Convexal subarachnoid haemorrhage in a patient under pembrolizumab-lenvatinib combination therapy.

A woman in her 60s was brought to the emergency department due to a new-onset seizure. She was drowsy on arrival and unable to provide a clinical history. She had a medical history of advanced endometrial cancer, for which she was under the therapeutic protocol pembrolizumab plus lenvatinib. Laboratorial investigations were unremarkable. The brain CT angiography provided further insight into the case by detecting a bilateral convexal subarachnoid haemorrhage with discrete bilateral opercular vasogenic oedema, without other noticeable structural changes. Cerebrospinal fluid analysis was macroscopically haemorrhagic, but otherwise unremarkable. The brain MRI did not provide additional information. Although considered a rare adverse reaction, cerebral haemorrhage has been described for both pembrolizumab and lenvatinib. We cautiously assumed a probable drug aetiology after a thorough review of potential causes. Following discontinuation of these drugs and under anti-convulsive therapy, the patient remained asymptomatic and was discharged home.

Therapeutic review: The role of tranexamic acid in management of traumatic brain injury, nontraumatic intracranial hemorrhage, and aneurysmal subarachnoid hemorrhage.

PURPOSE: To summarize current literature evaluating tranexamic acid in the management of intracranial bleeding associated with traumatic and nontraumatic brain injuries and implications for clinical practice. SUMMARY: Intracranial hemorrhage, regardless of etiology, is associated with high morbidity and mortality. Tranexamic acid is an antifibrinolytic with anti-inflammatory properties shown to reduce mortality in trauma patients with extracranial injuries. In traumatic brain injury, a large randomized trial found no difference in outcomes when tranexamic acid was compared to placebo; however, subgroup analyses suggested that it may reduce head injury-related mortality in the context of mild-to-moderate injury if treatment occurs within 1 hour of symptom onset. More recent out-of-hospital data have disputed these findings and even suggested harm in severely injured patients. In spontaneous, nontraumatic intracranial hemorrhage, treatment with tranexamic acid did not result in a difference in functional status; however, rates of hematoma expansion, even though modest, were significantly reduced. In aneurysmal subarachnoid hemorrhage, tranexamic acid may prevent rebleeding, but has not led to improved outcomes or reduced mortality, and there is concern for increased incidence of delayed cerebral ischemia. Overall, tranexamic acid has not been shown to result in increased risk of thromboembolic complications across these classes of brain injury. CONCLUSION: Despite its favorable safety profile overall, tranexamic acid does not seem to improve functional outcomes and cannot be routinely recommended. More data are needed to determine which head injury subpopulations are most likely to benefit from tranexamic acid and which patients are at increased risk for harm.

Severe methanol intoxication with atypical symptoms and imaging changes: a fatal case report.

Acute methanol intoxication can occur as accidental ingestion of adulterated spirits. We report a 51-year-old male patient with high anion-gap metabolic acidosis (pH 6.71, HCO3-4.2 mmol/l, K + 6.5mmol/l) because of severe methanol intoxication (450 mg/L, reference level <2.9 mg/L) who presented with atypical symptoms of dizziness and rapidly developed extensive subarachnoid hemorrhage and diffuse cerebral edema and died within several days. Clinicians should have suspicion for subarachnoid hemorrhage in patients with long-term drinking poisoned by methanol with dizziness, consciousness disturbances and severe metabolic acidosis.

Oral Contraceptives, Hormone Replacement Therapy, and Stroke Risk.

