I am interested in precision medicine (personalized medicine), notably in the context of acute neurological disorders leading to chronic neurodegenerative disease. The focus of my NeuroICU DoreLab for the last 20 years has been on translational research to explore and understand the etiopathology of neurological disorders. Our dedicated and passionate team of clinicians, basic scientists, students, and visiting scientists are mainly focusing on ischemic stroke (brain infarct), intracranial bleeding such as intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), and concussion/traumatic brain injury (TBI). We also are interested in neurocognitive deficits in AD, vascular-related dementia, and sickle cell diseases. We go from basic science to clinical retrospective and prospective studies and back to the bench. And we are open to team collaborations to determine potential biomarkers or genes that may help predict which patients can have complications at a later time and address which patients can potentially most benefit from an innovative treatment or intervention. This could explain and reduce variabilities in clinical trials and accelerate the review and adoption of new protocols and guidelines. I have graduated and mentored many most amazing Undergrads and Grad Students and Postdocs, Fellows and Junior Faculty. Supervisors: Supervisor
<p>(A) Representative brain sections and microphotographs of selected brain regions from th... more <p>(A) Representative brain sections and microphotographs of selected brain regions from the same corresponding sections used for immunohistochemistry quantification. (B) Quantitative analyses of Iba1 immunoreactivity in the ipsilateral brain regions represented as a percentage of their contralateral counterparts showing the lack of the effect of the EP1 knockout compared to WT mice. Data for animals of both genotypes with vehicle and saline treatments were pulled together. Description of the brain regions is the same as that in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113689#pone-0113689-g003" target="_blank">Figure 3</a>. No statistical differences were observed when using Student’s t-test (n = 16 for WT and n = 8 for EP1<sup>−/−</sup> mice).</p
With the population aging at an accelerated rate, the prevalence of stroke and financial burden o... more With the population aging at an accelerated rate, the prevalence of stroke and financial burden of stroke-related health care costs is expected to continue to increase. Intracerebral hemorrhage (ICH) is a devastating stroke subtype more commonly affecting the elderly population, whom display increased mortality and worse functional outcomes compared to younger patients. This study aimed to investigate the contribution of the prostaglandin E 2 (PGE 2 ) E prostanoid (EP) receptor subtype 3 in modulating anatomical outcomes and functional recovery following ICH in 24-mo-old mice. PGE 2 levels are dramatically upregulated following brain injury and have been shown to modulate the deleterious excitotoxic and neuroinflammatory processes resulting from activation of glial cells and infiltration of blood cells and proinflammatory molecules through its four EP receptors, EP1-4. EP3 is the most abundant EP receptor in the brain and we have previously shown that signaling through the PGE 2 -EP...
Intracerebral hemorrhage (ICH) has the highest morbidity, disability, and mortality rates of any ... more Intracerebral hemorrhage (ICH) has the highest morbidity, disability, and mortality rates of any stroke subtype, including ischemic stroke. When a hemorrhagic stroke occurs, the blood-brain barrier is broken and blood components enter the brain. A major cause of morbidity and mortality following ICH is the direct toxicity of blood metabolites, mainly free heme, on adjacent brain tissue. Hemopexin (Hpx) is the endogenous protein responsible for scavenging free heme; thereby, modulating its proxidant and proinflammatory properties. We hypothesized that the specific local overexpression of Hpx within the brain would attenuate anatomical and functional outcomes after experimentally inducing an ICH. We uniquely designed novel adeno-associated viral vectors (and control vectors) to specifically overexpress Hpx locally within the brain of C57BL/6N mice. After experimentally inducing an ICH using the autologous whole blood model, when compared to an identically treated control group, Hpx-ov...
Objective: Our goal is to identify supplements that can improve neuronal survival of postnatal ne... more Objective: Our goal is to identify supplements that can improve neuronal survival of postnatal neuronal cultures. Here, we hypothesize that resveratrol could rescue neurons that are stressed during the brain dissociation and plating procedures. Background: The standardized B27 supplement with neurobasal medium has been used to facilitate neuronal growth and attenuates glial proliferation. We have documented that resveratrol (3,4’5 trihydroxystilbene), a natural polyphenol and a bioactive component of red wine, have numerous neuroprotective properties both in vivo and after oxygen-glucose deprivation protocols. We have proposed that this stilbene would not likely act as a direct antioxidant but act as a bioactive agent capable to induce an intracellular cytoprotective cascade. Methods: Postnatal cultures of cortical neurons were derived from 0- to 1-day-old C57BL/6 mice. Brains were dissociated and neurons plated and maintained in three different media: neurobasal medium without any ...
