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Abstract The murine model of subarachnoid hemorrhage (SAH) is a valuable experimental tool for investigating molecular and cellular mechanisms, and the endovascular filament perforation technique can be used to simulate prominent pathophysiological features observed after human SAH; however, current validation methods for assessing an appropriate SAH model are limited. Here, we introduce a simple procedure for selecting a mouse model of diffuse SAH. SAH was induced in 24 mice using a standard filament perforation method. After confirming survival at 24 h, SAH was scored 0–1 based on T2*‐weighted images on whole‐brain magnetic resonance imaging (MRI) and visual surveillance of the cisterna magna (CM) through the dura mater. The CM‐based SAH grading correlated well with a reference parameter defined by extracted brain (r2 = 0.53, p

Anaphylaxis is a severe life-threatening hypersensitivity reaction induced by mast cell degranulation. Among the various mediators of mast cells, little is known about the role of tryptase. Therefore, we aimed to elucidate the role of protease-activating receptor-2 (PAR-2), a receptor activated by tryptase, in murine anaphylactic models using PAR-2-deficient mice and newly generated tryptase-deficient mice. Anaphylaxis was induced by IgE-dependent and IgE-independent mast cell degranulation in mice. PAR-2 deficiency exacerbated the decrease in body temperature and hypotension during anaphylaxis; however, the number of skin mast cells, degree of mast cell degranulation, and systemic and local vascular hyperpermeability were comparable in PAR-2 knockout and wild-type mice. Nitric oxide, which is produced by endothelial nitric oxide synthase (eNOS), is an indispensable vasodilator in anaphylaxis. In the lungs of anaphylactic mice, PAR-2 deficiency promoted eNOS expression and phosphorylation, suggesting a protective effect of PAR-2 against anaphylaxis by downregulating eNOS activation and expression. Based on the hypothesis that the ligand for PAR-2 in anaphylaxis is mast cell tryptase, tryptase-deficient mice were generated using CRISPR-Cas9. In wild-type mice, the PAR-2 antagonist exacerbated the body temperature drop due to anaphylaxis; however, the effect of the PAR-2 antagonist was abolished in tryptase-deficient mice. These results suggest that tryptase is a possible ligand of PAR-2 in anaphylaxis and that the tryptase/PAR-2 pathway attenuates the anaphylactic response in mice.

Background: Intravenous thrombolysis and mechanical thrombectomy are the first-line reperfusion therapies for acute ischemic stroke. Here, we describe the utility of diffusion magnetic resonance imaging (MRI) fiber tractography and 123I-iomazenil benzodiazepine receptor single-photon emission computed tomography to estimate the prognosis of post-stroke aphasia after successful reperfusion therapy. Case report: An 81-year-old man was admitted to the hospital approximately 3.5 h after the onset of symptoms, including decreased consciousness, right hemiparesis, and aphasia. An MRI revealed acute cerebral infarction due to M1 segment occlusion. Intravenous alteplase thrombolysis followed by endovascular thrombectomy resulted in recanalization of the left middle cerebral artery territory. A subsequent MRI showed no new ischemic or hemorrhagic lesions. Although the patient’s motor hemiparesis gradually recovered, motor aphasia persisted. Diffusion MRI fiber tractography performed 2 weeks after admission revealed partial injury to the left arcuate fasciculus, indicated by lower fractional anisotropy values than on the contralateral side. A decreased benzodiazepine receptor density was also detected in the left perisylvian and temporoparietal cortices. The patient showed no clear signs of further improvement in the chronic stage post-stroke and was discharged to a nursing home after 3 months. Conclusions: The application of functional neuroimaging techniques to assess neuronal damage to the primary brain regions 2 weeks after reperfusion therapy for large-vessel occlusion may allow for an accurate prognosis of post-stroke aphasia. This may have a direct clinical implication for navigating subacute-to-chronic phases of rehabilitative care.

Clazosentan has been shown to prevent vasospasm and reduce mortality in patients after aneurysmal subarachnoid hemorrhage (SAH) and has been approved for clinical use in Japan; however, its systemic events in the elderly (aged ≥ 75 years) have not been well-documented. Here, we report serious/intolerable cardiopulmonary complications requiring discontinuation of drug therapy in elderly SAH patients. In this single-center case series study, medical records of consecutive SAH patients treated postoperatively with clazosentan (10 mg/h) between June 2022 and May 2023 were reviewed retrospectively. Thirty-three patients received clazosentan therapy, of whom six were elderly with a mean age of 80.3 ± 5.2 (range 75–89) years. Among them, despite no obvious medical history of systemic abnormalities, clazosentan was discontinued in three (50%) patients due to pleural effusion and hypoxemia with or without hypotension at 5 ± 3 days after therapy initiation, which was higher than the incidence for younger patients (15%). The elderly patients had significantly lower urine output (1935 ± 265 vs. 1123 ± 371 mL/day, p = 0.03) and greater weight gain (2.1 ± 1.1 vs. 4.2 ± 1.9 kg from baseline, p = 0.04) than patients who completed the therapy. One 89-year-old female developed congestive heart failure and hydrostatic pulmonary edema associated with increased intravascular and lung volumes even after therapy was discontinued, while the remaining two cases recovered within 2 days after drug cessation. These results suggest that elderly patients are more vulnerable to fluid retention and have a higher risk of cardiopulmonary complications during clazosentan therapy than younger patients. Careful monitoring of urine volume and weight gain and caution regarding age- and therapy-related hemodynamic insufficiencies are required.