Influence of nimodipine combined with ulinastatin on neurological function and inflammatory reaction in patients with cerebral vasospasm after subarachnoid hemorrhage.

OBJECTIVE: This study aimed to discuss the influence of nimodipine+ulinastatin on the neurological function and inflammatory reaction in patients with cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH). METHODS: Overall, 90 patients with CVS after SAH who were admitted to our hospital were enrolled in this study and randomly divided into research and control groups (n = 45 for both groups). On the basis of conventional therapy, patients in the control group were injected with ulinastatin and those in the research group were injected with ulinastatin+nimodipine through an intravenous drip for 7 days with the others the same as those of the control group. RESULTS: Blood flow velocity in all cerebral arteries was lower in the research group than in the control group after treatment (P < 0.05). Calcitonin gene-related peptide and nitric oxide levels were higher in the research group than in the control group after treatment (P < 0.05). Endothelin levels were lower in the research group than in the control group (P < 0.05). The total effective rate was higher in the research group than in the control group (P < 0.05). Glasgow Coma Scale scores were higher in the research group than in the control group (P < 0.05). CONCLUSION: The drug combination of nimodipine and ulinastatin improved blood flow and neurological function in patients with CVS after SAH and enhanced the therapeutic efficacy; the underlying mechanism may be associated with the regulation of vascular endothelial dilatation function and the inhibition of relevant inflammatory factors' expression.

Reversible Cerebral Vasoconstriction Syndrome Following Exposure to Oleoresin Capsicum "Pepper Spray".

OBJECTIVES: To report a case associating the use of Oleoresin Capsicum Pepper Spray (OCPS) during law enforcement training with development of Reversible Cerebral Vasoconstriction Syndrome (RCVS). MATERIALS AND METHODS: RCVS is radiographically characterized by multifocal smooth narrowing of cerebral arteries heralded by clinical manifestations of recurrent thunderclap headaches. 70% of cases with RCVS have a clear precipitating factor and agents commonly implicated were cannabis, selective serotonin reuptake inhibitors, nasal decongestants, cocaine, postpartum state, eclampsia and strenuous physical/sexual activity.1 RESULTS: 24-year-old female police officer with no past medical history who presented with thunderclap headaches after exposure to pepper spray to her face during work training. Neurological examination was unremarkable. CT angiogram (CTA) of the head and neck and subsequent conventional angiogram revealed multifocal mild arterial narrowing of bilateral middle cerebral arteries (MCA), bilateral posterior cerebral arteries (PCA) and left anterior cerebral artery (ACA) concerning for RCVS. Eight weeks later, she had a repeat MRA head and neck demonstrating complete resolution of the previously noted narrowing of her cerebral arteries. CONCLUSIONS: OCPS is widely used in law enforcement training as well as by general population as a self- defense tool. It is generally assumed to be safe, although the consequences of its use can never be predicted with certainty.2 As our case highlights, use of OCPS may be associated with development of RCVS and awareness needs to be raised regarding this rare but serious complication.

COVID-19 Associated Reversible Cerebral Vasoconstriction Syndrome Successfully Treated with Nimodipine and Aspirin.

There have been limited cases linking SARS-CoV-2 infection with the development of reversible cerebral vasoconstriction syndrome (RCVS). We hereby report a rare case of RCVS in the setting of mild SARS-CoV-2 respiratory infection successfully treated with nimodipine and aspirin. SARS-CoV-2 attacks the ACE2-receptors, which are expressed in various body organs including the lungs, kidneys, and blood vessels. Vasoconstriction can result from down-regulation of the ACE2-receptors that can lead to sympathetic hypertonia of the cerebral blood vessel walls and/or over-activation of the renin-angiotensin axis.

Reversible cerebral vasoconstriction syndrome (RCVS) caused by over-the-counter calcium supplement ingestion.

A 59-year-old woman was found unresponsive at home. Initial neurologic examination revealed aphasia and right-sided weakness. Laboratory results demonstrated a serum calcium level of 17.3 mg/dL (corrected serum calcium for albumin concentration was 16.8 mg/dL). Extensive workup for intrinsic aetiology of hypercalcemia was unrevealing. Further discussion with family members and investigation of the patient's home for over-the-counter medications and herbal supplements revealed chronic ingestion of calcium carbonate tablets. CT angiogram of the brain revealed multifocal intracranial vascular segmental narrowing, which resolved on a follow-up cerebral angiogram done 2 days later. These findings were consistent with reversible cerebral vasoconstriction syndrome.Appropriate blood pressure control with parenteral agents, calcium channel blockade with nimodipine and supportive care therapies resulted in significant improvement in neurologic status. By discharge, patient had near-complete resolution of neurologic symptoms.

