New Windows, Same Old House

Weant, Kyle A.; Baker, Stephanie N.

doi:10.1097/tme.0b013e3182542bce

Cited by 6 publications

(4 citation statements)

References 40 publications

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“…This is similar to the goals of tPA treatment in terms of the importance of the therapeutic window [7, 8]. An early mobilization of protective power may prevent neurons from initiating the process of apoptosis/necrosis in the brain.…”

Section: Discussionmentioning

confidence: 62%

Effect of Electroacupuncture on Rat Ischemic Brain Injury: Importance of Stimulation Duration

Fei

Guo

Cheng

et al. 2013

Evidence-Based Complementary and Alternative Medicine

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We explored the optimal duration of electroacupuncture (EA) stimulation for protecting the brain against ischemic injury. The experiments were carried out in rats exposed to right middle cerebral artery occlusion (MCAO) for 60 min followed by 24-hr reperfusion. EA was delivered to “Shuigou” (Du 26) and “Baihui” (Du 20) acupoints with sparse-dense wave (5/20 Hz) at 1.0 mA for 5, 15, 30, and 45 min, respectively. The results showed that 30 min EA, starting at 5 minutes after the onset of MCAO (EA during MCAO) or 5 minutes after reperfusion (EA after MCAO), significantly reduced ischemic infarct volume, attenuated neurological deficits, and decreased death rate with a larger reduction of the ischemic infarction in the former group. Also in the group of EA during MCAO, this protective benefit was positively proportional to the increase in the period of stimulation, that is, increased protection in response to EA from 5- to 30-min stimulation. In all groups, EA induced a significant increase in cerebral blood flow and promoted blood flow recovery after reperfusion, and both blood flow volume and blood cell velocity returned to the preischemia level in a short period of time. Surprisingly, EA for 45 min did not show reduction in the neurological deficits or the infarct volume and instead demonstrated an increase in death rate in this group. Although EA for 45 min still increased the blood flow during MCAO, it led to a worsening of perfusion after reperfusion compared to the group subjected only to ischemia. The neuroprotection induced by an “optimal” period (30 min) of EA was completely blocked by Naltrindole, a δ-opioid receptor (DOR) antagonist (10 mg/kg, i.v.). These findings suggest that earlier EA stimulation leads to better outcomes, and that EA-induced neuroprotection against ischemia depends on an optimal EA-duration via multiple pathways including DOR signaling, while “over-length” stimulation exacerbates the ischemic injury.

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Section: Discussionmentioning

confidence: 62%

Effect of Electroacupuncture on Rat Ischemic Brain Injury: Importance of Stimulation Duration

Fei

Guo

Cheng

et al. 2013

Evidence-Based Complementary and Alternative Medicine

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“…Second, even though tPA increases cerebral perfusion, it is not neuroprotective or neurotrophic and does not promote cell survival. Third, because of the inherent difficulties with administering tPA, and the short therapeutic window, it is estimated that 45–50% of patients presenting within 4.5 hours are treated with tPA(10), however, this still represents less than 10% of all stroke patients (10–12). There remains a critical medical need for new therapeutics to be used an a monotherapy or in combination with tPA, to halt the debilitating neurodegenerative effects of AIS, the 4th leading cause of mortality and leading cause of adult morbidity in the USA.…”

Section: Introductionmentioning

confidence: 99%

Drug-Like Property Profiling of Novel Neuroprotective Compounds to Treat Acute Ischemic Stroke: Guidelines to Develop Pleiotropic Molecules

Lapchak

2012

Transl. Stroke Res.

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The development of novel neuroprotective compounds to treat acute ischemic stroke (AIS) has been problematic and quite complicated, since many candidates that have been tested clinically lacked significant pleiotropic activity, were unable to effectively cross the blood brain barrier (BBB), had poor bioavailability or were toxic. Moreover, the compounds did not confer significant neuroprotection or clinical efficacy measured using standard behavioral endpoints, when studied in clinical trials in a heterogeneous population of stroke patients. To circumvent some of the drug development problems describe above, we have used a rational funnel approach to identify and develop promising candidates. Using a step-wise approach, we have identified a series of compounds based upon two different neuroprotection assays. We have then taken the candidates and determined their “drug-like” properties. This guidelines article details in vitro screening assays used to show pleiotropic activity of a series of novel compounds; including enhanced neuroprotective activity compared to the parent compound fisetin. Moreover, for preliminary drug de-risking or risk reduction during development, we used compound assessment in the CeeTox assay, ADME toxicity using the AMES test for genotoxicity and interaction with Cytochrome P450 using CYP450 inhibition analysis against a spectrum of CYP450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) as a measure of drug interaction. Moreover, the compounds have been studied using a transfected Madin Darby canine kidney (MDCK) cell assay to assess blood brain barrier penetration (BBB). Using this series of assays, we have identified 4 novel molecules to be developed as an AIS treatment.

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“…Physicians have only limited options to treat ischemia-induced neuron death in stroke and cardiac arrest patients (e.g., tPA [ 25 ] and therapeutic hypothermia [ 26 ], resp. ), and these options can only be applied to a small subset of brain ischemia patients [ 27 ]. Therefore, with respect to preventing neurological damage after the injury had occurred, it is fair to conclude that the amount of research invested over the past decades has not produced a proportional return on investment.…”

Section: Brain Ischemiamentioning

confidence: 99%

Inductive and Deductive Approaches to Acute Cell Injury

DeGracia

Anggraini

Taha

et al. 2014

International Scholarly Research Notices

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Many clinically relevant forms of acute injury, such as stroke, traumatic brain injury, and myocardial infarction, have resisted treatments to prevent cell death following injury. The clinical failures can be linked to the currently used inductive models based on biological specifics of the injury system. Here we contrast the application of inductive and deductive models of acute cell injury. Using brain ischemia as a case study, we discuss limitations in inductive inferences, including the inability to unambiguously assign cell death causality and the lack of a systematic quantitative framework. These limitations follow from an overemphasis on qualitative molecular pathways specific to the injured system. Our recently developed nonlinear dynamical theory of cell injury provides a generic, systematic approach to cell injury in which attractor states and system parameters are used to quantitatively characterize acute injury systems. The theoretical, empirical, and therapeutic implications of shifting to a deductive framework are discussed. We illustrate how a deductive mathematical framework offers tangible advantages over qualitative inductive models for the development of therapeutics of acutely injured biological systems.

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New Windows, Same Old House

Cited by 6 publications

References 40 publications

Effect of Electroacupuncture on Rat Ischemic Brain Injury: Importance of Stimulation Duration

Effect of Electroacupuncture on Rat Ischemic Brain Injury: Importance of Stimulation Duration

Drug-Like Property Profiling of Novel Neuroprotective Compounds to Treat Acute Ischemic Stroke: Guidelines to Develop Pleiotropic Molecules

Inductive and Deductive Approaches to Acute Cell Injury

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