Intracerebral hemorrhage (ICH) is a type of hemorrhagic stroke associated with high mortality and... more Intracerebral hemorrhage (ICH) is a type of hemorrhagic stroke associated with high mortality and morbidity rates. Prolonged and unbalanced inflammatory responses after hemorrhagic stroke may negatively contribute to secondary brain injury. Prostaglandin E2 (PGE 2 ) is an important mediator of inflammation and plays a role in several neurologic disorders. PGE 2 has selective high affinity toward its membrane-bound G-protein-coupled receptors EP1, EP2, EP3, and EP4, which together arbitrate its neuromodulatory effects. We have previously shown in a middle cerebral artery occlusion model of ischemia/reperfusion-induced brain injury and a striatal NMDA-induced excitotoxicity model that mice pretreated intracerebroventricularly with a selective EP3 receptor agonist have larger brain lesions when compared to control mice. In the present study, we investigated whether EP3 receptor deletion (EP3 -/- ) would lead to improved anatomical and functional outcomes in young (2-4mo) and aged (22-2...
Intracerebral hemorrhage (ICH) is a stroke subtype associated with high morbidity and mortality. ... more Intracerebral hemorrhage (ICH) is a stroke subtype associated with high morbidity and mortality. With breakdown of the blood-brain barrier and entry of toxic blood components and metabolites within the brain, a highly oxidative environment ensues and leads to a toxic neuroinflammatory cascade. A major cause of the debilitation following brain hemorrhage is due to the direct toxicity of blood components, notably hemoglobin (Hb), the most upstream precipitating factor in the cascade. The acute phase plasma protein haptoglobin (Hp) binds Hb and inhibits its cytotoxic, pro-oxidative, and pro-inflammatory properties. In this study, we investigated whether the local and specific overexpression of Hp would aid in the safe detoxification and clearance of free Hb, thereby protecting the neuropil from Hb-mediated oxidative stress and improving ICH outcomes. Hp was overexpressed locally within the brain using uniquely designed adeno-associated viral vectors and ICH was induced using the intras...
Background: Prostaglandin F 2α (PGF 2α ) has been described to exert beneficial and detrimental e... more Background: Prostaglandin F 2α (PGF 2α ) has been described to exert beneficial and detrimental effects in various neurological disorders. Brain damage following an intracerebral hemorrhagic (ICH) stroke is associated with the release of inflammatory molecules such as PGF 2α ; however, the role of PGF 2α and its cognate FP receptor in ICH remains unclear. Methods: Using age (2.5-3.5 months) and weight-matched (20-30g) adult male WT and FP -/- C57BL/6a single unilateral intrastriatal injection of collagenase VII-S [0.04 Units in 0.2μL saline] was given using specific stereotaxic coordinates. To measure for functional outcomes, neurobehavioral assays were performed 24, 48 and 72h post-ICH. These included neurological deficit scoring (NDS) using a 24-point scale, accelerating speed rotarod test to measure motor deficits and forepaw grip strength (in grams) using a grip strength meter (GSM) to measure of sensorimotor ability. Results: NDS : 72h after ICH, FP -/- mice showed significantl...
Background: Intracerebral hemorrhagic (ICH) stroke is defined by the rupture of intracranial arte... more Background: Intracerebral hemorrhagic (ICH) stroke is defined by the rupture of intracranial artery that leads to the formation of an hematoma. Subsequently, neuronal damage is associated with the lysis of red blood cells which release hemoglobin. Hemoglobin breakdown product is the prooxidant toxic hemin. We and others have documented the various toxic or protective actions of the prostaglandin receptors in ischemic stroke. In this study, we aim to investigate the PGE2 EP1 G-protein coupled receptor’s contribution to hemin-induced neurotoxicity as an in vitro ICH model. Methods: Postnatal primary neuronal cultures were used to investigate hemin-induced neurotoxicity and the PGE2 EP1 receptor role. WT and EP1 -/- neurons were treated with vehicle and hemin (12.5-100uM) for 18h and cell viability measured using LDH and calceinAM/EthD-1 assays. Results: Hemin increased neuronal cytotoxicity when treated with 50 (25.0±2.2), 75 (34.7±4.5) and 100uM (50.1±4.2) compared to vehicle (16.5±1...
