Advancing age and ischemia elevate the electric threshold to elicit spreading depolarization in the cerebral cortex of young adult rats

Abstract

Spreading depolarizations of long cumulative duration have been implicated in lesion development and progression in patients with stroke and traumatic brain injury. Spreading depolarizations evolve less likely in the aged brain, but it remains to be determined at what age the susceptibility to spreading depolarizations starts to decline, especially in ischemia. Spreading depolarizations were triggered by epidural electric stimulation prior and after ischemia induction in the cortex of 7-30 weeks old anesthetized rats (n ¼ 38). Cerebral ischemia was achieved by occlusion of both common carotid arteries. Spreading depolarization occurrence was confirmed by the acquisition of DC potential and electrocorticogram. Cerebral blood flow variations were recorded by laser-Doppler flowmetry. Dendritic spine density in the cortex was determined in Golgi-COX stained sections. Spreading depolarization initiation required increasingly greater electric charge with older age, a potential outcome of consolidation of cortical connections, indicated by altered dendritic spine distribution. The threshold of spreading depolarization elicitation increased with ischemia in all age groups, which may be caused by tissue acidosis and increased K þ conductance, among other factors. In conclusion, the brain appears to be the most susceptible to spreading depolarizations at adolescent age; therefore, spreading depolarizations may occur in young patients of ischemic or traumatic brain injury at the highest probability.

The impact of aging on spreading depolarization in the intact and ischemic rat brain

“…17) clearly confirms our previous reports 57,82 . However, it has not been demonstrated that the CBF response to SD remains insufficient during reperfusion, as well.…”

“…For recurrent SDs triggered in the rat intact cortex as presented here, it has been shown repeatedly that the final, long lasting oligemic element of the CBF response is detectable to the first SD only 51,57,58 . Our present data demonstrate that the recovery of tissue pH from the SD-related acidosis also depends on the rank of an SD event in a sequence.…”

The impact of age on the elicitation of spreading depolarization and the implication of prostanoids in the associated cerebral blood flow response Hertelendy Péter

“…First, the rate of SD propagation was shown to decelerate in the aging rodent brain . Also, increasingly higher concentration of KCl was required to trigger SD in brain slices obtained from middle-aged rats with respect to young adults , which was later confirmed by our research group in anesthetized rat cerebral cortex (Menyhart et al, 2015;Menyhart et al, 2017). We have previously observed, that the same, incessant, standard trigger (1 M KCl) produced a lower number of recurrent SDs in the middleaged with respect to the young adult cerebral cortex in anesthetized rats .…”

“…Curiously, in another study, the generation of a spontaneous SD in immediate response to bilateral common carotid artery occlusion was more frequently encountered in old animals than in their young counterparts (Menyhart et al, 2017). Reflecting on the evidence presented here so far, this observation may seem perplexing at first, yet it is, in fact, complementary, and makes the interpretation of existing data more subtle.…”

“…Typically, recurrent SD waves with long cumulative duration may increase neuronal injury (Pinczolits et al, 2017; (Hartings et al, 2017;Nakamura et al, 2010) by (i) NMDA glutamate receptor over-activation that induces Ca 2+ overload and neuronal excitotoxicity ; (ii) the insufficiency of the CBF response to replenish ATP necessary for the uptake of K + by the Na + /K + ATPase (Hartings et al, 2017); or (iii) causing persistent tissue acidosis, particularly in aged animals (Menyhart et al, 2017).…”