Spreading depolarization remarkably exacerbates ischemia-induced tissue acidosis in the young and aged rat brain

Ákos Menyhárt,Eszter Farkas,Tihomir P Obrenovitch,Orsolya Ivánkovits-Kiss,Réka Tóth,Borbála É Szepes,M Tóth Orsolya,Tamás Puskás,Dániel Zölei-Szénási,Péter Makra,Ferenc Bari

doi:10.1038/s41598-017-01284-4

Abstract

Spreading depolarizations (SDs) occur spontaneously in the cerebral cortex of subarachnoid hemorrhage, stroke or traumatic brain injury patients. Accumulating evidence prove that SDs exacerbate focal ischemic injury by converting zones of the viable but non-functional ischemic penumbra to the core region beyond rescue. Yet the SD-related mechanisms to mediate neurodegeneration remain poorly understood. Here we show in the cerebral cortex of isoflurane-anesthetized, young and old laboratory rats, that SDs propagating under ischemic penumbra-like conditions decrease intra and- extracellular tissue pH transiently to levels, which have been recognized to cause tissue damage. Further, tissue pH after the passage of each spontaneous SD event remains acidic for over 10 minutes. Finally, the recovery from SD-related tissue acidosis is hampered further by age. We propose that accumulating acid load is an effective mechanism for SD to cause delayed cell death in the ischemic nervous tissue, particularly in the aged brain.

Highlights

Recurrent spreading depolarizations (SDs) have been recognized to be central to the progression of cerebral tissue damage following subarachnoid hemorrhage, stroke or traumatic brain injury[1]
We created penumbra-like conditions by inducing global forebrain ischemia in the rat, and investigated SD-related pH transients to prove that the occurrence of SD in the ischemic cortex is building up acid load to a level which has been recognized to cause tissue damage[19]
Much less is certain about distinct pHi variations of neurons, but a recent study has revealed that neurons undergo intracellular acidosis with SD onset, demonstrated by selectively loading these cells in neocortical brain slices with the pH-sensitive fluorescent dye BCECF29

Summary

Introduction

Recurrent spreading depolarizations (SDs) have been recognized to be central to the progression of cerebral tissue damage following subarachnoid hemorrhage, stroke or traumatic brain injury[1]. The most serious consequence of the occurrence of recurrent SDs after focal ischemic stroke is the conversion of viable but non-functional penumbra tissue into the irrevocably damaged core region, increasing lesions size and worsening neurological outcome[1]. Superimposed (i.e. recurrent SDs) on ischemia-induced acidosis characterized by pH values around 6.9 in the penumbra[15] It is, reasonable to propose that there is such an additive acid load, which would be an indicator of or, more importantly, a contributor to the SD-related metabolic crisis and related neurodegeneration in ischemic tissue[16]. We created penumbra-like conditions by inducing global forebrain ischemia in the rat, and investigated SD-related pH transients to prove that the occurrence of SD in the ischemic cortex is building up acid load to a level which has been recognized to cause tissue damage[19]. This approach fortifies the translational potential of this research, because stroke occurs more frequently[23], and the core region grows more rapidly at the expense of the penumbra at older age[24]

Methods

Results

Conclusion