Background: The consumption of flavanol containing foods, including (-)-epicatechin, has been lin... more Background: The consumption of flavanol containing foods, including (-)-epicatechin, has been linked to lower incidence of cardiovascular disease and stroke. We have previously demonstrated that epicatechin prophylaxis reduces stroke-induced anatomical and functional deficits in young, healthy mice; yet clinical stroke is primarily a disease of the elderly. Since neuroinflammation and vascular dysfunction are associated with aging, we aimed to test whether epicatechin is also protective in aging mice subjected to experimental stroke, and if so, whether this results from reduced glial cell activation and blood brain barrier permeability. Methods: Twelve-month-old wildtype and C57BL/6 Nrf2 knockout mice were administered 15mg/kg epicatechin, the minimum effective dose in young, healthy mice, prior to permanent distal middle cerebral artery occlusion. Mice were evaluated for functional recovery at one day post-stroke using the Adhesive Removal Test. Infarct volume, gliosis, and blood b...
Intracerebral hemorrhage (ICH) is the most severe form of stroke and is associated with high mort... more Intracerebral hemorrhage (ICH) is the most severe form of stroke and is associated with high mortality and morbidity. Neuroinflammation significantly contributes to ICH-induced brain injury and upregulation of prostaglandin E 2 (PGE 2 ) has been implicated in modulating these deleterious neuroinflammatory pathways. PGE 2 acts on mainly the four G-protein-coupled E prostanoid (EP) receptors, EP1-4, which each have different downstream signaling pathways, tissue distributions, and expression profiles. We have previously demonstrated that EP1 receptor deletion promotes injury following ICH, whereas deletion of EP2 and EP3 is neuroprotective in an equivalent experimental approach. Here, we aimed to investigate the time course, brain sub-region expression profile, and relative level of EP1-4 mRNA expression in young (5-7mo) and aged (12-13mo) wildtype (WT) and EP1 receptor knockout (EP1 -/- ) mice. Following ICH or sham surgery, EP1-4 mRNA levels were assessed by RT-qPCR. Minimal EP1-4 e...
Background and Purpose: Being the most abundant prostaglandin in brain, PGD 2 serves as a prime c... more Background and Purpose: Being the most abundant prostaglandin in brain, PGD 2 serves as a prime candidate to be investigated in neurologic conditions. Previously we have shown that DP1 -/- mice have greater brain damage after middle cerebral artery occlusion (MCAO) and NMDA-induced acute excitotoxicity. Characterization of cerebral vessels in C57BL/6 wildtype (WT) and DP1 -/- mouse brain shows no major differences. In the present study we are testing whether post-treatment with DP1 agonist BW245C improves cerebral blood flow (CBF), and minimizes brain damage and behavioral deficits after MCAO. Methods: To determine if BW245C can change basal CBF, WT and DP1 -/- mice were anesthetized with isoflurane and a laser Doppler flow (LDF) probe was affixed to the skull to record CBF. Once the baseline was obtained, mice were given a single i.p. injection of vehicle or 0.2mg/kg BW245C, and CBF was recorded for 2h at 10min intervals. To determine if BW245C can prevent brain damage after MCAO, ...
Introduction: Foods rich in polyphenols, such as flavanols, can lower the risk of ischemic heart ... more Introduction: Foods rich in polyphenols, such as flavanols, can lower the risk of ischemic heart disease and we recently demonstrated beneficial outcomes in ischemic stroke; however, the mechanism of protection has not been fully established. In this study, we assessed the hypothesis that epicatechin provides neuroprevention against oxygen glucose deprivation (OGD) in primary cortical neurons, and this protection occurs through activation of Nrf2. Epicatechin targets genes regulating expression of heme oxygenase 1 (HO1), ferritin and biliverdin, which can prevent free radical. Methods: Experiments were carried out to optimize and standardize various conditions for OGD and reoxygenation. Seven day old cultures from wildtype and Nrf2 knockout mice were pretreated with 50 and 100uM of epicatechin before 4h oxygen glucose deprivation followed by 24h reoxygenation. Neuronal survival was assessed by live calcein AM, LDH and MTT assay after 24h reoxygenation. Changes in protein expression ...
