The Neuroprotective Compound P7C3- A20 Promotes Neurogenesis and Improves Functional Outcomes After Focal Cerebral Ischemia

Don't worry, nothing will be done with this since it is just a dissertation and nobody in stroke reads research much less dissertations.  Only 120 pages

The Neuroprotective Compound P7C3- A20 Promotes Neurogenesis and Improves Functional Outcomes After Focal Cerebral Ischemia

UNIVERSITY OF MIAMI

THE NEUROPROTECTIVE COMPOUND P7C3-A20 PROMOTES NEUROGENESIS AND IMPROVES FUNCTIONAL OUTCOMES AFTER FOCAL CEREBRAL ISCHEMIA By Zachary Balmuth-Loris A DISSERTATION Submitted to the Faculty of the University of Miami< in partial fulfillment of the requirements for the degree of Doctor of Philosophy  Ischemic stroke is the second leading cause of death worldwide and the leading cause of adult long -term disability in the United States . Despite its prevalence, there are few therapeutic interventions available . The neuroprotective compound P7C3- A20 (A20) has been shown to reduce mature neuronal cell death while also increasing the net magnitude of postnatal neurogenesis in models of neurodegeneration and acute brain injury. A20 compounds demonstrate protection by enhancing the flux of nicotinamide adenine dinucleotide (N AD) in mammalian cells, a proposed therapeutic approach to treating cerebral ischemia. The studies carried out in this dissertation sought to investigate the effectiveness of A20 treatment after focal cerebral ischemia by assessing subacute and chronic histopathological and behavioral outcomes , as well as ischemia - induced neurogenesis . In the first series of experiments, rats underwent a weeklong course of A20 or vehicle treatment, beginning immediately after a 90 minute unilateral transient middle cere bral artery occlusion (tMCAO) . A20- treated rats performed significantly better than vehicle -treated controls in sensorimotor cylinder and grid- walk tasks, and in a chronic test of spatial learning and memory. These behavioral improvements with A20 treatment were correlated with significantly decreased cortical and hippocampal atrophy as well as increased neurogenesis in the subventricular zone and hippocampal dentate gyrus subgranular zone. Furthermore, cerebral ischemia significantly depleted NAD in the co rtex , but treating with A20 restored cortical NAD levels.

After demonstrating efficacy of A20 treatment at an early, post-ischemic timepoint, we then sought to examine A20’s treatment window of opportunity. Due to a limited therapeutic window, current stroke pharmacological treatment is rarely administered to ischemic patients. Therefore, we investigated a more clinically relevant time point and again treated tMCAO rats for one week with A20, beginning either immediately (iA20) or at a delayed point (dA20) 6 hours post-reperfusion. dA20 treatment significantly reduced ischemia-induced sensorimotor deficits in motor coordination and limb-use asymmetry as well as cognitive deficits in hippocampal -Ischemic stroke is the second leading cause of death worldwide and the leading cause of adult long-term disability in the United States. Despite its prevalence, there are few therapeutic interventions available. The neuroprotective compound P7C3-A20 (A20)has been shown to reduce mature neuronal cell death while also increasing the net magnitude of postnatal neurogenesis in models of neurodegeneration and acute brain injury. A20 compounds demonstrate protection by enhancing the flux of nicotinamide adenine dinucleotide (N AD) in mammalian cells, a proposed therapeutic approach to treating cerebral ischemia. The studies carried out in this dissertation sought to investigate the effectiveness of A20 treatment after focal cerebral ischemia by assessing subacute and chronic histopathological and behavioral outcomes, as well as ischemia-induced neurogenesis. In the first series of experiments, rats underwent a weeklong course of A20 or vehicle treatment, beginning immediately after a 90 minute unilateral transient middle cerebral artery occlusion (tMCAO). A20-treated rats performed significantly better than vehicle-treated controls in sensorimotor cylinder and grid- walk tasks, and in a chronic test of spatial learning and memory. These behavioral improvements with A20 treatment were correlated with significantly decreased cortical and hippocampal atrophy as well as increased neurogenesis in the subventricular zone and hippocampal dentate gyrus subgranular zone. Furthermore, cerebral ischemia significantly depleted NAD in the cortex, but treating with A20 restored cortical NAD levels. After demonstrating efficacy of A20 treatment at an early, post-ischemic timepoint, we then sought to examine A20’s treatment window of opportunity. Due to a limited therapeutic window, current stroke pharmacological treatment is rarely administered to ischemic patients. Therefore, we investigated a more clinically relevant time point and again treated tMCAO rats for one week with A20, beginning either immediately (iA20) or at a delayed point (dA20) 6 hours post-reperfusion. dA20 treatment significantly reduced ischemia-induced sensorimotor deficits in motor coordination and limb-use asymmetry as well as cognitive deficits in hippocampal-dependent spatial learning, memory retention, and working memory. In the cerebral cortex, dA20 treatment significantly increased tissue sparing 7 weeks after stroke and reduced infarct volumes 48 hours after reperfusion compared to vehicle-treated animals. At 48 hours after injury, there was no change in striatal infarct volumes between tMCAO groups. However, when tissue volume was reassessed at 7 weeks, A20-treated animals had a significant increase in striatal tissue volume, suggesting that A20’s protection in the ischemic striatum requires an extended treatment regimen. In the hippocampus, only iA20-treated animals had a significant increase in tissue sparing compared to vehicle-treated stroke animals. This translated into minimal hippocampal-dependent behavioral improvements with dA20 treatment. However, all rats treated with dA20 did demonstrate a significant improvement in both sensorimotor tasks compared to vehicle controls, suggesting a somatosensory driven recovery.

