Preclinical efficacy of human Albumin in subarachnoid hemorrhage

doi:10.1016/j.neuroscience.2016.12.033

Neuroscience

Volume 344, 6 March 2017, Pages 255-264

https://doi.org/10.1016/j.neuroscience.2016.12.033 Get rights and content

Highlights

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0.2 g/kg and 1.0 g/kg Albumin significantly improved neurological outcomes of SAH.
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The benefits of Albumin occurred within a favorable therapeutic window.
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Albumin likewise improved neurological outcomes in female and hypertensive rats.

Abstract

Human Albumin is a unique pleiotropic protein with multiple properties. Previous clinical and laboratory studies have indicated a possible beneficial effect of Albumin in subarachnoid hemorrhage (SAH). The present study aimed to further define the preclinical characteristics of Albumin. SAH was induced by endovascular perforation in Sprague–Dawley rats. In the dose-escalation study, Albumin ranging from 0.02 g/kg to 1.0 g/kg was intravenously infused immediately after SAH. In the therapeutic window study, 1.0 g/kg Albumin was administered at 0 h, 2 h, 4 h or 8 h after SAH. Physiologic variables were monitored in different Albumin treatment regimens. One day after SAH, neurological scores, SAH scores, blood–brain barrier permeability, neural degeneration and apoptosis were examined. The efficacy of Albumin for SAH was also determined in female rats and in spontaneously hypertensive rats. We found that 0.2 g/kg and 1.0 g/kg Albumin significantly attenuated sensorimotor deficits, brain edema, IgG leakage, and neuronal degeneration after SAH. The benefits of Albumin existed even when the administration was delayed to 4 h after SAH onset. No significant difference was found between 0.2 g/kg and 1.0 g/kg Albumin groups. In female rats and spontaneously hypertensive rats, Albumin likewise improved neurological outcomes and early brain injury. In conclusion, Albumin could reduce both cerebral lesions and functional deficits in the early stage of SAH. The beneficial regimen occurs within a favorable therapeutic window and is reproducible in different high-risk subjects.

Introduction

Subarachnoid hemorrhage (SAH) is associated with high mortality and poor prognosis (Connolly et al., 2012). However, few therapies are available in clinical settings. A number of drugs effective in animals have failed to be proved successful in human trials. One of the reasons accounting for this disparity may be the flawed methodology in both laboratory and clinical studies (Sehba et al., 2012). Omitting quality characteristics in animal studies will lead to an overestimation of the efficacy of candidate drugs (Philip et al., 2009, Minnerup et al., 2010). As such, a more rigorous preclinical evaluation, including the assessment of prolonged therapeutic window and the employment of animals with comorbidity (Sehba et al., 2012), is required for the preclinical therapy investigations of SAH.

Human Albumin (Alb) is known to have unique intravascular neuroprotective effects. It is able to reduce brain edema (Belayev et al., 2001), enhance neuronal survival (Belayev et al., 1999), and maintain blood–brain barrier (BBB) integrity in the cerebrovascular diseases (Belayev et al., 2005). The Albumin in Subarachnoid Hemorrhage (ALISAH) pilot study revealed that 1.25 g/kg/d Alb treatment is safe in patients and may produce a better outcome (Suarez et al., 2012). We previously demonstrated Alb improves long-term neurobehavioral sequelae after SAH through neurovascular remodeling (Xie et al., 2015). However, the preclinical characteristics of Alb have not been fully defined. Thus, the present study aimed to characterize the effects of different Alb treatment regimens for SAH. In particular, we examined the dose–response relationship and therapeutic window of Alb, and investigated whether this protection occurs in female rats and spontaneously hypertensive rats (SHR).

Section snippets

Animals

All experimental protocols were approved by the Jinling Hospital Animal Care and Use Committee and conducted in accordance with the recommendations in the guideline published in the National Institutes of Health guide for the Care and Use of Laboratory Animals. A total of 180 male SD rats weighting 270–320 g, 50 female SD rats weighting 230–250 g and 55 SHR weighting 240–280 g were used. Sample size was determined by power analysis based on pilot experiments (significance level 0.05, power 80%).