Non-steroidal anti-inflammatory drugs in the pathophysiology of vasospasms and delayed cerebral ischemia following subarachnoid hemorrhage: a critical review.

Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening condition associated with the development of early brain injury (EBI) and delayed cerebral ischemia (DCI). Pharmacological treatment of vasospasm following aSAH currently mainly comprises nimodipine administration. In the past few years, many drugs that can potentially benefit cases of subarachnoid hemorrhage have become available. The objective of this review is to critically assess the effects of non-steroidal anti-inflammatory drugs (NSAIDs) following aSAH. A systematic literature review was conducted following PRISMA guidelines. The search was aimed at studies addressing aSAH and NSAIDs during the 2010 to 2019 period, and it yielded 13 articles. Following the application of search criteria, they were divided into two groups, one containing 6 clinical articles and the other containing 7 experimental articles on animal models of aSAH. Inflammatory cerebral changes after aneurysm rupture contribute to the development of EBI, DCI and cerebral vasospasm. It appears that NSAIDs (especially coxibs) are even more effective in reducing vasospasm than nimodipine. Other beneficial effects of NSAIDs include reduction in mortality, improved functional outcome and increased hypoaggregability. However, despite these positive effects, there is only one randomized, double-blind, placebo-controlled trial showing a tendency towards a better outcome with lower incidence of vasospasm or mortality in patients following aSAH.

Hydrogen gas inhalation improves delayed brain injury by alleviating early brain injury after experimental subarachnoid hemorrhage.

Molecular hydrogen (H2) protect neurons against reactive oxygen species and ameliorates early brain injury (EBI) after subarachnoid hemorrhage (SAH). This study investigated the effect of H2 on delayed brain injury (DBI) using the rat SAH + unilateral common carotid artery occlusion (UCCAO) model with the endovascular perforation method. 1.3% H2 gas (1.3% hydrogen premixed with 30% oxygen and balanced nitrogen) inhalation was performed on days 0 and 1, starting from anesthesia induction and continuing for 2 h on day 0, and starting from anesthesia induction and continuing for 30 min on day 1. EBI was assessed on the basis of brain edema, expression of S100 calcium-binding protein B (S100B), and phosphorylation of C-Jun N-terminal kinase on day 2, and neurological deficits on day 3. Reactive astrogliosis and severity of cerebral vasospasm (CV) were assessed on days 3 and 7. DBI was assessed on the basis of neurological deficits and neuronal cell death on day 7. EBI, reactive astrogliosis, and DBI were ameliorated in the H2 group compared with the control group. CV showed no significant improvement between the control and H2 groups. This study demonstrated that H2 gas inhalation ameliorated DBI by reducing EBI without improving CV in the rat SAH + UCCAO model.

The Stabilization of Central Sympathetic Nerve Activation by Renal Denervation Prevents Cerebral Vasospasm after Subarachnoid Hemorrhage in Rats.

The poor prognosis of subarachnoid hemorrhage (SAH) might be associated with sympathetic nerve activation (catecholamine surge) initiated by hypothalamic injury. As renal denervation (RD) has been shown to exert protective effects on cardiovascular dysfunction by suppressing increased central sympathetic nerve activation, we examined whether RD improved the experimental SAH prognosis in this study. Two hundred thirty-eight male Sprague-Dawley rats were divided into sham-operated and SAH-operated groups, and then each rat was further separated into Sham-operated and RD-operated groups. Bilateral RD was performed approximately 45 min after SAH induction. We examined the effect of RD on early brain injury (EBI) and delayed cerebral ischemia (DCI) as a primary endpoint, and also explored the effect on cerebral vasospasm (CVS) as a secondary endpoint. Although RD did not exert significant effects on primary endpoint, RD significantly prevented CVS and reduced SAH-induced increases in the number of phosphorylated extracellular signal-regulated kinase (ERK)-positive endothelial cells, cyclooxygenase-2 expression, and macrophage infiltration in major cerebral arteries. Moreover, RD significantly decreased the areas displaying dopamine ß-hydroxylase and glial fibrillary acidic protein immunopositivity in the paraventricular nucleus of the hypothalamus and serum angiotensin II levels, all of which were increased by SAH. Although RD decreased systolic blood pressure, significant changes in cerebral blood flow were not observed compared with SAH + Sham group. Based on the findings, RD improved CVS by reducing endothelial cell damage and the effects were associated with the stabilization of central sympathetic nerve activation in a SAH model.

