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Jeffrey L. Saver - One of the best experts on this subject based on the ideXlab platform.

  • prehospital use of magnesium sulfate as neuroprotection in acute stroke
    The New England Journal of Medicine, 2015
    Co-Authors: Jeffrey L. Saver, Robin Conwit, Sidney Starkman, Marc Eckstein, Samuel J Stratton, Franklin D Pratt, Scott Hamilton, David S Liebeskind
    Abstract:

    BackgroundMagnesium sulfate is Neuroprotective in preclinical models of stroke and has shown signals of potential efficacy with an acceptable safety profile when delivered early after stroke onset in humans. Delayed initiation of Neuroprotective Agents has hindered earlier phase 3 trials of Neuroprotective Agents. MethodsWe randomly assigned patients with suspected stroke to receive either intravenous magnesium sulfate or placebo, beginning within 2 hours after symptom onset. A loading dose was initiated by paramedics before the patient arrived at the hospital, and a 24-hour maintenance infusion was started on the patient's arrival at the hospital. The primary outcome was the degree of disability at 90 days, as measured by scores on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability). ResultsAmong the 1700 enrolled patients (857 in the magnesium group and 843 in the placebo group), the mean (±SD) age was 69±13 years, 42.6% were women, and the mean pretreatment score...

  • Potential role of Neuroprotective Agents in the treatment of patients with acute ischemic stroke
    Current Treatment Options in Cardiovascular Medicine, 2003
    Co-Authors: Bruce Ovbiagele, Chelsea S. Kidwell, Sidney Starkman, Jeffrey L. Saver
    Abstract:

    Currently, intravenous recombinant tissue plasminogen activator is the only US Food and Drug Administration-approved therapy for acute ischemic stroke. Although efficacious, its usefulness is limited, mainly because of the very limited time window for its administration. Neuroprotective treatments are therapies that block the cellular, biochemical, and metabolic elaboration of injury during or after exposure to ischemia, and have a potential role in ameliorating brain injury in patients with acute ischemic stroke. More than 50 Neuroprotective Agents have reached randomized human clinical trials in focal ischemic stroke, but none have been unequivocally proven efficacious, despite successful preceding animal studies. The failed Neuroprotective trials of the past have greatly increased understanding of the fundamental biology of ischemic brain injury and have laid a strong foundation for future advance. Moreover, the recent favorable results of human clinical trials of hypothermia in human cardiac arrest and global brain ischemia have validated the general concept of neuroprotection for ischemic brain injury. Recent innovations in strategies of preclinical drug development and clinical trial design that rectify past defects hold great promise for Neuroprotective investigation, including novel approaches to accelerating time to initiation of experimental treatment, use of outcome measures sensitive to treatment effects, and trial testing of combination therapies rather than single Agents alone. Although no Neuroprotective agent is of proven benefit for focal ischemic stroke, several currently available interventions have shown promising results in preliminary trials and may be considered for cautious, off-label use in acute stroke, including hypothermia, magnesium sulfate, citicoline, albumin, and erythropoietin. Overall, the prospects for safe and effective Neuroprotective therapies to improve stroke outcome remain promising.

  • Potential role of Neuroprotective Agents in the treatment of patients with acute ischemic stroke
    Current treatment options in neurology, 2003
    Co-Authors: Bruce Ovbiagele, Chelsea S. Kidwell, Sidney Starkman, Jeffrey L. Saver
    Abstract:

    Currently, intravenous recombinant tissue plasminogen activator is the only US Food and Drug Administration-approved therapy for acute ischemic stroke. Although efficacious, its usefulness is limited, mainly because of the very limited time window for its administration. Neuroprotective treatments are therapies that block the cellular, biochemical, and metabolic elaboration of injury during or after exposure to ischemia, and have a potential role in ameliorating brain injury in patients with acute ischemic stroke. More than 50 Neuroprotective Agents have reached randomized human clinical trials in focal ischemic stroke, but none has been unequivocally proven efficacious, despite successful preceding animal studies. The failed Neuroprotective trials of the past have greatly increased understanding of the fundamental biology of ischemic brain injury and have laid a strong foundation for future advance. Moreover, the recent favorable results of human clinical trials of hypothermia in human cardiac arrest and global brain ischemia have validated the general concept of neuroprotection for ischemic brain injury. Recent innovations in strategies of preclinical drug development and clinical trial design that rectify past defects hold great promise for Neuroprotective investigation, including novel approaches to accelerating time to initiation of experimental treatment, use of outcome measures sensitive to treatment effects, and trial testing of combination therapies rather than single Agents alone. Although no Neuroprotective agent is of proven benefit for focal ischemic stroke, several currently available interventions have shown promising results in preliminary trials and may be considered for cautious, off-label use in acute stroke, including hypothermia, magnesium sulfate, citicoline, albumin, and erythropoietin. Overall, the prospects for safe and effective Neuroprotective therapies to improve stroke outcome remain promising.