BACKGROUND: Millions of women worldwide use exogenous hormones as oral contraceptives or hormone replacement therapy. Still, time-dependent and long-term consequences of exogenous hormones on stroke risk remains unclear. METHODS: We examined the association between self-reported oral contraceptive and hormone replacement therapy use and stroke risk in 257 194 women from the UK Biobank, born between 1939 and 1970. Outcomes included any type of stroke, ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Exposures were analyzed as time-varying variables in Cox regression models. RESULTS: During first year of oral contraceptive use, an increased event rate of any stroke was observed (hazard ratio [HR], 2.49 [95% CI, 1.44-4.30]), while the hazards were found to be comparable during remaining years of use (HR, 1.00 [95% CI, 0.86-1.14]), compared with nonusers. Similarly, first year of hormone replacement therapy use was associated with higher hazard rates of any stroke (HR, 2.12 [95% CI, 1.66-2.70]), as well as cause-specific stroke, including ischemic stroke (HR, 1.93 [95% CI, 1.05-3.57]) and subarachnoid hemorrhage (HR, 2.17 [95% CI, 1.25-3.78]), which remained increased for any stroke during remaining years of use (HR, 1.18 [95% CI, 1.05-1.31]), and after discontinuation (HR, 1.16 [95% CI, 1.02-1.32]). CONCLUSIONS: Oral contraceptive use and hormone replacement therapy were associated with an increased risk of stroke, especially during the first year of use, possibly due to immediate changes in hemostatic balance. This study provides new insights on the effects of hormone exposure on stroke risk and provide evidence of not only an overall risk but also a pronounced effects seen in the beginning of treatment.

Relationship between aspirin use and subarachnoid hemorrhage: A systematic Review and meta-analysis.

BACKGROUND: Aspirin has been associated with a decreasing risk of subarachnoid hemorrhage due to its anti-inflammatory mechanism of action and potential protective properties against aneurysm growth. OBJECTIVE: To determine the association between aneurysmal subarachnoid hemorrhage and aspirin use. METHODS: A systematic review of the literature and a meta-analysis were performed across the PubMed database. The following keywords were used: "aspirin, acetylsalicylic acid, 2-acetyloxy-benzoic acid, ruptured intracranial aneurysm, aneurysmal subarachnoid hemorrhage, spontaneous subarachnoid hemorrhage, intracerebral hemorrhage, spontaneous aneurysmal hemorrhage, spontaneous intracerebral bleeding". Studies that were performed with animals or analyzed patients with traumatic brain injury were excluded. A total of five studies were included in our meta-analysis, with a total of 19,222 patients evaluated. Statistical analysis was performed to determine the association between the use of aspirin and the risk of subarachnoid hemorrhage. RESULTS: Aspirin use reduce the risk of subarachnoid hemorrhage (odds ratio [OR] 0.51, 95 % confidence interval [CI] 0.34-0.76). CONCLUSION: Although some previous studies suggested that aspirin may potentially reduce the risk of subarachnoid hemorrhage, our meta-analysis found an association between the reduction of risk of aneurysmal subarachnoid hemorrhage.

Convexity Subarachnoid Hemorrhage Soon after Starting a Direct Oral Anticoagulant in 2 Patients with Acute Infarction.

Convexity subarachnoid hemorrhage (cSAH) is typically due to head trauma, but it rarely occurs subsequent to acute ischemic stroke. Direct oral anticoagulants (DOACs) have favorable bleeding profiles as compared with warfarin, and, to our knowledge, no DOAC has been regarded as a causative agent for cSAH. Here, we reported 2 patients with cSAH apparently caused by starting DOAC therapy. No hemorrhage had been evident just prior to treatment initiation, but cSAH occurred so soon after DOAC therapy began. Each of our patients had occlusion or severe stenosis of a major artery due to emboligenic disease, and cSAH occurred in the territory of the affected artery. Reperfusion and dynamic changes in perfusion pressure due may trigger cSAH. Clinicians should remain alert for cSAH when starting DOAC for treatment of embolic ischemic stroke during the acute phase.

Nimodipine-induced junctional bradycardia in an elderly patient with subarachnoid hemorrhage.