Physiologic variables, SAH severity and mortality

All rats showed similar values of arterial blood gases, plasma glucose, and plasma oncotic pressure. 1.0 g/kg Alb administered intravenously immediately decreased hematocrit by 17.8%, and the decrease was proved significant (P < 0.001). However, lower doses of Alb failed to induce remarkable change of hematocrit (P > 0.05). 1.0 g/kg, 0.2 g/kg and 0.1 g/kg Alb increased plasma colloid oncotic pressure by 33.3%, 21.6% and 7.5% (P < 0.001, P < 0.001, P < 0.01 respectively). 1.0 g/kg Alb administered

Discussion

In the first part of this study, we investigated the dose–escalation relationship and therapy window of Alb for SAH. We showed that both 0.2 g/kg and 1.0 g/kg Alb could reduce BBB disruption and cells’ injury in the rat model of subarachnoid hemorrhage, even if the treatment is delayed up to 4 h after SAH onset. However, Alb at the lower doses of 0.02 g/kg and 0.1 g/kg or being infused at 8 h after SAH showed no effects.

Alb is regarded as a hemodiluent for a long time. In clinical practice, Alb is

Acknowledgments

This work was supported by National Natural Science Foundation of China (grant no. 81200892, 31300900, 81471182, and 81400332).

References (27)

L. Belayev et al.
Neuroprotective effect of high-dose albumin therapy against global ischemic brain injury in rats
Brain Res
(1999)
G. Fanali et al.
Human serum albumin: from bench to bedside
Mol Aspects Med
(2012)
L.N. Grinberg et al.
The effects of heme-binding proteins on the peroxidative and catalatic activities of hemin
Free Radical Biol Med
(1999)
S. Kumar et al.
Free heme toxicity and its detoxification systems in human
Toxicol Lett
(2005)
F.A. Sehba et al.
The importance of early brain injury after subarachnoid hemorrhage
Prog Neurobiol
(2012)
T. Sugawara et al.
A new grading system evaluating bleeding scale in filament perforation subarachnoid hemorrhage rat model
J Neurosci Meth
(2008)
J. Yan et al.
The role of p53 in brain edema after 24 h of experimental subarachnoid hemorrhage in a rat model
Exp Neurol
(2008)
R. Ye et al.
Ginsenoside rd in experimental stroke: superior neuroprotective efficacy with a wide therapeutic window
Neurotherapeutics
(2011)
R. Ye et al.
Ginsenoside Rd attenuates early oxidative damage and sequential inflammatory response after transient focal ischemia in rats
Neurochem Int
(2011)
R. Ye et al.
Ginsenoside Rd attenuates mitochondrial dysfunction and sequential apoptosis after transient focal ischemia
Neuroscience
(2011)

J.B. Bederson et al.

Cortical blood flow and cerebral perfusion pressure in a new noncraniotomy model of subarachnoid hemorrhage in the rat

Stroke

(1995)

L. Belayev et al.

Human albumin therapy of acute ischemic stroke marked neuroprotective efficacy at moderate doses and with a broad therapeutic window

Stroke

(2001)

L. Belayev et al.

Albumin treatment reduces neurological deficit and protects blood-brain barrier integrity after acute intracortical hematoma in the rat

Stroke

(2005)