  • Neuroprotective Agents for the treatment of acute ischemic stroke
    Current Neurology and Neuroscience Reports, 2003
    Co-Authors: Bruce Ovbiagele, Chelsea S. Kidwell, Sidney Starkman, Jeffrey L. Saver
    Abstract:

    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.

  • design and retrospective analysis of the los angeles prehospital stroke screen lapss
    Prehospital Emergency Care, 1998
    Co-Authors: Chelsea S. Kidwell, Jeffrey L. Saver, Glenn B Schubert, Marc Eckstein, Sidney Starkman
    Abstract:

    Objectives. The therapeutic window for intervention in acute cerebral ischemia is brief. Prehospital identification of acute stroke patients and paramedic administration of Neuroprotective Agents may soon become critical components of successful acute stroke treatment. This preliminary study sought to demonstrate that a new prehospital screening instrument, the Los Angeles Prehospital Stroke Screen (LAPSS), sensitively identifies acute stroke patients. Further, the study evaluated the potential time savings that could be achieved by paramedic administration of Neuroprotective Agents in the field. Methods. The authors designed a simple stroke screening tool for use by prehospital personnel, emphasizing motor deficits. They then tested instrument performance and time savings retrospectively, employing data from patients enrolled within six hours of symptom onset in randomized stroke trials at three university-associated paramedic receiving hospitals. Results. Fifty of 83 patients enrolled in hyperacute stro...

Xin Wang - One of the best experts on this subject based on the ideXlab platform.

  • identification of melatonin receptor 1a agonists as Neuroprotective Agents in experimental models of ischemic injury
    Brain disorders & therapy, 2015
    Co-Authors: Xin Wang
    Abstract:

    T identification of Neuroprotective Agents for stroke remains elusive. We therefore test whether melatonin receptor 1A agonists melatonin, N-acetyl-serotonin (NAS) and ramelteon are Neuroprotective in experimental models of ischemic injury. We demonstrate that melatonin or NAS or ramelteon inhibits cell death induced by oxygen-glucose deprivation or H2O2 in primary cerebrocortical neurons and primary hippocampal neurons in vitro and organotypic hippocampal slice cultures ex vivo. We further found that melatonin and NAS reduce hypoxia/ischemia injury in the middle cerebral artery occlusion mouse model of cerebral ischemia in vivo. Our data show that melatonin and NAS are Neuroprotective by inhibiting the mitochondrial cell death pathway including the inhibition of the release of apoptogenic factors cytochrome C, Smac, and apoptosis-inducing factor from mitochondria to cytoplasm, and activation of caspase-3, -9. Furthermore, pro–IL-1 processing, and activation of caspase-1 are evaluated in melatonin-mediated neuroprotection. Moreover, we demonstrate that the Neuroprotective effects of NAS may result from the influence of mitochondrial permeability transition pore opening, mitochondrial fragmentation as well as the suppression of the autophagic cell death pathway under stress conditions by increasing LC3-II and Beclin-1 levels and decreasing p62 level. Taken together, we conclude that melatonin receptor 1A agonist’s melatonin, NAS and ramelteon have the potential as the novel therapies for ischemic injury.

  • plant derived Neuroprotective Agents in parkinson s disease
    American Journal of Translational Research, 2015
    Co-Authors: Wenxin Zhuang, Shuanhu Zhou, Xin Wang
    Abstract:

    Parkinson's disease (PD) is one of the most common degenerative disorders of the central nervous system among the elderly. The disease is caused by the slow deterioration of the dopaminergic neurons in the substantia nigra. Treatment strategies to protect dopaminergic neurons from progressive damage have received much attention. However there is no effective treatment for PD. Traditional Chinese medicines have shown potential clinical efficacy in attenuating the progression of PD. Increasing evidence indicates that constituents of some Chinese herbs include resveratrol, curcumin, and ginsenoside can be Neuroprotective. Since pathologic processes in PD including inflammation, oxidative stress, apoptosis, mitochondrial dysfunction, and genetic factors lead to neuronal degeneration, and these Chinese herbs can protect dopaminergic neurons from neuronal degeneration, in this article, we review the Neuroprotective roles of these herbs and summarize their anti-inflammatory, antioxidant, and anti-apoptotic effects in PD. In addition, we discuss their possible mechanisms of action in in vivo and in vitro models of PD. Traditional Chinese medicinal herbs, with their low toxicity and side-effects, have become the potential therapeutic interventions for prevention and treatment of PD and other neurodegenerative diseases.

