroprotective agents have either shown a lack of efficacy in clinical stroke trials or been limited by side effects. Ongoing clinical trials with novel agents are trying to enroll a more homogeneous population of stroke patients in an effort to demonstrate treatment benefit.

Acute Disease↗
PubMed2002

Neuroprotective agents in acute ischemic stroke.

The concept of neuroprotection relies on the principle that delayed neuronal injury occurs after ischemia. The phenomenon of the "ischemic cascade" has been described, and each step along this cascade provides a target for therapeutic intervention. A wide variety of drugs have been studied in humans. Ten classes of neuroprotective agents have reached phase III efficacy trials but have shown mixed results. They included calcium channel antagonists, NMDA receptor antagonists, lubeluzole, CDP-choline, the free radical scavenger tirilazad and ebselen, enlimomab, GABA agonist clomethiazole, the sodium channel antagonist fosphenytoin, magnesium, glycine site antagonist GV150526 and piracetam. Furthermore, the mechanisms that underlie the development of focal ischemic injury continue to be discovered, opening new therapeutic perspective for neuroprotection that might clinically be applicable in the future.

Acute Disease↗
PubMed1998

Neuroprotective agents in acute ischemic stroke.

Recent scientific data suggest that there is a "window of opportunity" between the onset of brain ischemia and irreversible neuronal death. Although neurons can withstand complete absence of blood flow for only minutes, collateral circulation typically surrounds the "core" of the stroke. In these brain regions known as the ischemic penumbra, brain tissue can survive for several hours following stroke onset. Recent studies suggest that neuroprotective agents would give these viable neurons the chance for recovery. This article reviews the mechanisms of ischemic neuronal injury, mechanism of action of neuroprotective agents, current neuroprotective clinical trials, and guidelines for patient care management.

Acute Disease↗
PubMed1998

To what extent have functional studies of ischaemia in animals been useful in the assessment of potential neuroprotective agents?

A general consensus is being reached on the use of a combination of mortality and functional end-points in clinical trials of neuroprotective agents. However, to date, few preclinical studies have examined the effects of putative neuroprotective agents on functional outcome after ischaemia. The data described in this review show the importance of combining both histopathological and neurobehavioural studies when evaluating the neuroprotective efficacy of anti-ischaemic agents in animal models of cerebral ischaemia. Here, Jackie Hunter, Ken Mackay and Derek Rogers argue that measures of functional improvement in models of ischaemia should be incorporated to characterize further the neuroprotection afforded by a compound that could aid the selection of doses and end-point measures in early clinical trials.

Animals↗
PubMed1999

Neuroprotective "agents" in surgery. Secret "agent" man, or common "agent" machine?

The search for clinically-effective neuroprotective agents has received enormous support in recent years--an estimated $200 million by pharmaceutical companies on clinical trials for traumatic brain injury alone. At the same time, the pathophysiology of brain injury has proved increasingly complex, rendering the likelihood of a single agent "magic bullet" even more remote. On the other hand, great progress continues with technology that makes surgery less invasive and less risky. One example is the application of endovascular techniques to treat coronary artery stenosis, where both the invasiveness of sternotomy and the significant neurological complication rate (due to microemboli showering the cerebral vasculature) can be eliminated. In this paper we review aspects of intraoperative neuroprotection both present and future. Explanations for the slow progress on pharmacologic neuroprotection during surgery are presented. Examples of technical advances that have had great impact on neuroprotection during surgery are given both from coronary artery stenosis surgery and from surgery for Parkinson's disease. To date, the progress in neuroprotection resulting from such technical advances is an order of magnitude greater than that resulting from pharmacologic agents used during surgery. The progress over the last 20 years in guidance during surgery (CT and MRI image-guidance) and in surgical access (endoscopic and endovascular techniques) will soon be complemented by advances in our ability to evaluate biological tissue intraoperatively in real-time. As an example of such technology, the NASA Smart Probe project is considered. In the long run (i.e., in 10 years or more), pharmacologic "agents" aimed at the complex pathophysiology of nervous system injury in man will be the key to true intraoperative neuroprotection. In the near term, however, it is more likely that mundane "agents" based on computers, microsensors, and microeffectors will be the major impetus to improved intraoperative neuroprotection.

