A Cost-Effective Rabbit Embolic Stroke Bioassay: Insight into the Development of Acute Ischemic Stroke Therapy

Lapchak, Paul A.

doi:10.1007/s12975-015-0386-x

Cited by 19 publications

(6 citation statements)

References 71 publications

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“…In addition, it would be relevant to study the therapeutic time window in the rabbit small clot embolic stroke model, in which the efficacy of the only marketed drug against ischemic stroke, tissue plasminogen activator (tPA), has been correlated with its effects in humans (Lapchak, 2010). This model also allows studies of the effect of combinations of UCCB01-144 and tPA on efficacy, safety, and therapeutic dose-and time window (Lapchak, 2015;Lapchak and Araujo, 2007).…”

Section: Discussionmentioning

confidence: 99%

Selectivity, efficacy and toxicity studies of UCCB01-144, a dimeric neuroprotective PSD-95 inhibitor

et al. 2019

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Inhibition of postsynaptic density protein-95 (PSD-95) decouples N-methyl-D-aspartate (NMDA) receptor downstream signaling and results in neuroprotection after focal cerebral ischemia. We have previously developed UCCB01-144, a potent dimeric PSD-95 inhibitor, which binds PSD-95 with high affinity and is neuroprotective in experimental stroke. Here, we investigate the selectivity, efficacy and toxicity of UCCB01-144 and compare with the monomeric drug candidate Tat-NR2B9c. Fluorescence polarization using purified proteins and pull-downs of mouse brain lysates showed that UCCB01-144 potently binds all four PSD-95-like membrane-associated guanylate kinases (MAGUKs). In addition, UCCB01-144 affected NMDA receptor signaling pathways in ischemic brain tissue. UCCB01-144 reduced infarct size in young and aged male mice at various doses when administered 30 min after permanent middle cerebral artery occlusion, but UCCB01-144 was not effective in young male mice when administered 1 hour post-ischemia or in female mice. Furthermore, UCCB01-144 was neuroprotective in a transient stroke model in rats, and in contrast to Tat-NR2B9c, high dose of UCCB01-144 did not lead to significant changes in mean arterial blood pressure or heart rate. Overall, UCCB01-144 is a potent MAGUK inhibitor that reduces neurotoxic PSD-95-mediated signaling and improves neuronal survival following focal brain ischemia in rodents under various conditions and without causing cardiovascular side effects, which encourages further studies towards clinical stroke trials.

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Section: Discussionmentioning

confidence: 99%

Selectivity, efficacy and toxicity studies of UCCB01-144, a dimeric neuroprotective PSD-95 inhibitor

et al. 2019

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“…It must pointed out that aged 24-month old rodents purchased from standard animal facilities cost in the range of $700-1500 per animal depending on gender, and with a standard study incorporating 20-40 rodents per gender can cost $100,000 for animals alone [30]. The options for research include the standardized rabbit embolic stroke model used in the development of tPA [17,27,28,35], and non-human primates (NHPs) recently used for the development of PSD-95 antagonists [36,37]. However, the principal investigator of the PSD-95 inhibitor studies, Dr. Tymianski stated that there is no evidence that NHPs are necessary or essential for translational stroke research.…”

Section: Noteworthy Commentsmentioning

confidence: 99%

“…However, the development of neuroprotective compounds has been fraught with problems, in particular, the lack of efficacy in many stroke clinical trials. There are many reasons for this failure, and they have been reviewed in detail elsewhere [12,[16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Translational Stroke Research Opportunities and a Strategy to Develop Effective Cytoprotection

Lapchak

2017

Transl. Stroke Res.

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“…Currently, there are established rodent, rabbit and primate embolism models that can be used to develop novel neuroprotective strategies [11, 12, 69–72, 16, 15, 14]. Of importance to modeling stroke for stroke therapy research and development, there may be a need to include glycemic variability [73–75], age [76], gender/sex [77], and hypertension [76], but there are still no FDA-approved neuroprotectives to document the best path forward, nor is there critical data demonstrating that extensive studies in animals with comorbidities are required for success (see also [12]. With the discoveries described above, early intervention was best (within 6 hours) and recommendations are made to prevent any delay in treating the stroke victim [1–6, 36].…”

Section: C) Neuroprotection: On the Horizon?mentioning

confidence: 99%

Critical Early Thrombolytic and Endovascular Reperfusion Therapy for Acute Ischemic Stroke Victims: a Call for Adjunct Neuroprotection

Lapchak

2015

Transl. Stroke Res.

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Today, there is an enormous amount of excitement in the field of stroke victim care due to the recent success of MR. CLEAN, SWIFT PRIME, ESCAPE, EXTEND-IA, and REVASCAT endovascular trials. Successful intravenous (IV) recombinant tissue plasminogen activation (rt-PA) clinical trials [i.e.: National Institutes of Neurodegenerative Disease and Stroke (NINDS) stroke trial; Third European Cooperative Acute Stroke Study (ECASSIII) and Third International Stroke study (IST-3)] also need to be emphasized. In the recent endovascular and thrombolytic trials, there is statistically significant improvement using both the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Score (mRS) scale, but neither approach promotes complete recovery in patients enrolled within any particular NIHSS or mRS score tier. Absolute improvement (mRS 0–2 at 90 days) with endovascular therapy is 13.5–31%, whereas thrombolytics alone also significantly improve patient functional independence, but to a lesser degree (NINDS rt-PA trial 13%). This article has 3 main goals: (1) first to emphasize the utility and cost-effectiveness of rt-PA to treat stroke; (2) second to review the recent endovascular trials with respect to efficacy, safety and cost-effectiveness as a stroke treatment; and (3) to further consider and evaluate strategies to develop novel neuroprotective drugs. A thesis will be put forth so that future stroke trials and therapy development can optimally promote recovery so that stroke victims can return to “normal” life.

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A Cost-Effective Rabbit Embolic Stroke Bioassay: Insight into the Development of Acute Ischemic Stroke Therapy

Cited by 19 publications

References 71 publications

Selectivity, efficacy and toxicity studies of UCCB01-144, a dimeric neuroprotective PSD-95 inhibitor

Selectivity, efficacy and toxicity studies of UCCB01-144, a dimeric neuroprotective PSD-95 inhibitor

Translational Stroke Research Opportunities and a Strategy to Develop Effective Cytoprotection

Critical Early Thrombolytic and Endovascular Reperfusion Therapy for Acute Ischemic Stroke Victims: a Call for Adjunct Neuroprotection

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