  • Neuroprotective Agents target molecular mechanisms of disease in ALS.
    Drug discovery today, 2014
    Co-Authors: Yongjin Zhu, Merit Cudkowicz, Anastasios Fotinos, Lilly L. J. Mao, Nazem Atassi, Edward W. Zhou, Sarfraz Ahmad, Yingjun Guan, James D. Berry, Xin Wang
    Abstract:

    Amyotrophic lateral sclerosis (ALS) is a debilitating disease characterized by progressive loss of voluntary motor neurons leading to muscle atrophy, weight loss and respiratory failure. Evidence suggests that inflammation, oxidative stress, mitochondrial dysfunction, apoptosis, glutamate excitotoxicity and proteasomal dysfunction are all responsible for ALS pathogenesis. We review Neuroprotective Agents with the ability to reduce ALS-related bodyweight loss, summarize the various therapies tested on animal models targeting the proposed molecular mechanisms, compare their effects on bodyweight loss, muscle damage, disease onset, duration and survival, and analyze their structure–activity relationships, with the overall goal of creating a screening strategy for further clinical application.

  • Therapeutic Neuroprotective Agents for amyotrophic lateral sclerosis
    Cellular and Molecular Life Sciences, 2013
    Co-Authors: Rachna S. Pandya, Haining Zhu, Robert Bowser, Robert M. Friedlander, Xin Wang
    Abstract:

    Amyotrophic lateral sclerosis (ALS) is a fatal chronic neurodegenerative disease whose hallmark is proteinaceous, ubiquitinated, cytoplasmic inclusions in motor neurons and surrounding cells. Multiple mechanisms proposed as responsible for ALS pathogenesis include dysfunction of protein degradation, glutamate excitotoxicity, mitochondrial dysfunction, apoptosis, oxidative stress, and inflammation. It is therefore essential to gain a better understanding of the underlying disease etiology and search for Neuroprotective Agents that might delay disease onset, slow progression, prolong survival, and ultimately reduce the burden of disease. Because riluzole, the only Food and Drug Administration (FDA)-approved treatment, prolongs the ALS patient’s life by only 3 months, new therapeutic Agents are urgently needed. In this review, we focus on studies of various small pharmacological compounds targeting the proposed pathogenic mechanisms of ALS and discuss their impact on disease progression.

Sean I Savitz - One of the best experts on this subject based on the ideXlab platform.

  • methodological quality of animal studies of Neuroprotective Agents currently in phase ii iii acute ischemic stroke trials
    Stroke, 2009
    Co-Authors: Maria Philip, Michael Benatar, Marc Fisher, Sean I Savitz
    Abstract:

    Background and Purpose— Numerous Neuroprotective Agents have proven effective in animal stroke studies, but every drug has failed to achieve its primary outcome when brought forward to clinical tri...

  • a critical appraisal of the nxy 059 neuroprotection studies for acute stroke a need for more rigorous testing of Neuroprotective Agents in animal models of stroke
    Experimental Neurology, 2007
    Co-Authors: Sean I Savitz
    Abstract:

    Neuroprotection represents a failed strategy to improve outcome after acute ischemic stroke (AIS). However, most Neuroprotective drugs have been inadequately studied in animal stroke models, which led to the creation of the STAIR guidelines on preclinical and clinical testing of therapeutics for AIS. NXY-059, a free radical spin trap agent, was felt by many to have followed these criteria and it was recently shown to improve outcome in AIS patients in the SAINT I trial. However, the repeat, SAINT II trial was a neutral study, the results of which cast doubt on neuroprotection as a viable strategy for AIS. A critical analysis of the NXY-059 preclinical data, however, reveals several shortcomings that have not been addressed in the literature. This report contends that the preclinical evaluation of NXY-059 lacked strenuous testing and was not shown to reproducibly lead to robust protection in extended time windows in clinically relevant stroke models, at several different academic research laboratories. The clinical trials of NXY-059 were inadequately designed, in part, because of inappropriate treatment windows and inclusion of diverse stroke patients. Future Neuroprotective Agents need more rigorous testing in animal models of focal cerebral ischemia and appropriate evaluation in clinical studies that better match the preclinical data.

