Nitric Oxide Production from Nitrite plus Ascorbate during Ischemia upon Hippocampal Glutamate NMDA Receptor Stimulation

Abstract

Nitric oxide (•NO), a diffusible free radical, is an intercellular messenger, playing a crucial role in several key brain physiological processes, including in neurovascular coupling (NVC). In the brain, glutamatergic activation of the neuronal nitric oxide synthase (nNOS) enzyme constitutes its main synthesis pathway. However, when oxygen (O2) supply is compromised, such as in stroke, ischemia, and aging, such •NO production pathway may be seriously impaired. In this context, evidence suggests that, as already observed in the gastric compartment, the reduction of nitrite by dietary compounds (such as ascorbate and polyphenols) or by specific enzymes may occur in the brain, constituting an important rescuing or complementary mechanism of •NO production. Here, using microsensors selective for •NO, we show that nitrite enhanced the •NO production in a concentration-dependent manner and in the presence of ascorbate evoked by N-methyl-D-aspartate (NMDA) and glutamate stimulation of rat hippocampal slices. Additionally, nitrite potentiated the •NO production induced by oxygen-glucose deprivation (OGD). Overall, these observations support the notion of a redox interaction of ascorbate with nitrite yielding •NO upon neuronal glutamatergic activation and given the critical role of NO as the direct mediator of neurovascular coupling may represents a key physiological mechanism by which •NO production for cerebral blood flow (CBF) responses to neuronal activation is sustained under hypoxic/acidic conditions in the brain.

Anxiolytic-like Activity, Antioxidant Properties, and Facilitatory Effects on the Short-Term Memory Retention of Molsidomine in Rats

“…NO has been shown to play an important role in the signaling and regulation of glutamatergic synapses by modulating ion channel firing, membrane fusion, fission, and compartmentalization or by facilitating protease-mediated protein degradation [ 17 ]. In particular, S-nitrosylation has been suggested to be involved in the pathogenesis of various neurodegenerative disorders, such as Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and Alzheimer’s disease [ 11 , 18 , 19 ].…”