Yuyang Wang

Aneurysmal subarachnoid haemorrhage (aSAH) is a catastrophic cerebrovascular event associated with high early mortality and substantial long-term disability. Delayed cerebral ischaemia (DCI) is among its most severe complications and a principal driver of secondary neurological injury. Despite decades of research describing diverse pathophysiological mechanisms, a unifying framework for DCI pathogenesis is still lacking, and its clinical prediction remains challenging. We therefore conducted a narrative review to synthesise current understanding of the spatiotemporal evolution of brain injury following aSAH, with emphasis on integrating mechanisms across overlapping clinical phases. Acute phase events from physical effects of bleeding, including intracranial pressure elevation, hyperacute vasospasm and microvascular thrombosis, sets off the evolution of downstream brain injuries. During the early phase, converging mechanisms such as neuroinflammation, oxidative stress, spreading depolarisation and blood–brain barrier disruption coalesce into pan-vascular dysfunction and systemic hypercoagulability. Rather than representing a singular vasospastic complication, these processes collectively evolve into pathobiological states characterised by large-artery vasospasm, microvascular constriction, diffuse capillary occlusion and supply–demand mismatch, ultimately precipitating DCI and cortical infarction. This review examines the key mechanisms underlying these aforementioned processes and aims to establish mechanistic continuity across the evolving phases of injury following aSAH.

Inhibition of the sodium pump in the locust central nervous system (CNS) causes repetitive spreading depolarization (SD) and a negative ultraslow potential (NUP) providing a model for investigation of phenomena relevant to human health. We show that impairment of the blood-brain barrier accelerates the NUP but has no impact on the trajectory of SD events. Hence, rapid mechanisms of onset and recovery of ion homeostasis occur against a background of slowly increasing neural damage.

Insects provide useful models for investigating evolutionarily conserved mechanisms underlying electrical events associated with brain injury and death. Spreading depolarizations (SD) are transient events that propagate through neuropil whereas the negative ultraslow potential (NUP) is sustained and reflects accumulating damage in the tissue. We used the locust, Locusta migratoria , to investigate ion homeostasis at the blood brain barrier (BBB) during SD and NUP induced by treatment with the Na ⁺ /K ⁺ -ATPase inhibitor, ouabain. We found that sustained SD caused by the metabolic inhibitor, sodium azide, was associated with a large reduction of K ⁺ efflux through the BBB at ganglia (= grey matter) but not at connectives (= white matter). This was accompanied by a large increase in tissue resistivity but no conductance changes of identified motoneuron dendrites in the neuropil. Males recovered more slowly from ouabain-induced SD, as previously described for anoxic SD. Impairment of barrier functions of the BBB pharmacologically with cyclosporin A or DIDS, or by cutting nerve roots, accelerated the NUP, thus promoting earlier and more frequent SD, but had no effect on the temporal parameters of SD. We conclude that the mechanisms underlying onset and recovery of SD are minimally affected by the damage associated with the NUP. We suggest that future research using tissue-specific genetic approaches in Drosophila to target identified molecular structures of the BBB are likely to be fruitful. New and Noteworthy: Inhibition of the sodium pump in the locust CNS causes repetitive spreading depolarization (SD) and a negative ultraslow potential (NUP) providing a model for investigation of phenomena relevant to human health. We show that impairment of the blood brain barrier accelerates the NUP but has no impact on the trajectory of SD events. Hence, rapid mechanisms of onset and recovery of ion homeostasis occur against a background of slowly increasing neural damage.

Anoxia and similar energetic crises trigger a shutdown of central neural processing in a process of spreading depolarization (SD) that is generally pathological in mammals and protective in insects. We show that older animals are slower to recover from SD in an insect model. Moreover, preventing oxidative stress with an antioxidant speeds recovery. These findings demonstrate the role of oxidative stress in contributing to the vulnerability of the aging insect central nervous system (CNS) in energetic emergencies.

Spreading depolarization (SD) is a critical mechanism underlying central nervous system (CNS) shutdown and injury under stress, yet the initiating ion channel remains unknown. Here, we used the marine poison palytoxin (PLTX), which converts the sodium-potassium ATPase (NKA) into an open channel, to initiate SD in intact locust CNS. We show for the first time that PLTX-induced SD is rapid and recoverable in vivo, providing support that NKA conversion to a channel may be the SD-initiating mechanism.

Spreading depolarization (SD) describes the near-complete depolarization of CNS neural cells as a consequence of chemical, electrical, and metabolic perturbations. It is well-established as the central mechanism underlying insect coma and various mammalian neurological dysfunctions. Despite significant progress in our understanding, the question remains: which cation channel, if any, generates SD in the CNS? Previously, we speculated that the sodium-potassium ATPase (NKA) might function as a large-conductance ion channel to initiate SD in insects, potentially mediated by a palytoxin (PLTX)-like endogenous activator. In the current study, we evaluate the effectiveness and properties of PLTX as an SD initiator in L. migratoria . Whereas bath-applied PLTX failed to ignite SD, direct injection into the neuropil triggered SD in 57% of the preparations. Notably, PLTX-induced SD onset was significantly more rapid compared to ouabain injection and azide controls, though their electrophysiological features remained similar. Furthermore, PLTX-induced SD was recoverable and resulted in a greater frequency of repetitive SD events compared to ouabain. Surprisingly, prior PLTX treatment disrupted the onset and recovery of subsequent SD evoked by other means. PLTX injection could attenuate the amplitude and hasten the onset time of azide-induced SD. Such an effect is associated with a complete inhibition at higher doses of subsequent anoxic SD induced through azide treatment or submersion. These results show that PLTX can trigger repetitive and reversible SD-like events in locusts and simultaneously interfere with anoxic SD occurrence. We suggest that the well-documented NKA pump conversion into an open non-selective cationic channel is a plausible mechanism of SD activation in the locust CNS, warranting additional investigations.