Treatment of stroke in aged male and female rats with Vepoloxamer and tPA reduces neurovascular damage

So I guess Vepoloxamer has been tested for a while. Has your incompetent doctor and hospital done anything to get this tested for stroke in humans?

Targeting microthrombosis and neuroinflammation with vepoloxamer for therapeutic neuroprotection after traumatic brain injury March 2018 

Synthetic, organic compound vepoloxamer (P-188) potentiates tissue plasminogen activator  September 2015 

The Combination of Tissue Plasminogen Activatorand Vepoloxamer Results in Sustained Neuroprotection in Aged Rats After Embolic Stroke  January 2019 

Treatment of traumatic brain injury with vepoloxamer (purified poloxamer 188)

 February 2018

Vepoloxamer enhances fibrinolysis of tPA (tissue-type plasminogen activator) on acute ischemic stroke October 2019 

You can thank the lack of any leadership in stroke for such incompetency

 The latest here:

Treatment of stroke in aged male and female rats with Vepoloxamer and tPA reduces neurovascular damage

Li Zhang^1* Hao Luo¹ Chao Li¹ Hua Teng¹ Brianna Powell¹ Mei Lu² Michael Chopp^1,3 Zheng Gang Zhang¹

• ¹Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
• ²Department of Biostatistics and Research Epidemiology, Henry Ford Hospital, Detroit, MI, United States
• ³Department of Physics, Oakland University, Rochester, MI, United States

Methods: Stroke is a leading cause of death and disability worldwide, mainly affecting the elderly. Unfortunately, current treatments for acute ischemic stroke warrant improvement. To date, tissue plasminogen activator (tPA) is of limited use in stroke patients mainly due to its narrow therapeutic window and potential for hemorrhagic complication. The adjuvant treatment with Vepoloxamer, a purified amphipathic polymer has been shown to enhance the thrombolytic efficacy of tPA treatment in young adult male rats after embolic stroke. However, most stroke patients are aged; therefore, the current study investigated the therapeutic effect of the combined tPA and Vepoloxamer treatment in aged male and female rats subjected to embolic stroke.

Male and female Wistar rats at 18 months of age were subjected to embolic middle cerebral artery occlusion and treated either with monotherapy of tPA or Vepoloxamer, a combination of these two agents, or saline at 4 h after stroke onset. Neurological outcomes were evaluated with a battery of behavioral tests including adhesive removal, foot-fault, and modified neurological severity score tests at 1 and 7 days after stroke onset, followed by histopathological analysis of infarct volume. Residual clot size and vascular patency and integrity were analyzed.

Results: The combination treatment with Vepoloxamer and tPA significantly reduced infarct volume and neurological deficits in male and female rats compared to rats treated with saline and the monotherapies of tPA and Vepoloxamer. While Vepoloxamer monotherapy moderately reduced neurological deficits, monotherapies with tPA and Vepoloxamer failed to reduce infarct volume compared to saline treatment. Furthermore, the combination treatment with tPA and Vepoloxamer accelerated thrombolysis, reduced ischemia and tPA-potentiated microvascular disruption, and concomitantly improved cerebrovascular integrity and perfusion in the male ischemic rats.

Conclusion: Combination treatment with tPA and Vepoloxamer at 4 h after stroke onset effectively reduces ischemic neurovascular damage by accelerating thrombolysis and reducing ischemia and tPA potentiated side effects in the aged rats. This funding suggests that the combination treatment with tPA and Vepoloxamer represents a promising strategy to potentially apply to the general population of stroke patients.

Introduction

Stroke is a leading cause of death and disability, mainly affecting the elderly. Currently, nearly 7.6 million people suffer an ischemic stroke globally each year and the numbers are expected to increase substantially with the aging population (1–3). The present standard of care for acute ischemic stroke is restricted to reperfusion interventions including endovascular thrombectomy and intravenous thrombolysis, primarily with tissue plasminogen activator (tPA), which mitigate stroke-related disability and mortality in a significant proportion of selected patients (4, 5). However, the current reperfusion interventions are limited by infrequent and delayed recanalization, and the risk of hemorrhagic complication (6–11). Moreover, as an FDA approved thrombolytic agent for acute ischemic stroke, the widespread use of tPA is limited largely due to its narrow therapeutic window (12–14). Nevertheless, while rapid recanalization of occluded cerebral vessels with timely thrombolysis and endovascular treatment is clearly beneficial to stroke outcome, futile reperfusion remains a major hurdle for the reperfusion therapies (6–11). Therefore, to improve the window of efficacy and safety of reperfusion interventions, it is imperative to develop novel and complementary agents to accelerate recanalization, while concomitantly protecting the cerebrovascular integrity.

Clinical evidence on thrombi retrieved from stroke patients revealed that the accumulation of platelets and neutrophils within thrombi alters the fibrin network and forms Neutrophil Extracellular Traps (NETs), which render thrombi less susceptible to thrombolysis (15, 16). In addition, we and others have observed a rapid recruitment of blood elements including platelets, fibrin, and neutrophils at the occlusion site and in downstream microvessels that lead to aggravation of perfusion deficits and blood brain barrier (BBB) disruption in experimental models of stroke (17–19). Thus, clinical and experimental data suggest that stroke induced prothrombotic and proinflammatory events on the cerebrovasculature may contribute to thrombolysis resistance and disruption of cerebrovascular integrity (16, 20).

Vepoloxamer is a purified amphipathic polymer and exerts potent anti-thrombotic, anti-inflammatory, and hemorheological properties in experimental neurovascular injury models including stroke and traumatic brain injury (21–23). We have shown that Vepoloxamer treatment reduces microvascular thrombosis via blocking stroke provoked platelet aggregation and activation in adult rats and that Vepoloxamer extends the tPA therapeutic window by enhancing thrombolysis and reducing tPA induced cerebrovascular disruption (21). Advanced age exacerbates BBB disruption and accelerates ischemic infarct progression (24–27). Also, individual elderly female and male stroke patients often show different responses to pharmacological inventions (28, 29). Accordingly, we investigated the therapeutic effect of the combined Vepoloxamer and tPA treatment on ischemic neurovascular damage in aged male and female rats.

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