Bath-Related Headache.

PURPOSE OF REVIEW: The purpose of this review is to summarize the most up-to-date literature on bath-related headache, a rare disorder. RECENT FINDINGS: Initially described in middle-aged Asian women, it is now reported in a wider demographic. More information is available about the pathophysiology of bath-related headache, including its classification as a subtype of reversible cerebral vasoconstriction syndrome (RCVS). Nimodipine can be effective in patients both with and without vasospasm. Bath-related headache is a rare form of thunderclap headache. Although its mechanism is still unclear, it is associated with vasospasm and RCVS. Controlled trials investigating the use of nimodipine and other agents may be useful in furthering our understanding of and treatment of this phenomenon.

Reversible cerebral vasoconstriction syndrome secondary to caffeine withdrawal.

We describe a 39-year-old man who developed thunderclap headaches during a hospital admission for accidental superficial burns. His magnetic resonance brain imaging was normal expect for diffuse segmental vasoconstriction. Prior to admission, he was consuming excessive amounts of caffeine which was restarted and slowly tapered and stopped over weeks. Repeat magnetic resonance angiogram showed resolution of segmental vasoconstriction. The implications of prescribed and non-prescribed drugs on cerebral vasculature have been discussed.

Evaluation function of transcranial two-dimensional and color Doppler ultrasonography (TCCS) for patients with different degrees of cerebral vasospasm before and after the nimodipine treatment.

OBJECTIVE: To evaluate the changes in cerebral hemodynamics of patients with different degrees of cerebral vasospasm before and after the nimodipine treatment using transcranial two-dimensional and color Doppler ultrasonography (TCCS). PATIENTS AND METHODS: A total of 77 patients with subarachnoid hemorrhage was collected; and the maximum peak systolic velocity (Vs), end diastolic velocity (Vd), time averaged maximum velocity (Vm), pulsatility index (PI) and resistance index (RI) of middle cerebral artery (MCA) were measured by spectral Doppler technique. The standard-dose nimodipine was given for clinical treatment, and changes in blood flow velocity of MCA were monitored by TCCS, and the therapeutic effect was observed. RESULTS: 68 out of 77 patients (88.3%) with subarachnoid hemorrhage were diagnosed as cerebral vasospasm (CVS), including 53 cases (77.9%) of mild spasm, 11 cases (16.2%) of moderate spasm and 4 cases (5.9%) of severe spasm. The sensibility of CVS detected by TCCS after operation was 88.3%. Color Doppler flow imaging (CDFI) showed that the blood flow was multicolored. After the nimodipine treatment, the measured values of MCA-Vs and RI were decreased in different degrees compared with those before treatment. CONCLUSIONS: Nimodipine has improving effects on CVS in different degrees, and TCCS can be used to evaluate the therapeutic effects on CVS.

Effect of Intra-Arterial and Intravenous Nimodipine Therapy of Cerebral Vasospasm After Subarachnoid Hemorrhage on Cerebrovascular Reactivity and Oxygenation.

