Phosphatidylserine: A Novel Target for Ischemic Stroke Treatment

Abstract

Over the past 40 years, research has heavily emphasized stroke treatments that directly target ischemic cascades after stroke onset. Much attention has focused on studying neuroprotective drugs targeting one aspect of the ischemic cascade. However, the single-target therapeutic approach resulted in minimal clinical benefit and poor outcomes in patients. Considering the ischemic cascade is a multifaceted and complex pathophysiological process with many interrelated pathways, the spotlight is now shifting towards the development of neuroprotective drugs that affect multiple aspects of the ischemic cascade. Phosphatidylserine (PS), known as the "eat-me" signal, is a promising candidate. PS is involved in many pathophysiological changes in the central nervous system after stroke onset, including apoptosis, inflammation, coagulation, and neuronal regeneration. Moreover, PS might also exert various roles in different phases after stroke onset. In this review, we describe the synthesis, regulation, and function of PS under physiological conditions. Furthermore, we also summarize the different roles of PS after stroke onset. More importantly, we also discuss several treatment strategies that target PS. We aim to advocate a novel stroke care strategy by targeting PS through a translational perspective.

Keywords: ischemic stroke; multiple targets; neuroprotection; phosphatidylserine.

Figure 1

The molecular mechanism for PS exposure. (A) Ca²⁺-dependent PS externalization. (B) Caspase-dependent PS externalization.

Figure 2

The physiological and pathological effects of PS. Under physiological conditions, PS is involved in cell survival and proliferation, removal of apoptotic cells, synaptic pruning, and coagulation. However, when PS is produced in excess or not removed in time, some diseases, such as cystic fibrosis, Scott syndrome, kidney stone disease, Alzheimer’s disease, and stroke, may happen.

Figure 3

The Pathophysiology role of PS externalization in ischemic stroke. (A) When the neurons underwent light stress, internal cascades of survival signaling became triggered to protect against cell death. Neurons had the ability to self-recover after light stress. However, in the subacute phase of ischemia, stressed but survived neurons in the penumbra displayed PS signal to induce microglia phagocytosis, resulting in loss of neurons. These neurons should be saved in time by reducing PS exposure or blocking PS exposure. (B) The remaining neurons were induced to die directly due to ischemia and hypoxia, which are characterized by exposure to PS in a caspase-dependent manner. These dead neurons need to be cleared in a timely manner to halt the inflammatory response. (C) During the chronic phase, stressed neurons to PS exposure were correlated with delayed neuronal loss. Research has indicated that blocking specific phagocytic pathways can prevent delayed neuronal death and functional impairment. (D) Activated platelets after ischemic stroke recruited clotting factors and promoted thrombosis.