Overall, our studies show that A20 treatment is an effective strategy against focal cerebral ischemia by mitigating chronic neurodegeneration, enhancing repair, and rescuing stroke-induced behavioral deficits when treated at a clinically relevant time point. Therefore, treatment with A20 compounds represent a novel therapeutic approach to safely augment NAD tissue levels, promoting two independent processes critical to protecting the brain from ischemic stroke; mature neuron survival and postnatal hippocampal neurogenesis throughout the post -ischemic brain.

Neuroprotective compound could save brain cells during stroke, rat study shows

It is good to be a rat in stroke except for the fact you usually get killed to examine your brain.  Any further research planned for humans? Like maybe following a stroke strategy? 

Neuroprotective compound could save brain cells during stroke, rat study shows

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March 2, 2017 at 9:29 PM

Researchers from the University of Iowa Carver College of Medicine and the University of Miami Miller School of Medicine have shown that a neuroprotective compound tested in rats provides two-pronged protection for brain cells during stroke and improves physical and cognitive outcomes in the treated animals.
Every year, nearly 800,000 Americans have a stroke and almost 130,000 die. Survivors often are left with long-term physical and cognitive disability that significantly alters their lives.
When a stroke interrupts the brain's blood supply, mature brain cells (neurons) die. In addition, reestablishing blood flow, known as reperfusion, also leads to processes that cause cell death. A part of the brain's natural response to stroke injury is to increase production of new brain cells in two specific regions (the subgranular zone of the hippocampal dentate gyrus and the subventricular zone of the lateral ventricles), which normally make a smaller number of new brain cells every day. Unfortunately, the vast majority of these newborn cells die within one to two weeks, limiting the benefit of this potential repair process. Minimizing the loss of brain cells is a primary goal for new stroke therapies.
"If we could prevent the mature brain cells from dying that would be beneficial," says Andrew Pieper, MD, PhD, professor of psychiatry in the UI Carver College of Medicine and co-senior study author. "But if we could also support or enhance this surge in neurogenesis (birth of new neurons), we might be able to further foster recovery, especially in terms of cognitive function, which is critically dependent on the hippocampus."
Using rats, Pieper and his colleagues Zachary B. Loris and W. Dalton Dietrich, PhD, tested the effects of a compound called P7C3-A20 on these two aspects of neuroprotection following ischemic stroke. Blood flow to the rats' brains was interrupted for 90 minutes and then the blockage was cleared allowing reperfusion. One group of rats was given the P7C3-A20 compound twice daily for seven days following the stroke. P7C3-A20 has previously been shown to prevent brain cell death in other animal models of neurologic injury, including Parkinson's disease, amyotrophic lateral sclerosis, stress-associated depression, and traumatic brain injury.
In terms of the brain itself, the P7C3-A20 compound reduced loss of brain tissue (atrophy) and increased survival of newborn neurons six weeks after stroke. In addition to the improved survival of both mature and newborn neurons, rats that received the P7C3-A20 compound for seven days after stroke also had better physical and cognitive outcomes than untreated rats. Treated rats had improved balance and coordination one week after stroke, and improved learning and memory one month after stroke. The findings were published recently in the journal Experimental Neurology.