BACKGROUND: For the treatment and prevention of delayed cerebral ischemia after subarachnoid hemorrhage, the vasodilating agent nimodipine (NDP) is widely employed. This study investigates the effect of NDP on cerebrovascular autoregulation, assessed by pressure reactivity index (PRx), and brain tissue oxygenation (pbrO2) when given continuously intravenously as an intra-arterial bolus or during continuous intra-arterial therapy. METHODS: Computerized continuous neuromonitoring data (intracranial pressure, mean arterial pressure, cerebral perfusion pressure [CPP], pbrO2, PRx) of 105 patients with aneurysmal SAH were retrospectively evaluated. The effect of NDP on all parameters was compared when applied intra-arterially for the treatment of severe macrovasospasm leading to perfusion deficits as either bolus treatment (n = 111 in 37 patients) or continuous infusion (n = 20 patients) to patients without or with only mild macrovasospasm who received either intravenous NDP or no NDP at all. RESULTS: Compared with patients without treatment, the intravenous application of NDP was associated with a significantly higher PRx. Autoregulation was strongly and long lastingly affected (high PRx) in continuous intra-arterial NDP infusion, accompanied by a sustained improvement of pbrO2. Intra-arterial bolus NDP application resulted as well in a significant increase of pbrO2 and PRx; the induced effect, however, was transient and subsided within 6 hours. Intracranial pressure, mean arterial pressure, and CPP were not affected during the monitoring period. CONCLUSION: The pharmacologically induced alteration of the cerebrovascular autoregulation by NDP correlates with changes of pbrO2 and indicates a beneficial effect on cerebral blood flow if CPP is maintained. This effect is limited to a few hours after bolus treatment and milder for intravenous compared with intra-arterial application.

Antagonistic Effects of Gingko biloba and Sophora japonica on Cerebral Vasoconstriction in Response to Histamine, 5-Hydroxytryptamine, U46619 and Bradykinin.

The aim of this study was to evaluate, for the first time, the antagonistic effects of Gingko biloba leaf (GB) and Sophora japonica L. flower bud (SJ) extracts on cerebral vasoconstriction in response to KCl, extracellular Ca[Formula: see text], histamine, 5-hydroxytryptamine (5-HT), 9,11-dideoxy-9[Formula: see text],11[Formula: see text]-methanoepoxy prostaglandin (PG) F[Formula: see text](U46619) and bradykinin (BK), in order to explain their traditional application for diseases associated with cerebral vasospasm. Isolated porcine basilar arteries (PBA) and endothelial cells from them were used as the study materials. Neither SJ nor GB had any effect on the contractions induced by KCl and extracellular Ca[Formula: see text]. SJ significantly inhibited the contraction induced by histamine, 5-HT, U46619 and BK, whereas GB inhibited histamine-induced contraction, but had no effects on the contractions induced by 5-HT, U46619 and BK. In the presence of diphenhydramine (a H1 receptor antagonist), ketanserin (a 5-HT2 receptor antagonist) and ONO-3708 (a thromboxane (TX) A2/PG receptor antagonist), the inhibitory effects of these extracts on the contractions induced by histamine, 5-HT and U46619 were abolished. SJ significantly inhibited the contractions induced by BK and PGF[Formula: see text], but in the presence of ONO-3708 (10[Formula: see text] M) had no effect on them. BK enhanced the production of PGF[Formula: see text] from cultured PBA endothelium cells, and SJ significantly attenuated this enhancement. These results suggest that SJ and GB have a H1-antagonistic effect, and that SJ also attenuates cerebral vasoconstriction mediated via 5-HT2 and TXA2/PG receptors. These findings appear to explain why SJ has been used traditionally as a therapeutic medication for cerebral vasospasm after cerebral hemorrhage.

Corticosteroids in the Management of Hyponatremia, Hypovolemia, and Vasospasm in Subarachnoid Hemorrhage: A Meta-Analysis.

BACKGROUND: Cerebral vasospasm and sodium and fluid imbalances are common sequelae of aneurysmal subarachnoid hemorrhage (SAH) and cause of significant morbidity and mortality. Studies have shown the benefit of corticosteroids in the management of these sequelae. We have reviewed the literature and analyzed the available data for corticosteroid use after SAH. METHODS: PubMed, EMBASE, and Cochrane electronic databases were searched without language restrictions, and 7 observational, controlled clinical studies of the effect of corticosteroids in the management of SAH patients were identified. Data on sodium and fluid balances, symptomatic vasospasm (SVS), and outcomes were pooled for meta-analyses using the Mantel-Haenszel random effects model. RESULTS: Corticosteroids, specifically hydrocortisone and fludrocortisone, decreased natriuretic diuresis and incidence of hypovolemia. Corticosteroid administration is associated with lower incidence of SVS in the absence of nimodipine, but does not alter the neurological outcome. CONCLUSIONS: Supplementation of corticosteroids with mineralocorticoid activity, such as hydrocortisone or fludrocortisone, helps in maintaining sodium and volume homeostasis in SAH patients. Larger trials are warranted to confirm the effects of corticosteroids on SVS and patient outcomes.