Subarachnoid hemorrhage is a devastating form of stroke with often detrimental outcomes for patients. Here we describe a patient with subarachnoid hemorrhage treated with nimodipine, which resulted in marked bradycardia with junctional atrioventricular heart block. Nimodipine is metabolized predominantly by the cytochrome P450 3A subfamily, and its use is often associated with adverse events, such as hypotension and bradycardia, which can be exacerbated by advanced age. Our patient had the CYP3A5*3/*3 genotype, possibly predisposing her to poor metabolism of this drug. Our case report demonstrates the potential for pharmacogenomics in patients with subarachnoid hemorrhage to help predict their response to nimodipine, minimize adverse drug reactions, and potentially individualize dosing to improve future clinical outcomes.

Factor Xa Inhibitor-Related Intracranial Hemorrhage: Results From a Multicenter, Observational Cohort Receiving Prothrombin Complex Concentrates.

BACKGROUND: Since the approval of the oral factor Xa inhibitors, there have been concerns regarding the ability to neutralize their anticoagulant effects after intracranial hemorrhage (ICH). Multiple guidelines suggest using prothrombin complex concentrates (PCCs) in these patients on the basis of research that includes a limited number of patients with ICH. Given this, we aimed to evaluate the safety and efficacy of PCCs for factor Xa inhibitor-related ICH in a large, multicenter cohort of patients. METHODS: This was a multicenter, retrospective, observational cohort study of patients with apixaban- or rivaroxaban-related ICH who received PCCs between January 1, 2015, and March 1, 2019. The study had 2 primary analysis groups: safety and hemostatic efficacy. The safety analysis evaluated all patients meeting inclusion criteria for the occurrence of a thrombotic event, which were censored at hospital discharge or 30 days after PCC administration. Patients with intracerebral, subarachnoid, or subdural hemorrhages who had at least 1 follow-up image within 24 hours of PCC administration were assessed for hemostatic efficacy. The primary efficacy outcome was the percentage of patients with excellent or good hemostasis on the basis of the modified Sarode criteria. Secondary outcomes included an evaluation of in-hospital mortality, length of stay, infusion-related reactions, and thrombotic event occurrence during multiple predefined periods. RESULTS: A total of 663 patients were included and assessed for safety outcomes. Of these, 433 patients met criteria for hemostatic efficacy evaluation. We observed excellent or good hemostasis in 354 patients (81.8% [95% CI, 77.9-85.2]). Twenty-five (3.8%) patients had a total of 26 thrombotic events, of which 22 occurred in the first 14 days after PCC administration. One patient had documentation of an infusion-related reaction. For the full cohort of patients, in-hospital mortality was 19.0%, and the median intensive care unit and hospital lengths of stay were 2.0 and 6.0 days, respectively. CONCLUSIONS: Administration of PCCs after apixaban- and rivaroxaban-related ICH provided a high rate of excellent or good hemostasis (81.8%) coupled with a 3.8% thrombosis rate. Randomized, controlled trials evaluating the clinical efficacy of PCCs in patients with factor Xa inhibitor-related ICH are needed.

Sevoflurane sedation attenuates early cerebral oedema formation through stabilisation of the adherens junction protein beta catenin in a model of subarachnoid haemorrhage: A randomised animal study.

BACKGROUND: Severe neurological impairment is a problem after subarachnoid haemorrhage (SAH). Although volatile anaesthetics, such as sevoflurane, have demonstrated protective properties in many organs, their use in cerebral injury is controversial. Cerebral vasodilation may lead to increased intracranial pressure (ICP), but at the same time volatile anaesthetics are known to stabilise the SAH-injured endothelial barrier. OBJECTIVE: To test the effect of sevoflurane on ICP and blood-brain barrier function. DESIGN: Randomised study. PARTICIPANTS: One hundred male Wistar rats included, 96 analysed. INTERVENTIONS: SAH was induced by the endoluminal filament method under ketamine/xylazine anaesthesia. Fifteen minutes after sham surgery or induction of SAH, adult male Wistar rats were randomised to 4 h sedation with either propofol or sevoflurane. MAIN OUTCOME MEASURES: Mean arterial pressure (MAP), ICP, extravasation of water (small), Evan's blue (intermediate) and IgG (large molecule) were measured. Zonula occludens-1 (ZO-1) and beta-catenin (ß-catenin), as important representatives of tight and adherens junction proteins, were determined by western blot. RESULTS: Propofol and sevoflurane sedation did not affect MAP or ICP in SAH animals. Extravasation of small molecules was higher in SAH-propofol compared with SAH-sevoflurane animals (79.1 ±â€Š0.9 vs. 78.0 ±â€Š0.7%, P = 0.04). For intermediate and large molecules, no difference was detected (P = 0.6 and P = 0.2). Both membrane and cytosolic fractions of ZO-1 as well as membrane ß-catenin remained unaffected by the injury and type of sedation. Decreased cytosolic fraction of ß-catenin in propofol-SAH animals (59 ±â€Š15%) was found to reach values of sham animals (100%) in the presence of sevoflurane in SAH animals (89 ±â€Š21%; P = 0.04). CONCLUSION: This experiment demonstrates that low-dose short-term sevoflurane sedation after SAH in vivo did not affect ICP and MAP and at the same time may attenuate early brain oedema formation, potentially by preserving adherens junctions. TRIAL REGISTRATION: No 115/2014 Veterinäramt Zürich.

