Developing a mouse model of acute encephalopathy using low-dose lipopolysaccharide injection and hyperthermia treatment

Abstract

Acute encephalopathy (AE) is mainly reported in East Asia and, in most cases, results from pediatric viral infections, leading to fever, seizure, and loss of consciousness. Cerebral edema is the most important pathological symptom of AE. At present, AE is classified into four categories based on clinical and pathophysiological features, and cytokine storm-induced AE is the severest among them. The pathogenesis of AE is currently unclear; this can be attributed to the lack of a simple and convenient animal model for research. Here, we hypothesized that the induction of systemic inflammation using lipopolysaccharide (LPS) injection followed by hyperthermia (HT) treatment can be used to develop an animal model of cytokine storm-induced AE. Postnatal eight-day-old mouse pups were intraperitoneally injected with low-dose LPS (50 or 100\u2009µg/kg) followed by HT treatment (41.5°C, 30\u2009min). Histological analysis of their brains was subsequently performed. Fluorescein isothiocyanate assay combined with immunohistochemistry was used to elucidate blood–brain barrier (BBB) disruption. LPS (100\u2009µg/kg) injection followed by HT treatment increased BBB permeability in the cerebral cortex and induced microglial activation. Astrocytic clasmatodendrosis was also evident. The brains of some pups exhibited small ischemic lesions, particularly in the cerebral cortex. Our results indicate that a low-dose LPS injection followed by HT treatment can produce symptoms of cytokine storm-induced AE, which is observed in diseases, such as acute necrotizing encephalopathy and hemorrhagic shock and encephalopathy syndrome. Thus, this mouse model can help to elucidate the pathogenetic mechanisms underlying AE. Impact statement Acute encephalopathy (AE), mainly reported in East Asia, is classified into four categories based on clinical and neuropathological findings. Among them, AE caused by cytokine storm is known as the severest clinical entity that causes cerebral edema with poor prognosis. Because suitable and convenient model animal of AE had not been developed, the treatment of patients with AE is not established. In the present study, we established a simple and convenient protocol to mimic AE due to cytokine storm. Our model animal should be useful to elucidate the pathogenesis of AE.