Malignant astrocyte swelling and impaired glutamate clearance drive the expansion of injurious spreading depolarization foci

Abstract

Spreading depolarizations (SDs) indicate injury progression and predict worse clinical outcome in acute brain injury. We demonstrate in rodents that acute brain swelling upon cerebral ischemia impairs astroglial glutamate clearance and increases the tissue area invaded by SD. The cytotoxic extracellular glutamate accumulation (>15 µM) predisposes an extensive bulk of tissue (4–5 mm2) for a yet undescribed simultaneous depolarization (SiD). We confirm in rat brain slices exposed to osmotic stress that SiD is the pathological expansion of prior punctual SD foci (0.5–1 mm2), is associated with astrocyte swelling, and triggers oncotic neuron death. The blockade of astrocytic aquaporin-4 channels and Na+/K+/Cl− co-transporters, or volume-regulated anion channels mitigated slice edema, extracellular glutamate accumulation (<10 µM) and SiD occurrence. Reversal of slice swelling by hyperosmotic mannitol counteracted glutamate accumulation and prevented SiD. In contrast, inhibition of glial metabolism or inhibition of astrocyte glutamate transporters reproduced the SiD phenotype. Finally, we show in the rodent water intoxication model of cytotoxic edema that astrocyte swelling and altered astrocyte calcium waves are central in the evolution of SiD. We discuss our results in the light of evidence for SiD in the human cortex. Our results emphasize the need of preventive osmotherapy in acute brain injury.

The Critical Role of Spreading Depolarizations in Early Brain Injury: Consensus and Contention

“…Yet cell death also develops [29]. A similar pattern of clustered SDs is also seen when aerobic metabolism in astrocytes is selectively blocked by aconitase inhibitors, which is associated with cell death [30,31]. Furthermore, this pattern is recorded in the ischemic penumbra in models of middle cerebral artery occlusion or photothrombosis in numerous studies.…”

Migraine Aura, Transient Ischemic Attacks, Stroke, and Dying of the Brain Share the Same Key Pathophysiological Process in Neurons Driven by Gibbs–Donnan Forces, Namely Spreading Depolarization

“…More suitable electrode material will hopefully enable us in the near future to record the spreading depolarization-initiated NUP in humans without these superimposed interferences ( Masvidal-Codina et al, 2018 ; Hartings, 2019 ). Another limitation is that the initial spreading depolarization component of terminal depolarization does not seem to be obligatory in all circumstances; it appears that terminal depolarization may also start directly with the NUP in the form of a simultaneous depolarization under certain conditions, e.g., astrocytic pre-damage ( Menyhart et al, 2021 ).…”

“…Glia dysfunction may accelerate neuronal death under ischemic conditions ( Largo et al, 1996a ; Kimelberg, 2005 ). Accordingly, impaired astrocyte function can abolish the typical slow spread of spreading depolarization in the ischemic zone and cause the commitment point to occur earlier ( Menyhart et al, 2021 ).…”

Resveratrol ameliorates oxaliplatin‑induced neuropathic pain via anti‑inflammatory effects in rats

“…Pro-inflammatory cytokines are mainly released by activated astrocytes ( 10 ). During the development of pain, astrocytes become reactive and last longer and undergo hyperplasia and hypertrophy within several days after injury ( 11 ). Activated astrocytes release numerous pro-inflammatory mediators and activate intracellular signaling to maintain the pain process ( 12 ).…”