Abstract
Cortical spreading depolarization (SD) involves activation of NMDA receptors and elicit neurovascular unit dysfunction. NMDA cannot trigger SD in newborns, thus its effect on neurovascular function is not confounded by other aspects of SD. The present study investigated if NMDA affected hypercapnia-induced microvascular and electrophysiological responses in the cerebral cortex of newborn pigs. Anesthetized piglets were fitted with cranial windows over the parietal cortex to study hemodynamic and electrophysiological responses to graded hypercapnia before/after topically applied NMDA assessed with laser-speckle contrast imaging and recording of local field potentials (LFP)/neuronal firing, respectively. NMDA increased cortical blood flow (CoBF), suppressed LFP power in most frequency bands but evoked a 2.5 Hz δ oscillation. The CoBF response to hypercapnia was abolished after NMDA and the hypercapnia-induced biphasic changes in δ and θ LFP power were also altered. MK-801 prevented NMDA-induced increases in CoBF and the attenuation of microvascular reactivity to hypercapnia. The neuronal nitric oxide synthase (nNOS) inhibitor (N-(4 S)-4-amino-5-[aminoethyl]aminopentyl-N′-nitroguanidin) also significantly preserved the CoBF response to hypercapnia after NMDA, although it didn’t reduce NMDA-induced increases in CoBF. In conclusion, excess activation of NMDA receptors alone can elicit SD-like neurovascular unit dysfunction involving nNOS activity.
Highlights
Cortical spreading depolarization (SD) involves activation of NMDA receptors and elicit neurovascular unit dysfunction
As we found a significant attenuation of CO2-reactivity after NMDA application similar to those previously observed in adult animal models following SDs, we used the NMDA-receptor inhibitor MK-801 and the selective neuronal nitric oxide synthase inhibitor (N-(4 S)-4-amino-5-[aminoethyl] aminopentyl-N′-nitroguanidin; AAAN) to pharmacologically characterize this effect
Ventilation with 5–10% CO2 resulted in graded hypercapnia that was similar in all experimental groups both for LSCI and for electrophysiology experiments (Table 1)
Summary
Cortical spreading depolarization (SD) involves activation of NMDA receptors and elicit neurovascular unit dysfunction. The present study investigated if NMDA affected hypercapniainduced microvascular and electrophysiological responses in the cerebral cortex of newborn pigs. Spreading depolarizations (SDs) are repeatable, slowly (3–4 mm/min) propagating waves of almost complete neuronal and glial depolarization at the wavefront with simultaneous depression of cortical electrical activity (cortical spreading depression) These electrophysiological changes are accompanied by transient elevations in interstitial H+, K+, glutamate levels and by a characteristic triphasic, in intact brains dominantly hyperemic microvascular response, the latter presumably helping to meet the increased metabolic demand necessary for the recovery of transmembrane ion gradients. We set out to investigate the effect of topical cortical application of NMDA on the cerebrocortical microvascular response to graded hypercapnia in a neonatal piglet model using laser-speckle
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