A Case of Reversible Cerebral Vasoconstriction Syndrome Triggered by High-Dose Methotrexate in a Boy With Lymphoma.

BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by thunderclap headaches and transient segmental cerebral arterial vasoconstriction. Many drugs have been identified as triggers of RCVS. However, RCVS induced by methotrexate (MTX), an antimetabolite agent, has never been reported. CASE: We report the first case of a 17-year-old Chinese student with a thunderclap headache after administration of high-dose methotrexate during the treatment of extranodal natural killer/T-cell lymphoma. Brain magnetic resonance angiography showed segmental constriction of the right anterior cerebral artery A1 segment, combined with nonaneurysmal cortical subarachnoid hemorrhage and vasogenic brain edema in brain magnetic resonance imaging. Cerebral images became normal 6 weeks later. DISCUSSION: MTX is associated with a variety of neurological toxicities, including aseptic meningitis, transverse myelopathy, acute and subacute encephalopathy, and leukoencephalopathy. However, this is the first report that MTX can trigger RCVS, although it is not a proof for causality. RCVS should be a differential diagnosis for a headache after MTX administration.

Blood cadmium concentration and risk of subarachnoid haemorrhage.

BACKGROUND: Cadmium is a toxic metal and exposure is mainly from diet and tobacco smoke. Cadmium is accumulated in blood vessels and may reduce synthesis of procollagen and inhibit proliferation of vascular smooth muscle cells. High blood cadmium has been associated with increased risk of myocardial infarction, stroke and unruptured intracranial aneurysms. We examined whether blood cadmium increase the risk of subarachnoid haemorrhage (SAH). METHODS: The Malmö Diet and Cancer cohort (n = 28,449) was examined in 1991-1996 and blood samples were taken. Incidence of SAH was followed up to 2014. Cadmium was measured in stored blood samples from incident SAH cases and matched controls (n = 93 vs n = 276) and odds ratio (OR) for SAH was assessed in a nested case control design. RESULTS: Subjects with cadmium concentration in the highest quartile had increased risk of SAH compared to those in the first quartile (OR: 3.22, 95%CI: 1.67-6.22). However, after adjusting for smoking, results were weakened and non-significant (OR: 1.57, 95%CI: 0.51-4.80). CONCLUSIONS: Cadmium concentration was associated with increased risk of SAH but this association was largely explained by smoking. Whether cadmium in tobacco may contribute to the vascular pathology and increased risk of SAH in smokers should be further studied.

Warfarin Reinitiation After Intracranial Hemorrhage: A Case Series of Heart Valve Patients.

Patients with mechanical heart valves are at high thrombotic risk and require warfarin. Among those developing intracranial hemorrhage, limited data are available to guide clinicians with antithrombotic reinitiation. This 13-patient case series of warfarin-associated intracranial hemorrhages found the time to reinitiate antithrombotic therapy (17 days, interquartile range 21.5 days), and changes to international normalized ratio targets were variable and neither correlated with the type, location, or etiology of bleed, nor the valve and associated thromboembolic risk. The initial presentation significantly impacted prognosis, and diligent assessment and follow-up may support positive long-term outcomes.