"There is no previous demonstration of a pharmacologic agent that both protects mature neurons from dying and also boosts the net magnitude of neurogenesis," Pieper says. "Our compound is beneficial in this animal model of stroke, and we're hopeful that it might eventually benefit patients."
"Currently there are limited treatments for acute stroke that make a real difference in patient's lives. There is an urgent need to identify, test, and translate new therapies to the clinic," adds Dietrich, co-senior study author and Scientific Director of The Miami Project to Cure Paralysis, professor of neurological surgery, neurology, biomedical engineering and cell biology at the University of Miami where the studies were conducted. "The ability to both protect and repair the injured nervous system has major implications on how we think about improving outcomes in millions of people each year with acute neurological injuries."
The neuronal protection provided by the P7C3-A20 compound was also associated with a boost in the levels of a substance called nicotinamide adenine dinucleotide (NAD) in the rats' brains. NAD is emerging as an important player in neuronal health and survival. Levels of this substance are depleted during stroke, and it has been proposed that increasing NAD levels may be a therapeutic target for treating stroke. In this study, P7C3-A20 treatment restored NAD to normal levels in the rats' cortex after a stroke.
Importantly, the study examined the effects of P7C3-A20 on cognitive and physical outcomes well beyond the time of the initial stroke. The sustained physical and cognitive improvement seen in the rats up to one month after the stroke suggests that the P7C3-A20 compound provides a long-term benefit.
"We found we can give the compound in this critical period immediately after the stroke and it has a lasting effect," notes Pieper, who also is a professor of neurology, radiation oncology, and a psychiatrist with the Iowa City Veterans Affairs Health Care System.
In recent years, advances in treatments that break up or remove stroke-causing blood clots have reduced the death rate for stroke and are improving outcomes for patients. The researchers hope that a treatment based on P7C3-A20 used in addition to the clot-clearing therapies might further improve outcomes by protecting brain cells during the traumatic ischemia/reperfusion period.

Source:

University of Iowa Health Care

Neuroprotective compound could save brain cells during stroke, rat study shows

WHOM do we talk to to get this followed up in humans? Or will this fall thru the cracks like most promising stroke research due to our fucking failures of stroke associations? I bet the lasting effect is because there are less dead and damaged neurons because of the treatment. It stopped some part of the neuronal cascade of death.

The latest here:
Neuroprotective compound could save brain cells during stroke, rat study shows

Researchers from the University of Iowa Carver College of Medicine and the University of Miami Miller School of Medicine have shown that a neuroprotective compound tested in rats provides two-pronged protection for brain cells during stroke and improves physical and cognitive outcomes in the treated animals.
Every year, nearly 800,000 Americans have a stroke and almost 130,000 die. Survivors often are left with long-term physical and cognitive disability that significantly alters their lives.
When a stroke interrupts the brain's blood supply, mature brain cells (neurons) die. In addition, reestablishing blood flow, known as reperfusion, also leads to processes that cause cell death. A part of the brain's natural response to stroke injury is to increase production of new brain cells in two specific regions (the subgranular zone of the hippocampal dentate gyrus and the subventricular zone of the lateral ventricles), which normally make a smaller number of new brain cells every day. Unfortunately, the vast majority of these newborn cells die within one to two weeks, limiting the benefit of this potential repair process. Minimizing the loss of brain cells is a primary goal for new stroke therapies.
"If we could prevent the mature brain cells from dying that would be beneficial," says Andrew Pieper, MD, PhD, professor of psychiatry in the UI Carver College of Medicine and co-senior study author. "But if we could also support or enhance this surge in neurogenesis (birth of new neurons), we might be able to further foster recovery, especially in terms of cognitive function, which is critically dependent on the hippocampus."
Using rats, Pieper and his colleagues Zachary B. Loris and W. Dalton Dietrich, PhD, tested the effects of a compound called P7C3-A20 on these two aspects of neuroprotection following ischemic stroke. Blood flow to the rats' brains was interrupted for 90 minutes and then the blockage was cleared allowing reperfusion. One group of rats was given the P7C3-A20 compound twice daily for seven days following the stroke. P7C3-A20 has previously been shown to prevent brain cell death in other animal models of neurologic injury, including Parkinson's disease, amyotrophic lateral sclerosis, stress-associated depression, and traumatic brain injury.
In terms of the brain itself, the P7C3-A20 compound reduced loss of brain tissue (atrophy) and increased survival of newborn neurons six weeks after stroke. In addition to the improved survival of both mature and newborn neurons, rats that received the P7C3-A20 compound for seven days after stroke also had better physical and cognitive outcomes than untreated rats. Treated rats had improved balance and coordination one week after stroke, and improved learning and memory one month after stroke. The findings were published recently in the journal Experimental Neurology.