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Intracerebral hemorrhage (ICH) is a subtype of stroke with high mortality. Secondary brain injury after surviving the initial ictus leads to severe neurological deficits, and has emerged as an attractive therapeutic target. Human serum albumin (HSA), a pluripotent protein synthesized mainly in the liver, has shown remarkable efficacy by targeting secondary brain injury pathways in rodent models of ICH, while results from relevant clinical research on albumin therapy remain unclear. Preclinical studies have shown albumin-mediated neuroprotection may stem from its biological functions, including its major antioxidation activity, anti-inflammatory responses, and anti-apoptosis. HSA treatment provides neuroprotective and recovery enhancement effects via improving short and long-term neurologic function, maintaining blood-brain barrier (BBB) integrity and reducing neuronal oxidative stress and apoptosis. Retrospective clinical studies have shown that admission hypoalbuminemia is a prognostic factor for poor outcomes in patients with ICH. However, clinical trial was terminated due to poor enrollment and its potential adverse effects. This review provides an overview of the physiological properties of albumin, as well as its potential neuroprotective and prognostic value and the resulting clinical implications.
Combination of Albumin/Fibrinogen Ratio and Admission Hunt-Hess Scale Score as an Independent Predictor of Clinical Outcome in Aneurysmal Subarachnoid Hemorrhage
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The albumin/fibrinogen ratio (AFR) is an independent predictor of clinical outcomes of some diseases; however, the prognostic value of AFR and the admission Hunt-Hess (HH) score is still unclear for patients with an aneurysmal subarachnoid hemorrhage (aSAH). This study aimed to assess the relationship between the AFR-HH score and 6-month outcomes of aSAH patients.
The clinical characteristics of aSAH patients admitted to our department between December 2017 and December 2021 were retrospectively analyzed. The candidate risk factors were screened using univariate regression analysis, and the independence of the resultant risk factors was evaluated by binary logistic regression analysis. The predictive value of the combined AFR and HH score for unfavorable outcomes was assessed using receiver operating characteristic curve analysis.
A total of 112 aSAH patients were included. Binary logistic regression analysis showed the perioperative period AFR, Glasgow coma scale score, and admission HH score were independent risk factors for unfavorable outcomes for aSAH patients. The receiver operating characteristic curve analysis showed the predictive capacity of AFR plus the admission HH score outperformed the AFR, Glasgow coma scale score, and admission HH scale alone and the combination of the AFR and Glasgow coma scale score.
A low AFR during the perioperative period is associated with unfavorable outcomes for aSAH patients at 6 months. The combination of the AFR and admission HH scale score provides superior predictive capacity to either the AFR or HH scale score alone.
Enhancing S-nitrosoglutathione reductase decreases S-nitrosylation of Drp1 and reduces neuronal apoptosis in experimental subarachnoid hemorrhage both in vivo and in vitro
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During the operation, the body temperature of the rat was maintained at 37 °C ± 0.5 °C with a heating pad. Physiological parameters, including arterial blood gas (pH, PCO2 and PO2), mean arterial blood pressure and plasma glucose are monitored according to the previous method (R. Wang, Li et al., 2017; L. Wang, Li et al., 2017). Rats were excluded if serious postoperative complications such as hemiplegia, irritability, or dehydration occurred.
Subarachnoid hemorrhage (SAH) is a hemorrhagic stroke with a high mortality and disability rate. Nitric oxide (NO) can promote blood supply through vasodilation, leading to protein S-nitrosylation. However, the function of S-nitrosylation in neurons after SAH remains unclear. Excessive NO in the pathological state is converted into S-nitrosoglutathione (GSNO) and stored in cells, which leads to high S-nitrosylation of intracellular proteins and causes nitrosative stress. S-nitrosoglutathione reductase (GSNOR) promotes GSNO degradation and protects cells from excessive S-nitrosylation. We conducted an in vivo rat carotid puncture model and an in vitro neuron hemoglobin intervention. The results showed that SAH induction increased NO, GSNO, neuron protein S-nitrosylation, and neuronal apoptosis, while decreasing the level and activity of GSNOR. GSNOR overexpression by lentivirus decreased GSNO but had little effect on NO. GSNOR overexpression also improved short- and long-term neurobehavioral outcomes in rats and alleviated nitrosative stress. Furthermore, GSNOR reduced neuronal apoptosis and played a neuroprotective role by alleviating Drp1 S-nitrosylation, reducing mitochondrial division. Thus, the regulation of GSNOR in early brain injury and neuronal denitrosylation may play an important role in neuroprotection.
Neutrophil-to-albumin ratio as a novel marker predicting unfavorable outcome in aneurysmal subarachnoid hemorrhage
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According to previous studies, it has been reported that low serum albumin is independently correlated with poor outcomes in patients with aSAH [20]. However, although the exact mechanism of hypoalbuminemia in aSAH patients remains unclear, a few experimental studies have revealed that albumin mediates its neuroprotection through reduction of cerebral lesions and neurovascular remodeling [21,22], including that albumin can induce delayed neuronal death [23]. In addition, it has been reported that albumin leads to expansion of intravascular blood volume and enhanced microvascular circulation to potentially reduce the DCI secondary to vasospasm [7,24,25].