Bromadiolone poisoning leading to subarachnoid haemorrhage: A case report and review of the literature.

WHAT IS KNOWN AND OBJECTIVE: Many cases of rodenticide poisoning have been reported. Bromadiolone, often called a super-warfarin, is a second-generation dicoumarin rodenticide with long half-life. The main clinical manifestations of bromadiolone poisoning are excessive or inappropriate bleeding of skin mucosa, digestive tract and urinary tract. However, the phenomenon of central nervous system (CNS) toxicity is an uncommon medical emergency. We present a case of SAH and intracerebral haematoma mediated by bromadiolone intoxication, revealing that bromadiolone poisoning might cause intracerebral haematoma. CASE DESCRIPTION: A 44-year-old woman presented with skin mucosa haemorrhage and haematuresis initially. The patient developed lethargy, headache, nausea and vomiting. The toxicology test result revealed that the presence of bromadiolone in her blood. Coagulation test results showed a longer prothrombin time (PT), activated partial thromboplastin time (APTT) and a high international normalized ratio (INR). SAH, frontal lobe haematoma, midline shift and brain oedema were discovered by skull CT examination. The coagulation disorders were addressed after the treatment of vitamin K and fresh frozen plasma. The intracranial symptoms were relieved after surgery and the treatment with mannitol. WHAT IS NEW AND CONCLUSION: This case suggests that bromadiolone poisoning should be diagnosed and treated as early as possible. Bromadiolone poisoning might cause SAH and intracerebral haematoma, which is rare but potentially lethal. It is important to strengthen the diagnosis and post-treatment monitoring.

Effects of a new magnesium-rich artificial cerebrospinal fluid on contractile 5-hydroxytryptamine and endothelin receptors in rat cerebral arteries.

Objectives Cerebral vasospasm after subarachnoid haemorrhage (SAH) is associated with cerebrovascular contractile receptor upregulation resulted from haemolysis in the subarachnoid space. This study developed a new magnesium-rich artificial cerebrospinal fluid (MACSF) formula and investigated its effects on receptor-mediated contraction in rat basilar arteries. Methods Clear and haemorrhagic cerebrospinal fluid (CSF) were collected from patients with hydrocephalus or SAH. MACSF was freshly prepared using clinical intravenous injections. Rat basilar arteries were segmented and incubated with clear CSF, haemorrhagic CSF or MACSF. The contractile responses were studied by myograph. The messenger ribonucleic acid (mRNA) and protein expression of 5-hydroxytryptamine 1B (5-HT1B), endothelin subtype B (ETB) and endothelin subtype A (ETA) receptors were evaluated by real-time polymerase chain reaction (PCR) and Western blot analyses. Results Haemorrhagic CSF exposure shifted the contractile curves induced by 5-hydroxytryptamine (5-HT), sarafotoxins 6c (S6c) and endothelin-1 (ET-1) leftward with increased maximal contraction values. Furthermore, mRNA and protein expression were markedly elevated for 5-HT1B, ETB and ETA receptors on arteries exposed to haemorrhagic CSF. However, the contractile responses to 5-HT, S6c or ET-1 and expression of 5-HT1B, ETB and ETA receptors in rat cerebral arteries exposed to MACSF remained unaffected compared to those exposed to clear CSF. Besides, unlike normal saline which can inactive in-vitro vessels, MACSF can maintain their physiological activity. Conclusion Haemorrhagic CSF induces upregulation of 5-HT1B, ETB and ETA receptors in rat cerebral arteries. However, MACSF can maintain in-vitro rat basilar arteries in good physiological activity and normal expression of contractile 5-HT and ET receptors.

The dual-functional memantine nitrate MN-08 alleviates cerebral vasospasm and brain injury in experimental subarachnoid haemorrhage models.