Sarel F. Malan - One of the best experts on this subject based on the ideXlab platform.

  • Versatility of 7-substituted coumarin molecules as antimycobacterial Agents, neuronal enzyme inhibitors and Neuroprotective Agents
    Molecules, 2017
    Co-Authors: Erika Kapp, Hanri Visser, Germaine B. Foka, Sylvester I. Omoruyi, Adaze B. Enogieru, Elizabeth M. Streicher, Samantha L. Sampson, Sarel F. Malan, Digby F. Warner, Okobi E. Ekpo
    Abstract:

    A medium-throughput screen using Mycobacterium tuberculosis H37Rv was employed to screen an in-house library of structurally diverse compounds for antimycobacterial activity. In this initial screen, eleven 7-substituted coumarin derivatives with confirmed monoamine oxidase-B and cholinesterase inhibitory activities, demonstrated growth inhibition of more than 50% at 50 µM. This prompted further exploration of all the 7-substituted coumarins in our library. Four compounds showed promising MIC99 values of 8.31–29.70 µM and 44.15–57.17 µM on M. tuberculosis H37Rv in independent assays using GAST-Fe and 7H9+OADC media, respectively. These compounds were found to bind to albumin, which may explain the variations in MIC between the two assays. Preliminary data showed that they were able to maintain their activity in fluoroquinolone resistant mycobacteria. Structure-activity relationships indicated that structural modification on position 4 and/or 7 of the coumarin scaffold could direct the selectivity towards either the inhibition of neuronal enzymes or the antimycobacterial effect. Moderate cytotoxicities were observed for these compounds and slight selectivity towards mycobacteria was indicated. Further Neuroprotective assays showed significant neuroprotection for selected compounds irrespective of their neuronal enzyme inhibitory properties. These coumarin molecules are thus interesting lead compounds that may provide insight into the design of new antimicrobacterial and Neuroprotective Agents.

  • polycyclic propargylamine and acetylene derivatives as multifunctional Neuroprotective Agents
    European Journal of Medicinal Chemistry, 2014
    Co-Authors: Frank T Zindo, Sarel F. Malan, Quinton R Barber, Jacques Joubert, Jacobus J Bergh, Jacobus P Petzer
    Abstract:

    The aim of this study was to design drug-like molecules with multiple Neuroprotective mechanisms which would ultimately inhibit N-methyl-D-aspartate (NMDA) receptors, block L-type voltage gated calcium channels (VGCC) and inhibit apoptotic processes as well as the monoamine oxidase-B (MAO-B) enzyme in the central nervous system. These types of compounds may act as Neuroprotective and symptomatic drugs for disorders such as Alzheimer's and Parkinson's disease. In designing the compounds we focused on the structures of rasagiline and selegiline, two well known MAO-B inhibitors and proposed Neuroprotective Agents. Based on this consideration, the compounds synthesised all contain the propargylamine functional group of rasagiline and selegiline or a derivative thereof, conjugated to various polycyclic cage moieties. Being non-polar, these polycyclic moieties have been shown to aid in the transport of conjugated compounds across the blood-brain barrier, as well as cell membranes and have secondary positive Neuroprotective effects. All novel synthesised polycyclic derivatives proved to have significant anti-apoptotic activity (p < 0.05) which was comparable to the positive control, selegiline. Four compounds (12, 15 and 16) showed promising VGCC and NMDA receptor channel inhibitory activity ranging from 18% to 59% in micromolar concentrations and compared favourably to the reference compounds. In the MAO-B assay, 8-phenyl-ethynyl-8-hydroxypentacycloundecane (10), exhibited MAO-B inhibition of 73.32% at 300 μM. This compound also reduced the percentage of apoptotic cells by as much as 40% when compared to the control experiments.

  • synthesis and evaluation of fluorescent heterocyclic aminoadamantanes as multifunctional Neuroprotective Agents
    Bioorganic & Medicinal Chemistry, 2011
    Co-Authors: Jacques Joubert, Sarel F. Malan, Sandra Van Dyk, Ivan R Green
    Abstract:

    A series of fluorescent heterocyclic adamantane amines were synthesised with the goal to develop novel fluorescent ligands for neurological assay development. These derivatives demonstrated multifunctional Neuroprotective activity through inhibition of the N-methyl-d-aspartate receptor/ion channel, calcium channels and the enzyme nitric oxide synthase. It also exhibited a high degree of free radical scavenging potential. N-(1-adamantyl)-2-oxo-chromene-3-carboxamide (8), N-adamantan-1-yl-5-dimethyl-amino-1-naphthalenesulfonic acid (11) and N-(1-cyano-2H-isoindol-2-yl) adamantan-1-amine (12) were found to possess a high degree of multifunctionality with favourable physical-chemical properties for bioavailability and blood-brain barrier permeability. The ability of these heterocyclic adamantane amine derivatives as nitric oxide synthase inhibitors, calcium channel modulators, NMDAR inhibitors and effective antioxidants, indicate that they may find application as multifunctional drugs in neuroprotection.