Effect of endothelin receptor antagonists on clinically relevant outcomes after experimental subarachnoid hemorrhage: a systematic review and meta-analysis.

In clinical trials, endothelin receptor antagonists (ETRAs) reduced vasospasm but did not improve functional outcome after subarachnoid hemorrhage (SAH). We assessed the effects of treatment with ETRAs on clinically relevant outcomes in animal studies modelling SAH by performing a systematic review of the literature for controlled animal studies of ETRAs for the treatment of SAH. Primary outcomes were neurobehavioral outcomes and case fatality. Secondary outcomes were cerebral vasospasm and cerebral blood flow. Summary estimates were calculated using normalized mean difference random effects meta-analysis. We included 27 studies (55 experiments, 639 animals). Neurobehavioral scores were reported in none of the experiments, and case fatality in 8 (15%). Treatment with ETRAs was associated with a pooled odds ratio for case fatality of 0.61 (95% confidence interval (CI), 0.27 to 1.39); a 54% increase (95% CI, 39 to 69) in cerebral arterial diameter; and a 93% increase (95% CI, 58 to 129) in cerebral blood flow. We conclude that there is no evidence from animal studies that treatment with an ETRA improves clinically relevant outcomes after SAH. The reduction in cerebral vasospasm observed in animal studies is consistent with that observed in clinical trials, an effect that is not associated with better functional outcome in patients.

Glycyrrhizin Attenuates Proinflammatory Cytokines through a Peroxisome Proliferator-Activated Receptor-γ-Dependent Mechanism and Experimental Vasospasm in a Rat Model.

The peroxisome proliferator-activated receptor (PPAR) is downregulated in the cortex of experimental subarachnoid hemorrhage (SAH) animals. This study is to examine the effect of glycyrrhizin on the alternation of PPARs and proinflammatory cytokines in a rodent SAH model. CSF cytokines were evaluated by RT-PCR. Basilar arteries (BAs) were harvested to examine PPARs (RT-PCR and Western blot), and a morphological examination was conducted. Deformed endothelium and tortuous elastic lamina were observed in the BAs of the SAH groups, but they were absent in the glycyrrhizin groups or the healthy controls. The PPAR-γ and -δ protein levels were reduced in the SAH groups (p < 0.01). Glycyrrhizin significantly increased the expressed PPAR-γ protein and mRNA (preconditioning) and PPAR-δ mRNA (both treatment and preconditioning), which corresponded to the reduced IL-1ß and TNF-α levels. The administration of a PPAR-γ inhibitor, BADGE, halted the reduction of IL-1ß and TNF-α in the glycyrrhizin groups. Conclusively, glycyrrhizin exerts anti-inflammatory effects on SAH-induced vasospasm and attenuates the expression of PPARs, especially PPAR-γ, which corresponds to the severity of SAH-related inflammation. These findings also offer credit to the antivasospastic effect of glycyrrhizin and its vasculoprotective effect in animals subjected to SAH.

Double cisterna magna blood injection model of experimental subarachnoid hemorrhage in dogs.

Several animal subarachnoid hemorrhage (SAH) models have been proposed to study the etiology and treatment for cerebral vasospasm. We describe the experimental procedures of a canine double-hemorrhage model of SAH and discuss the pathophysiological parameters and occurrence of angiographic delayed cerebral vasospasm using magnetic resonance (MR) imaging and digital subtraction angiography. Autologous blood was injected twice on days 1 and 3 into the cerebellomedullary cistern of 36 female beagles. All animals showed delayed angiographic vasospasm in the vertebrobasilar arteries on day 7. The degree of vasospasm was 29-42 % of the arterial diameter. However, this model showed no symptomatic vasospasm or ischemic changes detected by MR imaging. This animal model can produce reproducible delayed vasospasm without detectable cerebral infarction on MR imaging. This model allows evaluation of the effect of treatment on delayed vasospasm in the same animals. The canine double-hemorrhage model of SAH is suitable for the quantitative and chronological study of delayed angiographic vasospasm, but not for investigating early brain injury and delayed cerebral ischemia.

Magnesium lithospermate B, an active extract of Salvia miltiorrhiza, mediates sGC/cGMP/PKG translocation in experimental vasospasm.