BACKGROUND AND PURPOSE: Cerebral vasospasm and neuronal apoptosis after subarachnoid haemorrhage (SAH) is the major cause of morbidity and mortality in SAH patients. So far, single-target agents have not prevented its occurrence. Memantine, a non-competitive NMDA re3ceptor antagonist, is known to alleviate brain injury and vasospasm in experimental models of SAH. Impairment of NO availability also contributes to vasospasm. Recently, we designed and synthesized a memantine nitrate MN-08, which has potent dual functions: neuroprotection and vasodilation. Here, we have tested the therapeutic effects of MN-08 in animal models of SAH. EXPERIMENTAL APPROACH: Binding to NMDA receptors (expressed in HEK293 cells), NO release and vasodilator effects of MN-08 were assessed in vitro. Therapeutic effects of MN-08 were investigated in vivo, using rat and rabbit SAH models. KEY RESULTS: MN-08 bound to the NMDA receptor, slowly releasing NO in vitro and in vivo. Consequently, MN-08 relaxed the pre-contracted middle cerebral artery ex vivo and increased blood flow velocity in small vessels of the mouse cerebral cortex. It did not, however, lower systemic blood pressure. In an endovascular perforation rat model of SAH, MN-08 improved the neurological scores and ameliorated cerebral vasospasm. Moreover, MN-08 also alleviated cerebral vasospasm in a cisterna magna single-injection model in rabbits. MN-08 attenuated neural cell apoptosis in both rat and rabbit models of SAH. Importantly, the therapeutic benefit of MN-08 was greater than that of memantine. CONCLUSION AND IMPLICATIONS: MN-08 has neuroprotective potential and can ameliorate vasospasm in experimental SAH models.

Síndrome de vasoconstricción cerebral reversible asociado a anastrozol: una causa inusual de alto impacto / Reversible cerebral vasoconstriction syndrome associated with anastrozole: an unusual cause of high impact

Introducción. El síndrome de vasoconstricción cerebral reversible (SVCR) es una entidad de baja incidencia, de etiología multifactorial y amplio espectro de presentación. El principal síntoma es la cefalea de tipo trueno. Puede estar acompañado de focalización neurológica y cursar con desenlaces clínicos variable que incluso pueden llevar a la muerte. El diagnóstico es clínico e imaginológico, y el tratamiento incluye adoptar medidas generales de monitorización, manejo sintomático, identificar la etiología y actuar sobre ella para evitar recurrencia. Caso clínico. Mujer de 71 años con antecedente de cáncer de seno, tratada inicialmente con tamoxifeno; por presentar urticaria, se escalonó tratamiento con anastrozol. Ingresó por cefalea de tipo trueno, afasia anterior y somnolencia. La paciente refirió un evento similar una semana antes del ingreso. En la resonancia magnética cerebral evidenció una hemorragia subaracnoidea (HSA) pequeña de la convexidad temporoparietal izquierda, y la panangiografía documentó vasoespasmo en la región parietal posterior, lo que confirmó el diagnóstico de SVCR más HSA. Durante el ingreso presentó tres eventos de iguales características, que requirieron monitorización intensiva y dos panangiografías terapéuticas con nimodipino intraarterial, con posterior resolución del vasoespasmo. Permanece asintomática seis meses después. Conclusión. El SVCR constituye un reto diagnóstico dada su presentación variable y su etiología multifactorial. En este caso, el SVCR más HSA está asociado al uso de anastrozol. Hasta el momento no hay casos descritos de inhibidores de la aromatasa asociados a esta patología, que debe comunicarse para su farmacovigilancia