Coronary Artery Bypass↗
PubMed2003

Neuroprotective agents for the treatment of acute ischemic stroke.

Neuroprotective treatments are therapies designed to interrupt the cellular, biochemical, and metabolic elaboration of injury during or following exposure to ischemia; they encompass a rapidly expanding array of pharmacologic interventions. Various classes of neuroprotective agents have reached phase III efficacy trials in focal ischemic stroke, but none has proven effective, despite successful preceding animal studies. This notwithstanding, recent favorable results of hypothermia in human cardiac arrest trials have validated the general concept of neuroprotection. In addition, the promise of neuroprotective therapy for focal acute ischemic stroke has been renewed by innovations in strategies of preclinical drug development and clinical trial design that rectify past defects, including trial testing of combination therapies rather than single agents and novel approaches to accelerating time to initiation of experimental treatment.

Animals↗
PubMed2004

[Endogenous anticonvulsant and neuroprotective agents].

Elucidation of the biochemical basis of neuronal degeneration following seizures, ischemia or hypoglycemia appears to be one of the most urgent problems of contemporary science. Close attention has been devoted to endogenous anticonvulsant and/or neuroprotective agents which help to maintain a neuronal homeostasis under pathological conditions. The list of putative neuroprotectants is very long and includes substances with diverse chemical structures, such as, e.g., adenosine, amino acids (kinurenic acid, taurine), neuropeptides (opioid peptides, thyreoliberine, neuropeptide Y, galanin, VIP/PACAP) and some neurosteroids (allopregnanolone, dehydroepiandrosterone). In recent years great progress has been made in the studies into not only their biosynthesis, metabolism and regulation of release in the nervous tissue, but also molecular and functional characteristics of their receptors. Apart from fast ionic effects leading to repolarization of the neuronal membrane, these endogenous neuroprotective agents may exert long-term effects on intracellular second messengers and genomic mechanisms which are crucially involved in the regulation of excitotoxic and apoptotic cascades. It is still an open question whether in the foreseeable future the presented direction of research will allow us to regulate endogenous anticonvulsant and neuroprotective mechanisms in a subtle way in order to substitute for or support other forms of treatment.

Epilepsy↗
PubMed2003

Congenital and acquired brain injury. 4. New frontiers: neuroimaging, neuroprotective agents, cognitive-enhancing agents, new technology, and complementary medicine.

UNLABELLED: This self-directed learning module explores the clinical application of new and evolving research frontiers in the field of neuroimaging, neuroprotective agents, and cognition-enhancing medications as applied to patients with brain injury. The current and potential clinical applications of robotic technology, virtual reality, and telemedicine in the field of physical medicine and rehabilitation is explored. The evidence to support a growing interest in and application of complementary medicine techniques in brain injury and other disorders is reviewed. OVERALL ARTICLE OBJECTIVES: (a) To explore the current research and potential clinical applications of medical and technologic advances in neuroprotective agents, cognition-enhancing agents, neuroimaging, virtual reality, robotics, and telemedicine as applicable to brain injury and (b) to identify the evidence to support an expanding use of complementary medicine in brain injury.

Brain Injuries↗
PubMed2003

Animal models of stroke: do they have value for discovering neuroprotective agents?

There has been a series of high-profile failures of drugs in clinical trials of acute ischaemic stroke that were designed to meet criteria necessary for drug regulatory approval. This has, again, called into question the value of animal models for identifying effective neuroprotective agents. Here, we review evidence that physiological changes (reperfusion, hyperglycaemia, hypothermia and blood pressure) produce comparable changes in outcome in both animal models and human stroke patients, which indicates that the models should identify clinically effective neuroprotective agents. We suggest that most clinical failures have occurred because compounds were administered differently in animal and clinical studies. We review earlier guidelines on the information that is necessary from preclinical studies before a compound enters clinical trials, and propose modifications to these guidelines.

Animals↗