BACKGROUND: Soluble guanylyl cyclases (sGCs) and Ras homolog gene family, member A (rhoA)/Ras homolog gene family kinase(rho-kinase) plays a role in vascular smooth muscle relaxation in subarachnoid hemorrhage (SAH). It is of interest to examine the effect of MLB on rhoA/ROCK and sGC/cGMP/PKG expression. METHODS: A rodent SAH model was employed. Tissue samples were for sGC α 1, sGC ß 1, PKG, rhoA, ROCK (Western blot), and cGMP (ELISA) measurement. RESULTS: MLB morphologically improved convolution of the internal elastic lamina, distortion of endothelial wall, and necrosis of the smooth muscle in the SAH rats. Expressed cGMP, sGC α 1, sGC ß 1, and PKG in the SAH groups were reduced (P < 0.01), and MLB precondition significantly induced cGMP, sGCα1, sGCß1, and PKG. L-NAME reversed the vasodilation effect of MLB, reduced the bioexpression of PKG and cGMP (P < 0.01), and tends to reduce sGCα1 level and induce rhoA, ROCK level in MLB precondition + SAH groups. CONCLUSION: These results demonstrate that sGC/cGMP/PKG and NO/ET pathways play pivotal roles in SAH-induced vasospasm. Through activating sGC/cGMP/PKG pathway and partially by inactivating rho-kinase in a NO-dependent mechanism, MLB shows promise to be an effective strategy for the treatment of this disease entity.

Continuous selective intra-arterial application of nimodipine in refractory cerebral vasospasm due to aneurysmal subarachnoid hemorrhage.

BACKGROUND: Cerebral vasospasm is one of the leading courses for disability in aneurysmal subarachnoid hemorrhage. Effective treatment of vasospasm is therefore one of the main priorities for these patients. We report about a case series of continuous intra-arterial infusion of the calcium channel antagonist nimodipine for 1-5 days on the intensive care unit. METHODS: In thirty patients with aneurysmal subarachnoid hemorrhage and refractory vasospasm continuous infusion of nimodipine was started on the neurosurgical intensive care unit. The effect of nimodipine on brain perfusion, cerebral blood flow, brain tissue oxygenation, and blood flow velocity in cerebral arteries was monitored. RESULTS: Based on Hunt & Hess grades on admission, 83% survived in a good clinical condition and 23% recovered without an apparent neurological deficit. Persistent ischemic areas were seen in 100% of patients with GOS 1-3 and in 69% of GOS 4-5 patients. Regional cerebral blood flow and computed tomography perfusion scanning showed adequate correlation with nimodipine application and angiographic vasospasm. Transcranial Doppler turned out to be unreliable with interexaminer variance and failure of detecting vasospasm or missing the improvement. CONCLUSION: Local continuous intra-arterial nimodipine treatment for refractory cerebral vasospasm after aSAH can be recommended as a low-risk treatment in addition to established endovascular therapies.

Nimodipine attenuation of early brain dysfunctions is partially related to its inverting acute vasospasm in a cisterna magna subarachnoid hemorrhage (SAH) model in rats.

Subarachnoid hemorrhage (SAH)-induced brain injury is highly related to neurological deficits and mortality. Regional cerebral blood flow (rCBF) changes and vasoconstriction are two complications that occur soon after SAH experimentally. In this study we investigated the changes in rCBF and vertebro-basilar arterial diameter in a cisterna megna SAH model in Sprague-Dawley rats and intended to explore whether improving early rCBF reduction and cerebral vasospasm could contribute to alleviating blood-brain barrier (BBB) dysfunction. In rats for rCBF, vasospasm and BBB permeability assessments, nimodipine (NDP) or saline was administered intravenously 5 minutes after SAH. rCBF within the first 60 minutes after SAH was measured by laser Doppler flowmetry. BBB permeability indexed by Evans Blue extravasation was assessed 4 hours after SAH. Angiography for the caliber changes of the vertebro-basilar artery were conducted 30 minutes post SAH. Pronounced rCBF reduction and vasospasm were observed soon after SAH, followed by BBB permeability increment. NDP administration could improve rCBF and attenuate vasospasm, followed by the alleviation of BBB permeability. Our results demonstrate that early improvement of cerebral circulation by NDP may contribute to the reduction in brain injury indexed by BBB disruption.