Intracerebral hemorrhage (ICH) is the second most prevalent type of stroke, after ischemic stroke... more Intracerebral hemorrhage (ICH) is the second most prevalent type of stroke, after ischemic stroke, and has exceptionally high morbidity and mortality rates. After spontaneous ICH, one primary goal is to restrict hematoma expansion, and the second is to limit brain edema and secondary injury. Various types of transfusion therapies have been studied as treatment options to alleviate the adverse effects of ICH etiopathology. The objective of this work is to review transfusions with platelets, fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), and red blood cells (RBCs) in patients with ICH. Furthermore, tranexamic acid infusion studies have been included due to its connection to ICH and hematoma expansion. As stated, the first line of therapy is limiting bleeding in the brain and hematoma expansion. Platelet transfusion is used to promote recovery and mitigate brain damage, notably in patients with severe thrombocytopenia. Additionally, tranexamic acid infusion, FFP, and...
Background: Spontaneous intracerebral hemorrhage (ICH) is the deadliest and most debilitating for... more Background: Spontaneous intracerebral hemorrhage (ICH) is the deadliest and most debilitating form of stroke with a first year mortality rate as high as 50% to 60%. Role of prostaglandin E2 (PGE2) receptor EP1 has been extensively studies in ischemic stroke; however, the precise role of this receptor in intracerebral hemorrhage-induced brain injury is unknown. Therefore, in this study we determined the role of the EP1 receptor in collagenase-induced hemorrhagic stroke. Methods: ICH was induced randomly in 2.0-2.5 month old male C57BL/6 wildtype (WT) and EP1 knockout (EP1-/-) mice by intrastriatal injection of collagenase. Functional outcomes including neurologic deficits, rotarod performance, open field activity, and adhesive removal performance were evaluated at 72h post ICH. Hematoma volume, and cell survival and death, were assessed using cresyl violet and Fluoro-Jade staining respectively. Microglial activation was estimated using Iba1 immunoreactivity. Phagocytosis was assessed...
Background: Epidemiological studies indicate that flavanol consumption reduces the propensity to ... more Background: Epidemiological studies indicate that flavanol consumption reduces the propensity to develop cerebrovascular disease. Available data suggest actions on multiple pro-inflammatory pathways, yet it remains unclear which pathways mediate functional recovery after stroke. Our goal is to begin identifying the mechanisms by which the flavanol (-)-epicatechin (EC) improves anatomical and functional outcomes. Based upon data from initial dose-response experiments, ongoing studies are investigating hypothesized protective pathways involving matrix metalloproteinase-mediated blood brain barrier protection and Nrf2 transcriptional activation. Methods: Male, 8-10wk old C57BL/6 mice were pretreated with EC 90m prior to permanent distal middle cerebral artery occlusion. Vehicle or EC was administered by oral gavage to mimic dietary consumption. Mice were evaluated 1, 4 and 7d post-stroke for performance on various sensorimotor tasks prior to histological assessments. Results: Initial e...
Background and Purpose: The association of PGD2 with vasculature and blood makes it a prime candi... more Background and Purpose: The association of PGD2 with vasculature and blood makes it a prime candidate to be investigated in stroke. We have shown earlier that DP1 -/- have greater brain damage after MCAO and excitotoxicity. Here, we test whether DP1 agonist BW245C treatment after stroke improves cerebral blood flow (CBF), consequently minimizing anatomical and functional deficits. Methods: First, to determine if BW245C can change basal CBF, WT and DP1 -/- mice were given a single i.p. injection of vehicle or 0.02, 0.2, 2.0mg/kg BW245C, and CBF was recorded for 2h. Next, to determine whether BW245C can prevent brain damage after MCAO, WT and DP1 -/- mice were subjected to 60min MCAO and 96h reperfusion. Immediately at reperfusion, mice were given a single i.p. injection of vehicle or 0.02, 0.2, 2.0mg/kg BW245C. These mice were also tested for various functional outcomes. Further, to determine if BW245C can improve CBF after stroke, BW245C was given during occlusion and changes in pen...
