New Insights of Early Brain Injury after Subarachnoid Hemorrhage: A Focus on the Caspase Family

Abstract

Spontaneous subarachnoid hemorrhage (SAH), primarily caused by ruptured intracranial aneurysms, remains a prominent clinical challenge with a high rate of mortality and morbidity worldwide. Accumulating clinical trials aiming at the prevention of cerebral vasospasm (CVS) have failed to improve the clinical outcome of patients with SAH. Therefore, a growing number of studies have shifted focus to the pathophysiological changes that occur during the periods of early brain injury (EBI). New pharmacological agents aiming to alleviate EBI have become a promising direction to improve outcomes after SAH. Caspases belong to a family of cysteine proteases with diverse functions involved in maintaining metabolism, autophagy, tissue differentiation, regeneration, and neural development. Increasing evidence shows that caspases play a critical role in brain pathology after SAH. Therefore, caspase regulation could be a potential target for SAH treatment. Herein, we provide an overview pertaining to the current knowledge on the role of caspases in EBI after SAH, and we discuss the promising therapeutic value of caspase-related agents after SAH.

Keywords: Subarachnoid hemorrhage; caspase regulation; caspase-related agents; caspases; cerebral vasospasm; early brain injury.

Fig. (1)

Mechanism of Early Brain Injury After SAH. Abbreviations: SAH, subarachnoid hemorrhage; ICP, intracranial pressure; CBF, cerebral blood flow; BBB, blood-brain barrier.

Fig. (2)

Schematic illustration of signaling pathways related to caspases during SAH. Caspases have been implicated in BBB disfunction, oxidative stress, neuroinflammation, apoptosis, necroptosis, pyroptosis and autophagy after SAH. Apoptosis can proceed in two ways: intrinsic or extrinsic. Intrinsic apoptosis is initiated by a death-inducing stimulus, which causes activation of p53 and pro-apoptotic Bcl-2 proteins such as Bax and Bak. This leads to MOMP and activation of a death-inducing platform called the apoptosome. Following this caspase-9 is cleaved and activates other effector caspases such as caspase-3. Extrinsic or receptor-mediated apoptosis involves complex formation by DISC, activation of caspase-8, which initiates apoptosis by directly activating effector caspases. Depending on ligands (TNF and Fas) different complexes are formed. TNF stimulates TNFR1 that recruits TRADD, RIPK1, TRAFs and IAPs into a complex called TRADD-dependent complex I. Subsequent removal of polyubiquitin on RIPK1, dissociates this complex and allows it to interact with TRADD, procaspase-8, and FADD as complex IIa/DISC. This results in caspase-8 activation, leading to apoptosis. Under the conditions that also the activation of caspase-8 is hampered (complex IIb), RIPK1 will recruit RIPK3 resulting in the phosphorylation of MLKL and the induction of necroptosis. Necroptosis can also occur following stimulation of LPS by causing RIPK3 phosphorylation. Some caspases such as caspase-3, mediate cleavage of crucial autophagic proteins and thus indirectly control autophagy. Recognition of DAMPs by their respective inflammasome-sensors such as NLRP3 leads to the assembly of a multi- protein complex termed the inflammasome. Consequently, caspase-1 undergoes autoproteolytic processing to lock the protease in its active form. Caspase-1 directly cleaves its substrates gasdermin D and the pro-inflammatory cytokines pro-IL-1b and pro-IL-18. The 31kDa N-terminal cleavage fragment of Gsdmd forms pores in the host cell membrane, thereby mediating the release of cytoplasmic content, the mature IL-1b and IL-18 and the other DAMPs IL-1a, HMGB1, and ATP. Alternatively, detection of cytosolic LPS coming from Gram-negative bacteria by the murine caspase-11 or its human orthologs caspases-4 and -5 initiates activation of the proteolytic activity thereby cleaving gasdermin D resulting in pyroptosis. Abbreviations: MOMP, mitochondrial outer membrane permeabilization; DISC: death-domain-containing proteins; FADD, FAS-associated death domain; TNFR1, TNF receptor 1; TRADD, TNF receptor-associated death domain; RIPK1, receptor-interacting protein kinase 1; RIPK3, receptor-interacting protein kinase 3; MLKL, mixed lineage kinase domain-like; DAMPs, danger-associated molecular patterns.