Abstract
Hemorrhagic stroke is a life-threatening neurological disease characterized by high mortality and morbidity. Various pathophysiological responses are initiated after blood enters the interstitial space of the brain, compressing the brain tissue and thus causing cell death. Recently, three new programmed cell deaths (PCDs), necroptosis, pyroptosis, and ferroptosis, were also found to be important contributors in the pathophysiology of hemorrhagic stroke. Additionally, blood–brain barrier (BBB) dysfunction plays a crucial role in the pathophysiology of hemorrhagic stroke. The primary insult following BBB dysfunction may disrupt the tight junctions (TJs), transporters, transcytosis, and leukocyte adhesion molecule expression, which may lead to brain edema, ionic homeostasis disruption, altered signaling, and immune infiltration, consequently causing neuronal cell death. This review article summarizes recent advances in our knowledge of the mechanisms regarding these new PCDs and reviews their contributions in hemorrhagic stroke and potential crosstalk in BBB dysfunction. Numerous studies revealed that necroptosis, pyroptosis, and ferroptosis participate in cell death after subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH). Endothelial dysfunction caused by these three PCDs may be the critical factor during BBB damage. Also, several signaling pathways were involved in PCDs and BBB dysfunction. These new PCDs (necroptosis, pyroptosis, ferroptosis), as well as BBB dysfunction, each play a critical role after hemorrhagic stroke. A better understanding of the interrelationship among them might provide us with better therapeutic targets for the treatment of hemorrhagic stroke.
Highlights
Hemorrhagic stroke, including intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH), is an important public health concern with high morbidity and mortality worldwide (Scimemi, 2018; Fang et al, 2019)
RIP1/RIP3 mediated hemin-induced neuron death, which can be reversed by nec-1 Inhibition of the interaction between IL-1 receptor 1 (IL-1R1) and the necrosome complex reduces neuron death and improves neurological functions after ICH Inhibition of RIPK3 attenuates early brain injury after SAH, possibly through alleviating necroptosis E3 ligase carboxyl terminus of Hsp70-interacting protein (CHIP) inhibits neuron necroptosis and pathological inflammation following ICH Inhibition of necroptosis by nec-1 rescues SAH-induced synaptic impairments in hippocampus Melatonin ameliorates microglial necroptosis by regulating A20 after ICH RIP3 induced neuron necroptosis involved in the pathological process after SAH Nec-1 attenuates brain swelling and blood–brain barrier (BBB) disruption and reduces necroptosis after SAH
It has been found that RIPK1 and RIPK3 were significantly decreased, with reduced necrotic cell death, under the treatment of nec-1 in mice after ICH, further suggesting that nec-1 inhibited necroptosis after ICH (Su et al, 2015)
Summary
Hemorrhagic stroke, including intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH), is an important public health concern with high morbidity and mortality worldwide (Scimemi, 2018; Fang et al, 2019). Numerous studies have attempted to inhibit necroptosis by using nec-1 to reduce cell death and improve neurological function, thereby indirectly demonstrating the existence of necroptosis in the pathophysiological development after hemorrhagic stroke (Laird et al, 2008; King et al, 2014; Majmundar et al, 2016). Nec-1 presented the capacity to reduce hematoma volume and neurovascular injury, while improving neurological outcomes after ICH in mice (King et al, 2014; Majmundar et al, 2016) They did not reveal detailed information pertaining to the cell types and mechanisms of necroptosis in their studies. It should be mentioned that nec-1 administration may suppress the apoptotic and autophagic pathways after ICH and Frontiers in Cellular Neuroscience | www.frontiersin.org
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