Compelling evidence shows that inflammation contributes to the development of aneurysmal subarachnoid hemorrhage (aSAH). Several studies have conducted in the recent past have revealed that the neutrophil-to-albumin ratio (NAR) is a new marker of inflammation. However, whether NAR can predict the prognosis of patients with aSAH has not been fully elucidated. Therefore, the aim of this study was to investigate the relationship between NAR and prognosis of aSAH.
A total of 555 consecutive patients diagnosed with aSAH were retrospectively enrolled. The NAR was assessed for each patient upon admission. At the same time, the demographic and clinical parameters of patients were collected. The Glasgow Outcome Scale (GOS, a score of 1–3) at 3 months was used to evaluate disease outcomes.
Patients with unfavorable outcomes at 3 months were considerably older, had high levels of intraventricular and subarachnoidal hemorrhage, exhibited severe clinical conditions at admission, developed in-hospital complications, such as pneumonia and delayed cerebral ischemia. At admission, the NAR for GOS scores 4–5 was median [IQR] 0.231 [0.177–0.288] whereas that for GOS score 1–3 was 0.349 [0.264–4.449]; p < 0.001. The analysis revealed that the NAR was independently associated with unfavorable outcomes in patients with aSAH after adjusting for potential confounding factors (risk ratio [95% CI] 3.554 [2.601–4.857] per 0.1-point increment; p < 0.001). Moreover, a NAR of 0.274 was determined to be the best cutoff threshold for distinguishing between favorable and unfavorable outcomes in ROC analyses (AUC [95% CI] 0.782 [0.740–0.823]; p < 0.001; GOS 3–5: NAR ≥ 0.274 134/247 [54.3%] vs NAR < 0.274 47/308 [15.3%]; p < 0.001).
This study demonstrates that NAR may be a novel prognostic marker in patients with aSAH. Elevated NAR is an independent factor predicting unfavorable outcome in patients with aSAH.
Natural biomaterials in brain repair: A focus on collagen
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The administration of moderate doses of HSA after a focal ischemic injury provided significant improvement in neurological function, reduced infarct volume and prevented brain swelling in rat models (Belayev et al., 2001; Yao et al., 2010). In a brain hemorrhage rat model, lower doses of albumin showed similar effects, in addition to preserving the BBB and reducing apoptosis (Wang et al., 2017). However, to date, albumin did not show significant therapeutic benefits in clinical trials for patients with ischaemic stroke (Ginsberg et al., 2013; Martin et al., 2016).
Biomaterials derived from natural resources have increasingly been used for versatile applications in the central nervous system (CNS). Thanks to their biocompatibility and biodegradability, natural biomaterials offer vast possibilities for future clinical repair strategies for the CNS. These materials can be used for diverse applications such as hydrogels to fill the tissue cavities, microparticles to deliver drugs across the blood-brain barrier, and scaffolds to transplant stem cells. In this review, various uses of prominent protein and polysaccharide biomaterials, with a special focus on collagen, in repair and regenerative applications for the brain are summarized together with their individual advantages and disadvantages.
Inhibition of miR-103-3p Preserves Neurovascular Integrity Through Caveolin-1 in Experimental Subarachnoid Hemorrhage
2021, Neuroscience
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Then the coronal sections of 14 μm thick were cut on a Leica CM1950 cryostat and stored at −80 °C. Sections were fixed in 4% paraformaldehyde for 15 min at room temperature before histological staining (Wang et al., 2017). To evaluate BBB permeability morphologically, brain immunolocalization of IgG was studied (Xie et al., 2015).
Caveolin-1 (Cav-1) is a constitutive structural protein of caveolae in the plasma membrane. It plays an important role in maintaining blood brain barrier (BBB) integrity. In this study, we identified that miR-103-3p, a hypoxia-responsive miRNA, could interact with Cav-1. In endothelial cells, miR-103-3p mimic diminished the expression of Cav-1 and tight junction proteins, which were rescued by the inhibition of miR-103-3p. We found a substantial increase of miR-103-3p and decease of Cav-1 in the rat subarachnoid hemorrhage (SAH) model. Pre-SAH intracerebroventricularly injection of miR-103-3p antagomir relieved Cav-1 loss, sequentially reduced BBB permeability and improved neurological function. Finally, we demonstrated that the salutary effects of miR-103-3p antagomir were abolished in Cav-1 knock-out mice, suggesting that Cav-1 was required for the miR-103-3p inhibition-induced neurovascular protection. Taken together, our findings suggest that the inhibition of miR-103-3p could exert neuroprotective effects through preservation of Cav-1 and BBB integrity, making miR-103-3p a novel therapeutic target for SAH.

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^†: The first two authors contributed equally to this work.

View full text

Preclinical efficacy of human Albumin in subarachnoid hemorrhage

Highlights

Abstract

Introduction

Section snippets

Animals

Physiologic variables, SAH severity and mortality

Discussion

Acknowledgments

Brain Res

Mol Aspects Med

Free Radical Biol Med

Toxicol Lett

Prog Neurobiol

J Neurosci Meth

Exp Neurol

Neurotherapeutics

Neurochem Int

Neuroscience

Cortical blood flow and cerebral perfusion pressure in a new noncraniotomy model of subarachnoid hemorrhage in the rat

Stroke

Human albumin therapy of acute ischemic stroke marked neuroprotective efficacy at moderate doses and with a broad therapeutic window

Stroke

Albumin treatment reduces neurological deficit and protects blood-brain barrier integrity after acute intracortical hematoma in the rat

Stroke