Introduction: Cerebral ischemia is a devastating disease with a high incidence of death and disab... more Introduction: Cerebral ischemia is a devastating disease with a high incidence of death and disability; however, effective therapeutics remain limited. The transcriptional factor Nrf2 has been shown to play a pivotal role in the endogenous defense against brain oxidative stress and inflammation; therefore, it represents a promising target for stroke intervention. The natural potential Nrf2-inducer ginseng, extracted from the root of Panax ginseng C.A.Meyer, has been widely used in East Asia for thousands of years, exhibiting potent anti-inflammatory and antioxidative properties. However, the long-term effects of Nrf2 and the standardized Korean red ginseng extract (ginseng) on permanent cerebral ischemic damage have not yet been reported. Methods: Wildtype (WT) and Nrf2 –/– adult mice were treated with either vehicle (water) or ginseng for 7 days and subjected to the permanent distal middle cerebral artery occlusion (pdMCAO). The infarct volume, the reactive astrogliosis and microgl...
<p>(A) Representative brain sections and microphotographs of selected brain regions from th... more <p>(A) Representative brain sections and microphotographs of selected brain regions from the same corresponding sections used for immunohistochemistry quantification. (B) Quantitative analyses of Iba1 immunoreactivity in the ipsilateral brain regions represented as a percentage of their contralateral counterparts showing the lack of the effect of the EP1 knockout compared to WT mice. Data for animals of both genotypes with vehicle and saline treatments were pulled together. Description of the brain regions is the same as that in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113689#pone-0113689-g003" target="_blank">Figure 3</a>. No statistical differences were observed when using Student’s t-test (n = 16 for WT and n = 8 for EP1<sup>−/−</sup> mice).</p
With the population aging at an accelerated rate, the prevalence of stroke and financial burden o... more With the population aging at an accelerated rate, the prevalence of stroke and financial burden of stroke-related health care costs is expected to continue to increase. Intracerebral hemorrhage (ICH) is a devastating stroke subtype more commonly affecting the elderly population, whom display increased mortality and worse functional outcomes compared to younger patients. This study aimed to investigate the contribution of the prostaglandin E 2 (PGE 2 ) E prostanoid (EP) receptor subtype 3 in modulating anatomical outcomes and functional recovery following ICH in 24-mo-old mice. PGE 2 levels are dramatically upregulated following brain injury and have been shown to modulate the deleterious excitotoxic and neuroinflammatory processes resulting from activation of glial cells and infiltration of blood cells and proinflammatory molecules through its four EP receptors, EP1-4. EP3 is the most abundant EP receptor in the brain and we have previously shown that signaling through the PGE 2 -EP...
Intracerebral hemorrhage (ICH) has the highest morbidity, disability, and mortality rates of any ... more Intracerebral hemorrhage (ICH) has the highest morbidity, disability, and mortality rates of any stroke subtype, including ischemic stroke. When a hemorrhagic stroke occurs, the blood-brain barrier is broken and blood components enter the brain. A major cause of morbidity and mortality following ICH is the direct toxicity of blood metabolites, mainly free heme, on adjacent brain tissue. Hemopexin (Hpx) is the endogenous protein responsible for scavenging free heme; thereby, modulating its proxidant and proinflammatory properties. We hypothesized that the specific local overexpression of Hpx within the brain would attenuate anatomical and functional outcomes after experimentally inducing an ICH. We uniquely designed novel adeno-associated viral vectors (and control vectors) to specifically overexpress Hpx locally within the brain of C57BL/6N mice. After experimentally inducing an ICH using the autologous whole blood model, when compared to an identically treated control group, Hpx-ov...
Objective: Our goal is to identify supplements that can improve neuronal survival of postnatal ne... more Objective: Our goal is to identify supplements that can improve neuronal survival of postnatal neuronal cultures. Here, we hypothesize that resveratrol could rescue neurons that are stressed during the brain dissociation and plating procedures. Background: The standardized B27 supplement with neurobasal medium has been used to facilitate neuronal growth and attenuates glial proliferation. We have documented that resveratrol (3,4’5 trihydroxystilbene), a natural polyphenol and a bioactive component of red wine, have numerous neuroprotective properties both in vivo and after oxygen-glucose deprivation protocols. We have proposed that this stilbene would not likely act as a direct antioxidant but act as a bioactive agent capable to induce an intracellular cytoprotective cascade. Methods: Postnatal cultures of cortical neurons were derived from 0- to 1-day-old C57BL/6 mice. Brains were dissociated and neurons plated and maintained in three different media: neurobasal medium without any ...
