Nitric Oxide: Exploring the Contextual Link with Alzheimer’s Disease

Abstract

Neuronal inflammation is a systematically organized physiological step often triggered to counteract an invading pathogen or to rid the body of damaged and/or dead cellular debris. At the crux of this inflammatory response is the deployment of nonneuronal cells: microglia, astrocytes, and blood-derived macrophages. Glial cells secrete a host of bioactive molecules, which include proinflammatory factors and nitric oxide (NO). From immunomodulation to neuromodulation, NO is a renowned modulator of vast physiological systems. It essentially mediates these physiological effects by interacting with cyclic GMP (cGMP) leading to the regulation of intracellular calcium ions. NO regulates the release of proinflammatory molecules, interacts with ROS leading to the formation of reactive nitrogen species (RNS), and targets vital organelles such as mitochondria, ultimately causing cellular death, a hallmark of many neurodegenerative diseases. AD is an enervating neurodegenerative disorder with an obscure etiology. Because of accumulating experimental data continually highlighting the role of NO in neuroinflammation and AD progression, we explore the most recent data to highlight in detail newly investigated molecular mechanisms in which NO becomes relevant in neuronal inflammation and oxidative stress-associated neurodegeneration in the CNS as well as lay down up-to-date knowledge regarding therapeutic approaches targeting NO.

Rho‐associated protein kinases as therapeutic targets for both vascular and parenchymal pathologies in Alzheimer's disease

“…Possible mechanisms mediated by endothelial nitric oxide include vasodilation, maintenance of cerebral blood flow, and stimulation of SMC proliferation and regeneration (Asiimwe et al . ).…”

“…Nitric oxide modulates a broad array of physiological processes in both the parenchyma and the brain vasculature. Tissue-specific effects of nitric oxide are achieved through differential expression of the three isoforms of nitric oxide synthase: the constitutively expressed neuronal nitric oxide synthase, endothelial nitric oxide synthase (eNOS), and the inducible nitric oxide synthase (Asiimwe et al 2016). In the brain vasculature, eNOS, the isoform expressed in endothelial cells, appears to be more closely associated with AD etiology compared to the other two isoforms: In AD patients, expression of eNOS in cerebral capillaries is inversely correlated with severity of disease burden, whereas correlative relationships with inducible nitric oxide synthase and neuronal nitric oxide synthase are weaker (Jeynes and Provias 2009).…”

Anti-Inflammatory Effect of <i>o</i>-Vanillic Acid on Lipopolysaccharide-Stimulated Macrophages and Inflammation Models

“…Excessive NO production plays the main role in inflammation and arthritis. NO is an unstable molecule that triggers the formation of oxidative free radicals such as peroxynitrite (ONOO−) [32]. Therefore, the reduction in production of NO by transcriptional downregulation of iNOS gene has appreciable therapeutic effect in the treatment of inflammation.…”

The attenuating effects of plumbagin on pro-inflammatory cytokine expression in LPS-activated BV-2 microglial cells

“…The BV-2 cells can be activated by lipopolysaccharides, LPS, and the enzyme iNOS, in particular, is a microglial activation indicator (Jellinger and Stadelmann, 2001). Activated microglia cells induce iNOS synthesis that generates NO, which is essential for host defenses in response to external foreign bodies or tissue damage (Asiimwe et al, 2016; Moncada et al, 1991). The increasing levels of NO production lead to neuronal respiration inhibition and glutamate release, which might lead to the excitotoxic death of neurons and tissue damage (Bal-Price and Brown, 2001).…”