RESUMO
The recent public awareness of the incidence and possible long-term consequences of traumatic brain injury only heightens the need to develop effective approaches for treating this neurological disease. In this report, we identify a new therapeutic target for traumatic brain injury by studying the role of astrocytes, rather than neurons, after neurotrauma. We use in vivo multiphoton imaging and show that mechanical forces during trauma trigger intercellular calcium waves throughout the astrocytes, and these waves are mediated by purinergic signalling. Subsequent in vitro screening shows that astrocyte signalling through the 'mechanical penumbra' affects the activity of neural circuits distant from the injury epicentre, and a reduction in the intercellular calcium waves within astrocytes restores neural activity after injury. In turn, the targeting of different purinergic receptor populations leads to a reduction in hippocampal cell death in mechanically injured organotypic slice cultures. Finally, the most promising therapeutic candidate from our in vitro screen (MRS 2179, a P2Y1 receptor antagonist) also improves histological and cognitive outcomes in a preclinical model of traumatic brain injury. This work shows the potential of studying astrocyte signalling after trauma to yield new and effective therapeutic targets for treating traumatic brain injury.
Assuntos
Difosfato de Adenosina/análogos & derivados , Astrócitos/efeitos dos fármacos , Lesões Encefálicas/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Difosfato de Adenosina/farmacologia , Difosfato de Adenosina/uso terapêutico , Animais , Astrócitos/metabolismo , Lesões Encefálicas/metabolismo , Cálcio/metabolismo , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/lesões , Córtex Cerebral/metabolismo , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Ratos , Ratos Sprague-DawleyRESUMO
We present a case report and review of the literature of rib osteomyelitis in a pediatric patient presenting to the emergency department (ED) with fever and increased work of breathing. The patient was seen on a return visit to the ED after discharge with presumed viral illness approximately 12 hours prior. On the second ED visit, there was concern for occult bacteremia, and work-up ultimately revealed a subperiosteal abscess with rib osteomyelitis, a rare etiology for fever in the pediatric patient. The patient was treated with antibiotics, had surgical debridement, and fully recovered.