Intracerebral hemorrhage (ICH) is a type of hemorrhagic stroke associated with high mortality and... more Intracerebral hemorrhage (ICH) is a type of hemorrhagic stroke associated with high mortality and morbidity rates. Prolonged and unbalanced inflammatory responses after hemorrhagic stroke may negatively contribute to secondary brain injury. Prostaglandin E2 (PGE 2 ) is an important mediator of inflammation and plays a role in several neurologic disorders. PGE 2 has selective high affinity toward its membrane-bound G-protein-coupled receptors EP1, EP2, EP3, and EP4, which together arbitrate its neuromodulatory effects. We have previously shown in a middle cerebral artery occlusion model of ischemia/reperfusion-induced brain injury and a striatal NMDA-induced excitotoxicity model that mice pretreated intracerebroventricularly with a selective EP3 receptor agonist have larger brain lesions when compared to control mice. In the present study, we investigated whether EP3 receptor deletion (EP3 -/- ) would lead to improved anatomical and functional outcomes in young (2-4mo) and aged (22-2...
Intracerebral hemorrhage (ICH) is a stroke subtype associated with high morbidity and mortality. ... more Intracerebral hemorrhage (ICH) is a stroke subtype associated with high morbidity and mortality. With breakdown of the blood-brain barrier and entry of toxic blood components and metabolites within the brain, a highly oxidative environment ensues and leads to a toxic neuroinflammatory cascade. A major cause of the debilitation following brain hemorrhage is due to the direct toxicity of blood components, notably hemoglobin (Hb), the most upstream precipitating factor in the cascade. The acute phase plasma protein haptoglobin (Hp) binds Hb and inhibits its cytotoxic, pro-oxidative, and pro-inflammatory properties. In this study, we investigated whether the local and specific overexpression of Hp would aid in the safe detoxification and clearance of free Hb, thereby protecting the neuropil from Hb-mediated oxidative stress and improving ICH outcomes. Hp was overexpressed locally within the brain using uniquely designed adeno-associated viral vectors and ICH was induced using the intras...
Background: Prostaglandin F 2α (PGF 2α ) has been described to exert beneficial and detrimental e... more Background: Prostaglandin F 2α (PGF 2α ) has been described to exert beneficial and detrimental effects in various neurological disorders. Brain damage following an intracerebral hemorrhagic (ICH) stroke is associated with the release of inflammatory molecules such as PGF 2α ; however, the role of PGF 2α and its cognate FP receptor in ICH remains unclear. Methods: Using age (2.5-3.5 months) and weight-matched (20-30g) adult male WT and FP -/- C57BL/6a single unilateral intrastriatal injection of collagenase VII-S [0.04 Units in 0.2μL saline] was given using specific stereotaxic coordinates. To measure for functional outcomes, neurobehavioral assays were performed 24, 48 and 72h post-ICH. These included neurological deficit scoring (NDS) using a 24-point scale, accelerating speed rotarod test to measure motor deficits and forepaw grip strength (in grams) using a grip strength meter (GSM) to measure of sensorimotor ability. Results: NDS : 72h after ICH, FP -/- mice showed significantl...
Background: Intracerebral hemorrhagic (ICH) stroke is defined by the rupture of intracranial arte... more Background: Intracerebral hemorrhagic (ICH) stroke is defined by the rupture of intracranial artery that leads to the formation of an hematoma. Subsequently, neuronal damage is associated with the lysis of red blood cells which release hemoglobin. Hemoglobin breakdown product is the prooxidant toxic hemin. We and others have documented the various toxic or protective actions of the prostaglandin receptors in ischemic stroke. In this study, we aim to investigate the PGE2 EP1 G-protein coupled receptor’s contribution to hemin-induced neurotoxicity as an in vitro ICH model. Methods: Postnatal primary neuronal cultures were used to investigate hemin-induced neurotoxicity and the PGE2 EP1 receptor role. WT and EP1 -/- neurons were treated with vehicle and hemin (12.5-100uM) for 18h and cell viability measured using LDH and calceinAM/EthD-1 assays. Results: Hemin increased neuronal cytotoxicity when treated with 50 (25.0±2.2), 75 (34.7±4.5) and 100uM (50.1±4.2) compared to vehicle (16.5±1...