Yue Wei Guo - One of the best experts on this subject based on the ideXlab platform.

  • design synthesis and biological evaluation of novel chiral oxazino indoles as potential and selective Neuroprotective Agents against aβ25 35 induced neuronal damage
    Bioorganic & Medicinal Chemistry Letters, 2016
    Co-Authors: Jing Chen, Hai-yan Zhang, Wei Xiao, Lingxue Tao, Jianrong Wang, Yue Wei Guo
    Abstract:

    A series of chiral oxazino-indoles have been synthesized via a key intermolecular oxa-Pictet-Spengler reaction. These compounds exhibited significant and selective Neuroprotective effects against Aβ25-35-induced neuronal damage. This is the first report of evaluating the influence of chiral diversity of oxazino-indoles on their Neuroprotective activities, with the structure-activity relationship been analyzed. The highly active compounds 3f, 3g, 4g, 4h, and 6b all performed over 90% cell protection, providing a new direction for the development of Neuroprotective Agents against Alzheimer's disease.

  • Synthesis and biological evaluation of novel marine-derived indole-based 1,2,4-oxadiazoles derivatives as multifunctional Neuroprotective Agents
    Bioorganic and Medicinal Chemistry Letters, 2015
    Co-Authors: Cheng-shi Jiang, Jing Xu Gong, Yan Fu, Hai-yan Zhang, Zhen-zhong Wang, Wei Xiao, Li Zhang, Yue Wei Guo
    Abstract:

    Phidianidines (1), isolated from the marine opisthobranch mollusk Phidiana militaris, present the first example of natural products possessing an 1,2,4-oxadiazole ring system and show various bioactivities. However, the structure-activity relationship study related to 1 has not been reported yet. As our ongoing effect toward marine-derived potential Neuroprotective Agents, a series of phidianidine-based derivatives have been synthesized and evaluated for Neuroprotective effects against amyloid-β25-35(Aβ25-35)-, hydrogenperoxide (H2O2)-, and oxygen-glucose deprivation (OGD)-induced neurotoxicity in SH-SY5Y cells. The bioassay results indicated that some of analogs, especially 2q and 2r, exhibited good in vitro Neuroprotective effects in the above three screening models. The preliminary SAR study indicated that substituent groups introduced to the benzene ring play a crucial role in their bioactivity. In particular, the linear alkoxy group at 4-position favors the Neuroprotective activity, while a bulky group could lead the activity decrease or loss. These findings could provide an alternative strategy for the development of novel indole-based 1,2,4-oxadiazole derivatives for the treatment of Alzheimer's disease.

  • synthesis and biological evaluation of 21 arylidenepregnenolone derivatives as Neuroprotective Agents
    Bioorganic & Medicinal Chemistry Letters, 2012
    Co-Authors: Cheng-shi Jiang, Jing Xu Gong, Hai-yan Zhang, Xianjun Guo, Tingting Zhu, Yue Wei Guo
    Abstract:

    A series of 21-arylidenepregnenolone derivatives and their corresponding epoxides were synthesized. The Neuroprotective effects of these steroidal compounds against amyloid-β(25-35) (Aβ(25-35))- and hydrogen peroxide (H(2)O(2))-induced neurotoxicity in PC12 cells, and oxygen-glucose deprivation (OGD)-induced neurotoxicity in SH-SY5Y cells were evaluated. The bioassay results indicated that several 3β-pregn-21-benzylidene-20-one derivatives displayed potent in vitro Neuroprotective effects in different screening models, for example, compounds 2b, 3a, 3b, and 3s showing significant activities against Aβ(25-35)-induced neurotoxicity in PC12 cells, 2b showing significant activities against H(2)O(2)-induced neurotoxicity in PC12 cells, and 2g, 3b, and 3e showing potent protection against OGD insult. The results suggested that introduction of an arylidene group into steroidal nucleus played an important role in Neuroprotective activity, while the formation of epoxy group at C-5,6 could be also important for the Neuroprotective activity in some degree. The pharmacological data reported here are helpful for the design of novel steroidal Neuroprotective candidates.