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"There is no previous demonstration of a pharmacologic agent that both protects mature neurons from dying and also boosts the net magnitude of neurogenesis," Pieper says. "Our compound is beneficial in this animal model of stroke, and we're hopeful that it might eventually benefit patients."
"Currently there are limited treatments for acute stroke that make a real difference in patient's lives. There is an urgent need to identify, test, and translate new therapies to the clinic," adds Dietrich, co-senior study author and Scientific Director of The Miami Project to Cure Paralysis, professor of neurological surgery, neurology, biomedical engineering and cell biology at the University of Miami where the studies were conducted. "The ability to both protect and repair the injured nervous system has major implications on how we think about improving outcomes in millions of people each year with acute neurological injuries."
The neuronal protection provided by the P7C3-A20 compound was also associated with a boost in the levels of a substance called nicotinamide adenine dinucleotide (NAD) in the rats' brains. NAD is emerging as an important player in neuronal health and survival. Levels of this substance are depleted during stroke, and it has been proposed that increasing NAD levels may be a therapeutic target for treating stroke. In this study, P7C3-A20 treatment restored NAD to normal levels in the rats' cortex after a stroke.
Importantly, the study examined the effects of P7C3-A20 on cognitive and physical outcomes well beyond the time of the initial stroke. The sustained physical and cognitive improvement seen in the rats up to one month after the stroke suggests that the P7C3-A20 compound provides a long-term benefit.
"We found we can give the compound in this critical period immediately after the stroke and it has a lasting effect," notes Pieper, who also is a professor of neurology, radiation oncology, and a psychiatrist with the Iowa City Veterans Affairs Health Care System.
In recent years, advances in treatments that break up or remove stroke-causing blood clots have reduced the death rate for stroke and are improving outcomes for patients. The researchers hope that a treatment based on P7C3-A20 used in addition to the clot-clearing therapies might further improve outcomes by protecting brain cells during the traumatic ischemia/reperfusion period.

Source:

University of Iowa Health Care

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Posted in: Medical Science News | Medical Research News | Medical Condition News

Tags: Adenine, Blood, Brain, Brain Cell, Cell, Cognitive Function, Compound, Cortex, Depression, Disability, Health Care, Heart, Hippocampus, Ischemic Stroke, Nervous System, Neurogenesis, Neurology, Oncology, Paralysis, Parkinson's Disease, Psychiatry, Sclerosis, Stress, Stroke, Surgery, Traumatic Brain Injury, Veterans Affairs

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The neuroprotective compound P7C3-A20 promotes neurogenesis and improves cognitive function after ischemic stroke

How many decades will it take before followup studies are done in humans? I'm guessing never because we have fucking failures of stroke associations and NO stroke strategy or stroke leadership. Or you just could hire your own researchers to test this out.
http://www.sciencedirect.com/science/article/pii/S0014488617300055

• Zachary B. Loris^{a, b},
• Andrew A. Pieper^{c, ,} ,
• W. Dalton Dietrich^{a, b, ,}

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http://dx.doi.org/10.1016/j.expneurol.2017.01.006

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Highlights

•

The neuroprotective compound P7C3-A20 was proposed as a therapeutic for stroke.

•

P7C3-A20 reduced sensorimotor and cognitive deficits that occur after stroke.

•

P7C3-A20 significantly increased neurogenesis in both neurogenic niches.

•

P7C3-A20 significantly reduced both hippocampal and cortical atrophy which was strongly correlated to tissue sparing.

•

P7C3-A20 treatment enhanced flux of nicotinamide adenine dinucleotide.

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Abstract

Ischemic stroke is a devastating condition with few therapeutic interventions available. The neuroprotective compound P7C3-A20 inhibits mature neuronal cell death while also increasing the net magnitude of postnatal neurogenesis in models of neurodegeneration and acute injury. P7C3 compounds enhance flux of nicotinamide adenine dinucleotide (NAD) in mammalian cells, a proposed therapeutic approach to treating cerebral ischemia. The effectiveness of P7C3-A20 treatment on chronic histopathological and behavioral outcomes and neurogenesis after ischemic stroke has not previously been established. Here, a transient middle cerebral artery occlusion in rats was followed by twice daily injection of P7C3-A20 or vehicle for 7 days. P7C3-A20-treated rats performed significantly better than vehicle-treated controls in sensorimotor cylinder and grid-walk tasks, and in a chronic test of spatial learning and memory. These behavioral improvements with P7C3-A20 treatment were correlated with significantly decreased cortical and hippocampal atrophy, and associated with increased neurogenesis in the subventricular zone and hippocampal dentate gyrus subgranular zone. Furthermore, cerebral ischemia significantly reduced NAD in the cortex but P7C3-A20 treatment restored NAD to sham levels. Thus, P7C3-A20 treatment mitigates neurodegeneration and augments repair in the brain after focal ischemia, which translates into chronic behavioral improvement. This suggests a new therapeutic approach of using P7C3 compounds to safely augment NAD and thereby promote two independent processes critical to protecting the brain from ischemic stroke: mature neuron survival and postnatal hippocampal neurogenesis throughout the post-ischemic brain.

Keywords

• Aminopropyl carbazole;
• Ischemic stroke;
• Neuroprotection;
• Neurogenesis;
• P7C3-A20;
• NAD

Correspondence to: Andrew A. Pieper, Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Ave, PBDB 1318, Iowa City, IA 52242, United States.

Correspondence to: W. Dalton Dietrich, Department of Neurological Surgery, University of Miami Leonard M. Miller School of Medicine, 1095 NW 14th Terrace, Suite 2-30, Miami, FL 33136-1060, United States.