Nitric oxide from inflammatory‐activated glia synergizes with hypoxia to induce neuronal death

Abstract

Inflammatory-activated glia are seen in numerous central nervous system (CNS) pathologies and can kill nearby neurons through the release of cytotoxic mediators. Glia, when activated, can express the inducible isoform of nitric oxide synthase (iNOS) producing high levels of nitric oxide (NO), which can kill neurons in certain conditions. We show, however, that inflammatory activation of glia in a mature culture of cerebellar granule neurons and glia causes little or no neuronal death under normal (21%) oxygen conditions. Similarly, hypoxia (2% oxygen) or low levels of an NO donor (100 microM DETA/NO) caused little or no neuronal death in nonactivated cultures. If inflammatory activation of glia or addition of NO donor was combined with hypoxia, however, extensive neuronal death occurred. Death in both cases was prevented by the N-methyl-D-aspartate (NMDA) receptor blocker MK-801, implying that death was mediated by the glutamate receptor. Low levels of NO were found to increase the apparent K(M) of cellular oxygen consumption for oxygen, probably due to NO-induced inhibition of mitochondrial respiration, in competition with oxygen, at cytochrome oxidase. Necrotic death, induced by hypoxia plus DETA/NO, was increased further by deoxyglucose, an inhibitor of glycolysis, suggesting that necrosis was mediated by energy depletion. Hypoxia was found to be a potent stimulator of microglia proliferation, but this proliferation was not significant in inflammatory-activated cultures. These results suggest that low levels of NO can induce neuronal death under hypoxic conditions, mediated by glutamate after NO inhibition of respiration in competition with oxygen. Brain inflammation can thus sensitize to hypoxia-induced death, which may be important in pathologies such as stroke, neurodegeneration, and brain aging.

Cerebrolysin protects against rotenone-induced oxidative stress and neurodegeneration

“…64 Low levels of nitric oxide can also induce neuronal death under hypoxic conditions by inhibiting mitochondrial respiration in competition with oxygen at cytochrome oxidase. 65 Nitric oxide synthesized by the neuronal NOS might be also involved in neurotoxic effects of rotenone. 66 The present study provides evidence that the administration of cerebrolysin had reduced the increase in nitric oxide level in different brain regions caused by rotenone.…”

Neuronal-glial Interactions Define the Role of Nitric Oxide in Neural Functional Processes

“…Accordingly, NMDA receptor-mediated toxicity towards cerebellar granule neurons was potentiated by co-culture with immunostimulated microglia or by co-exposure to an NO donor [107]. Additional evidences on the neurotoxic role of excessive NO production from activated microglia comes from studies demonstrating exacerbation of damage due to excitotoxic-like conditions, such as glucose deprivation and hypoxia [108-110]. Moreover it has been demonstrated that nitric oxide caused neuronal death not only via NMDA receptors, but it could also act directly upon immature neurons, through a not fully defined mechanism [111].…”

Switching from astrocytic neuroprotection to neurodegeneration by cytokine stimulation

“…The pathological and toxicological role of astrocytes may be highly model-specific, as they contribute to the metabolism of some toxicants (Schildknecht et al 2012) and they show a large plasticity, e.g., by taking the role of stem cells (Robel et al 2011). Moreover, astrocytes and microglia produce a large variety of different mediators that may affect neurons, e.g., direct excitotoxicants, like glutamate, or indirect excitotoxic mediators, such as NO (Bal-Price and Brown 2001;Bal-Price et al 2002;Gandelman et al 2010;Gegg and Clark 1036;Mander et al 2005), lipid mediators/small molecules (Mayo et al 2014;Simon et al 2002;Wang et al 2012), reactive oxygen species (Ma et al 2013), proteases (cathepsin B), cytokines (Lee et al 2013a;Mattson et al 1997), complement factors (Pekny et al 2007;Walker et al 1998), but their respective contribution to human pathology needs further clarification (Lioy et al 2011;Williams et al 2014). Lack of knowledge of the relevant damage mediators has prevented the development of targeted therapies for modulation of astrogliosis, but some drugs like riluzole (Carbone et al 2012) or CEP1347 (Falsig et al 2004b) have astrocyte-modulating properties besides their main mode of action.…”