Background: The consumption of flavanol containing foods, including (-)-epicatechin, has been lin... more Background: The consumption of flavanol containing foods, including (-)-epicatechin, has been linked to lower incidence of cardiovascular disease and stroke. We have previously demonstrated that epicatechin prophylaxis reduces stroke-induced anatomical and functional deficits in young, healthy mice; yet clinical stroke is primarily a disease of the elderly. Since neuroinflammation and vascular dysfunction are associated with aging, we aimed to test whether epicatechin is also protective in aging mice subjected to experimental stroke, and if so, whether this results from reduced glial cell activation and blood brain barrier permeability. Methods: Twelve-month-old wildtype and C57BL/6 Nrf2 knockout mice were administered 15mg/kg epicatechin, the minimum effective dose in young, healthy mice, prior to permanent distal middle cerebral artery occlusion. Mice were evaluated for functional recovery at one day post-stroke using the Adhesive Removal Test. Infarct volume, gliosis, and blood b...
Intracerebral hemorrhage (ICH) is the most severe form of stroke and is associated with high mort... more Intracerebral hemorrhage (ICH) is the most severe form of stroke and is associated with high mortality and morbidity. Neuroinflammation significantly contributes to ICH-induced brain injury and upregulation of prostaglandin E 2 (PGE 2 ) has been implicated in modulating these deleterious neuroinflammatory pathways. PGE 2 acts on mainly the four G-protein-coupled E prostanoid (EP) receptors, EP1-4, which each have different downstream signaling pathways, tissue distributions, and expression profiles. We have previously demonstrated that EP1 receptor deletion promotes injury following ICH, whereas deletion of EP2 and EP3 is neuroprotective in an equivalent experimental approach. Here, we aimed to investigate the time course, brain sub-region expression profile, and relative level of EP1-4 mRNA expression in young (5-7mo) and aged (12-13mo) wildtype (WT) and EP1 receptor knockout (EP1 -/- ) mice. Following ICH or sham surgery, EP1-4 mRNA levels were assessed by RT-qPCR. Minimal EP1-4 e...
Background and Purpose: Being the most abundant prostaglandin in brain, PGD 2 serves as a prime c... more Background and Purpose: Being the most abundant prostaglandin in brain, PGD 2 serves as a prime candidate to be investigated in neurologic conditions. Previously we have shown that DP1 -/- mice have greater brain damage after middle cerebral artery occlusion (MCAO) and NMDA-induced acute excitotoxicity. Characterization of cerebral vessels in C57BL/6 wildtype (WT) and DP1 -/- mouse brain shows no major differences. In the present study we are testing whether post-treatment with DP1 agonist BW245C improves cerebral blood flow (CBF), and minimizes brain damage and behavioral deficits after MCAO. Methods: To determine if BW245C can change basal CBF, WT and DP1 -/- mice were anesthetized with isoflurane and a laser Doppler flow (LDF) probe was affixed to the skull to record CBF. Once the baseline was obtained, mice were given a single i.p. injection of vehicle or 0.2mg/kg BW245C, and CBF was recorded for 2h at 10min intervals. To determine if BW245C can prevent brain damage after MCAO, ...
Introduction: Foods rich in polyphenols, such as flavanols, can lower the risk of ischemic heart ... more Introduction: Foods rich in polyphenols, such as flavanols, can lower the risk of ischemic heart disease and we recently demonstrated beneficial outcomes in ischemic stroke; however, the mechanism of protection has not been fully established. In this study, we assessed the hypothesis that epicatechin provides neuroprevention against oxygen glucose deprivation (OGD) in primary cortical neurons, and this protection occurs through activation of Nrf2. Epicatechin targets genes regulating expression of heme oxygenase 1 (HO1), ferritin and biliverdin, which can prevent free radical. Methods: Experiments were carried out to optimize and standardize various conditions for OGD and reoxygenation. Seven day old cultures from wildtype and Nrf2 knockout mice were pretreated with 50 and 100uM of epicatechin before 4h oxygen glucose deprivation followed by 24h reoxygenation. Neuronal survival was assessed by live calcein AM, LDH and MTT assay after 24h reoxygenation. Changes in protein expression ...
Intracerebral hemorrhage (ICH) is the second most prevalent type of stroke, after ischemic stroke... more Intracerebral hemorrhage (ICH) is the second most prevalent type of stroke, after ischemic stroke, and has exceptionally high morbidity and mortality rates. After spontaneous ICH, one primary goal is to restrict hematoma expansion, and the second is to limit brain edema and secondary injury. Various types of transfusion therapies have been studied as treatment options to alleviate the adverse effects of ICH etiopathology. The objective of this work is to review transfusions with platelets, fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), and red blood cells (RBCs) in patients with ICH. Furthermore, tranexamic acid infusion studies have been included due to its connection to ICH and hematoma expansion. As stated, the first line of therapy is limiting bleeding in the brain and hematoma expansion. Platelet transfusion is used to promote recovery and mitigate brain damage, notably in patients with severe thrombocytopenia. Additionally, tranexamic acid infusion, FFP, and...
