Xenon Neuroprotection in Experimental Stroke

Sheng, Siyuan; Lei, Beilei; James, Michael L.; Lascola, Christopher D.; Venkatraman, Talaignair N.; Jung, Jin Yong; Maze, Mervyn; Franks, Nicholas P.; Pearlstein, Robert D.; Sheng, Huaxin; Warner, David S.

doi:10.1097/aln.0b013e3182746b81

Cited by 61 publications

(15 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Xenon differs, perhaps because it serves as a NMDA receptor antagonist by competitively inhibiting the glycine site [29]. While this likely contributes to improved stroke outcome [30], unlike the heterogeneous CMR effects of ketamine and N 2 O, xenon causes a consistent decrease in CMR across a broad range of brain regions [31]. …”

Section: Resting Cerebral Blood Flow and Metabolismmentioning

confidence: 99%

Anesthesia in Experimental Stroke Research

Hoffmann

Sheng

Ayata

et al. 2016

Transl. Stroke Res.

Self Cite

View full text Add to dashboard Cite

Anesthetics have enabled major advances in development of experimental models of human stroke. Yet their profound pharmacologic effects on neural function can confound the interpretation of experimental stroke research. Anesthetics have drug and dose-specific effects on cerebral blood flow and metabolism, neurovascular coupling, autoregulation, ischemic depolarizations, excitotoxicity, inflammation, neural networks, and numerous molecular pathways relevant for stroke outcome. Both pre- and post-conditioning properties have been described. Anesthetics also modulate systemic arterial blood pressure, lung ventilation, and thermoregulation, all of which may interact with the ischemic insult as well as the therapeutic interventions. These confounds present a dilemma. Here, we provide an overview of the anesthetic mechanisms of action and molecular and physiologic effects on factors relevant to stroke outcomes that can guide the choice and optimization of the anesthetic regimen in experimental stroke.

show abstract

Section: Resting Cerebral Blood Flow and Metabolismmentioning

confidence: 99%

Anesthesia in Experimental Stroke Research

Hoffmann

Sheng

Ayata

et al. 2016

Transl. Stroke Res.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Protein quantification and multiplex array were analyzed by 2-way ANOVA followed by t test, comparing vehicle and treatment groups at each time point. Based on known variance within this model [31,32], a sample size of 10 mice per group was calculated to demonstrate a 50% treatment effect in MWM latencies over days 28-31 after injury for a 3-group repeated measures ANOVA. A p value <0.05 was considered statistically significant.…”

Section: Methodsmentioning

confidence: 99%

Progesterone Improves Neurobehavioral Outcome in Models of Intracerebral Hemorrhage

Lei

Wang²,

Jeong³

et al. 2015

Neuroendocrinology

Self Cite

View full text Add to dashboard Cite

In models of acute brain injury, progesterone improves recovery through several mechanisms including modulation of neuroinflammation. Secondary injury from neuroinflammation is a potential therapeutic target after intracerebral hemorrhage (ICH). For potential translation of progesterone as a clinical acute ICH therapeutic, the present study sought to define efficacy of exogenous progesterone administration in ICH-relevant experimental paradigms. Young and aged C57BL/6 male, female, and ovariectomized (OVX) mice underwent left intrastriatal collagenase (0.05-0.075 U) or autologous whole blood (35 μl) injection. Progesterone at varying doses (4-16 mg/kg) was administered at 2, 5, 24, 48, and 72 h after injury. Rotarod and Morris water maze latencies were measured on days 1-7 and days 28-31 after injury, respectively. Hematoma volume, brain water content (cerebral edema), complementary immunohistochemistry, multiplex cytokine arrays, and inflammatory proteins were assessed at prespecified time points after injury. Progesterone (4 mg/kg) administration improved rotarod and water maze latencies (p < 0.01), and decreased cerebral edema (p < 0.05), microglial proliferation, and neuronal loss (p < 0.01) in young and aged male, young OVX, and aged female mice. Brain concentration of proinflammatory cytokines and Toll-like receptor-associated proteins were also decreased after progesterone (4 mg/kg) treatment (p < 0.01). Progesterone-treated young female mice showed no detectable effects. Exogenous progesterone improved short- and long-term neurobehavioral recovery and modulated neuroinflammation in male and OVX mice after ICH. Future studies should validate these findings, and address timing and length of administration before translation to clinical trial.

show abstract

“…Therapeutic hypothermia using physical cooling methods has been studied as treatments for a number of brain and peripheral organ disorders, including ischemic and hemorrhage strokes (Sheng, et al, 2012, Wu and Grotta, 2013), epileptic seizures (Motamedi, et al, 2013, Srinivasakumar, et al, 2013), spinal cord injury (Ahmad, et al, 2014), perinatal asphyxia (Rey-Funes, et al, 2013) and others. In contrast, the potential benefits of hypothermic therapy for the treatment of TBI, especially in neonates and children, have been much less investigated.…”

Section: Introductionmentioning

confidence: 99%

Pharmacologically induced hypothermia attenuates traumatic brain injury in neonatal rats

Wei

Espinera

et al. 2015

Experimental Neurology

View full text Add to dashboard Cite

Neonatal brain trauma is linked to higher risks of mortality and neurological disability. The use of mild to moderate hypothermia has shown promising potential against brain injuries induced by stroke and traumatic brain injury (TBI) in various experimental models and in clinical trials. Conventional methods of physical cooling, however, are difficult to use in acute treatments and in induction of regulated hypothermia. In addition, general anesthesia is usually required to mitigate the negative effects of shivering during physical cooling. Our recent investigations demonstrate the potential therapeutic benefits of pharmacologically induced hypothermia (PIH) using the neurotensin receptor (NTR) agonist HPI201 (formerly known as ABS201) in stroke and TBI models of adult rodents. The present investigation explored the brain protective effects of HPI201 in a P14 rat pediatric model of TBI induced by controlled cortical impact. When administered via intraperitoneal (i.p.) injection, HPI201 induced dose-dependent reduction of body and brain temperature. A six-hour hypothermic treatment, providing an overall 2-3°C reduction of brain and body temperature, showed significant effect of attenuating the contusion volume versus TBI controls. Attenuation occurs whether hypothermia is initiated 15 min or 2 hr after TBI. No shivering response was seen in HPI201-treated animals. HPI201 treatment also reduced TUNEL-positive and TUNEL/NeuN-colabeled cells in the contusion area and peri-injury regions. TBI-induced blood brain barrier damage was attenuated by HPI201 treatment, evaluated using the Evans Blue assay. HPI201 significantly decreased MMP-9 levels and Caspase-3 activation, both of which are pro-apototic, while it increased anti-apoptotic Bcl-2 gene expression in the peri-contusion region. In addition, HPI201 prevented the up-regulation of pro-inflammatory tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6. In sensorimotor activity assessments, rats in the HPI201 treated group exhibited improved functional recovery after TBI versus controls. These data support that PIH therapy using our NTR agonist is effective in reducing neuronal and BBB damage, attenuating inflammatory response and detrimental cellular signaling, and promoting functional recovery after TBI in the developing brain, supporting its potential for further evaluation towards clinical development.

show abstract

Xenon Neuroprotection in Experimental Stroke

Cited by 61 publications

References 59 publications

Anesthesia in Experimental Stroke Research

Anesthesia in Experimental Stroke Research

Progesterone Improves Neurobehavioral Outcome in Models of Intracerebral Hemorrhage

Pharmacologically induced hypothermia attenuates traumatic brain injury in neonatal rats

Contact Info

Product

Resources

About