Introduction. Reversible cerebral vasoconstriction syndrome (RCVS) is a low incidence disability with a multifactorial etiology and a wide array of symptoms. The main symptom is a thunderclap headache, accompanied sometimes with various neurological deficits that can lead to death. RCVS is usually diagnosed through radiological imaging technology. The treatment includes adopting general measures of monitoring, symptomatic management, identifying the etiology and acting on it to avoid recurrence. Case report. A 71-year-old woman with a history of breast cancer originally treated with tamoxifen. Due to urticaria, the anastrozole management was staggered. She was admitted for aphasia, drowsiness and a thunderclap headache. The patientreported a similar event two weeks prior admission. In rain resonance, there was evidence of small sub-arachnoidal haemorrhage (SAH) of the left parietal temporal convexity and cerebral angiography. As well as documented vasospasm in the posterior parietal region confirming the diagnosis of RCVS plus SAH. During the stay, she presented three events with the same characteristics, requiring intensive monitoring and two therapeutic panangiographies with intra-arterial nimodipine with subsequent resolution of the vessel spasm. The patient remains asymptomatic six months later. Conclusion. RCVS is difficult to diagnose given its wide array of symptoms and multifactorial etiology. In this case, RCVS plus SAH is associated with the use of anastrozole. So far there are no reported cases of aromatase inhibitors associated with this pathology and should be reported in the literature for pharmacovigilance

Central action of rapamycin on early ischemic injury and related cardiac depression following experimental subarachnoid hemorrhage.

Early brain injury and related cardiac consequences play a key role in the devastating outcomes after subarachnoid hemorrhage (SAH). We reported that rapamycin exerts neuroprotection against cortical hypoxia early after SAH, but its mechanism is poorly understood. This in vivo study aimed to determine the potential role of the transcription factor STAT3 in the rapamycin-mediated neuroprotection in a mouse model of SAH. Forty C57BL/6 N mice were treated with an intracerebroventricular injection of rapamycin or vehicle (control) given after SAH induction by a filament perforation method, with or without STAT3 (Stattic) or ERK (PD98059) inhibitor pretreatment. Cerebral blood flow signals (%vascularity), brain tissue oxygen saturation (SbtO2), and cardiac output (CO) were analyzed using an ultrasound/photoacoustic imaging system. Clinically relevant neurocardiac depression was notable in severe SAH mice. Rapamycin improved %vascularity, SbtO2, and CO on day 1 after SAH onset. The beneficial effects of rapamycin on cerebral blood flow and oxygenation persisted until day 3, resulting in a significant reduction in post-SAH new cerebral infarctions and survival, as well as improved neurological functions, compared to the control group. All of the effects were attenuated by pretreatment with Stattic or PD98059. These data suggest that ERK and JAK/STAT3 pathways play an important role in the neurocardiac protection by rapamycin after SAH. We propose that rapamycin is a novel pharmacological strategy to target STAT3 activation, with a possible crosstalk through the ERK pathway, for the treatment of post-SAH early brain injury.

TAT-mGluR1 Attenuation of Neuronal Apoptosis through Prevention of MGluR1α Truncation after Experimental Subarachnoid Hemorrhage.

Excessive glutamate-mediated overactivation of metabotropic glutamate receptor 1 (mGluR1) plays a leading role in neuronal apoptosis following subarachnoid hemorrhage (SAH). TAT-mGluR1, a fusion peptide consisting of a peptide spanning the calpain cleavage site of mGluR1α and the trans-activating regulatory protein (TAT) of HIV, effectively blocks mGluR1α truncation and protects neurons against excitotoxic damage. This study investigated the effects of TAT-mGluR1 on neuronal apoptosis in the rat SAH model. Here, we report that SAH caused activation of calpain and truncation of mGluR1α; intraperitoneally administered TAT-mGluR1 did not affect calpain activity, while it blocked truncation of mGluR1α after SAH. Intraperitoneally administered FITC-labeled TAT-mGluR1 was colocalized with mGluR1α in thecortex after SAH. Furthermore, TAT-mGluR1 significantly improved the neurological deficit, increased p-PI3K, p-Akt, and p-GSK3ß, downregulated Bax, upregulated Bcl-2, and reduced cortical apoptosis in the basal cortex at 24 h after SAH. These findings indicated that TAT-mGluR1 acted against SAH-induced cell apoptosis through preventing mGluR1α truncation.