Background: Spontaneous intracerebral hemorrhage (ICH) is the deadliest and most debilitating for... more Background: Spontaneous intracerebral hemorrhage (ICH) is the deadliest and most debilitating form of stroke with a first year mortality rate as high as 50% to 60%. Role of prostaglandin E2 (PGE2) receptor EP1 has been extensively studies in ischemic stroke; however, the precise role of this receptor in intracerebral hemorrhage-induced brain injury is unknown. Therefore, in this study we determined the role of the EP1 receptor in collagenase-induced hemorrhagic stroke. Methods: ICH was induced randomly in 2.0-2.5 month old male C57BL/6 wildtype (WT) and EP1 knockout (EP1-/-) mice by intrastriatal injection of collagenase. Functional outcomes including neurologic deficits, rotarod performance, open field activity, and adhesive removal performance were evaluated at 72h post ICH. Hematoma volume, and cell survival and death, were assessed using cresyl violet and Fluoro-Jade staining respectively. Microglial activation was estimated using Iba1 immunoreactivity. Phagocytosis was assessed...
Background: Epidemiological studies indicate that flavanol consumption reduces the propensity to ... more Background: Epidemiological studies indicate that flavanol consumption reduces the propensity to develop cerebrovascular disease. Available data suggest actions on multiple pro-inflammatory pathways, yet it remains unclear which pathways mediate functional recovery after stroke. Our goal is to begin identifying the mechanisms by which the flavanol (-)-epicatechin (EC) improves anatomical and functional outcomes. Based upon data from initial dose-response experiments, ongoing studies are investigating hypothesized protective pathways involving matrix metalloproteinase-mediated blood brain barrier protection and Nrf2 transcriptional activation. Methods: Male, 8-10wk old C57BL/6 mice were pretreated with EC 90m prior to permanent distal middle cerebral artery occlusion. Vehicle or EC was administered by oral gavage to mimic dietary consumption. Mice were evaluated 1, 4 and 7d post-stroke for performance on various sensorimotor tasks prior to histological assessments. Results: Initial e...
Background and Purpose: The association of PGD2 with vasculature and blood makes it a prime candi... more Background and Purpose: The association of PGD2 with vasculature and blood makes it a prime candidate to be investigated in stroke. We have shown earlier that DP1 -/- have greater brain damage after MCAO and excitotoxicity. Here, we test whether DP1 agonist BW245C treatment after stroke improves cerebral blood flow (CBF), consequently minimizing anatomical and functional deficits. Methods: First, to determine if BW245C can change basal CBF, WT and DP1 -/- mice were given a single i.p. injection of vehicle or 0.02, 0.2, 2.0mg/kg BW245C, and CBF was recorded for 2h. Next, to determine whether BW245C can prevent brain damage after MCAO, WT and DP1 -/- mice were subjected to 60min MCAO and 96h reperfusion. Immediately at reperfusion, mice were given a single i.p. injection of vehicle or 0.02, 0.2, 2.0mg/kg BW245C. These mice were also tested for various functional outcomes. Further, to determine if BW245C can improve CBF after stroke, BW245C was given during occlusion and changes in pen...
Introduction: Cerebral ischemia is a devastating disease with a high incidence of death and disab... more Introduction: Cerebral ischemia is a devastating disease with a high incidence of death and disability; however, effective therapeutics remain limited. The transcriptional factor Nrf2 has been shown to play a pivotal role in the endogenous defense against brain oxidative stress and inflammation; therefore, it represents a promising target for stroke intervention. The natural potential Nrf2-inducer ginseng, extracted from the root of Panax ginseng C.A.Meyer, has been widely used in East Asia for thousands of years, exhibiting potent anti-inflammatory and antioxidative properties. However, the long-term effects of Nrf2 and the standardized Korean red ginseng extract (ginseng) on permanent cerebral ischemic damage have not yet been reported. Methods: Wildtype (WT) and Nrf2 –/– adult mice were treated with either vehicle (water) or ginseng for 7 days and subjected to the permanent distal middle cerebral artery occlusion (pdMCAO). The infarct volume, the reactive astrogliosis and microgl...
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