Pathologic role of glial nitric oxide in adult and pediatric neuroinflammatory diseases

It is well established that glial cells have critical roles in the inflammatory processes in the central nervous system (CNS). These cells can be activated by a variety of endogenous and exogenous stimuli (i.e. gliosis) and can produce high levels of bioactive compounds that are noxious for neuronal cell function. One of the most important molecules released by activated glial cells is the bioactive free radical nitric oxide (NO). Although NO physiologically acts as both neuromodulator and neurotransmitter in the brain, excess production of NO by glial cells has diverse harmful effects on neuronal function, causing neuronal cell injury/death. The production of NO is induced by overexpression of the inducible isoform of NO synthase (iNOS) enzyme in glial cells. In this review, we describe the possible mechanisms that underlie the iNOS-mediated overproduction of glial NO in several pediatric and adult neuropathologic conditions such as periventricular leukomalacia (PVL), Krabbe's disease, X-linked adrenoleukodystrophy (ALD) and multiple sclerosis (MS). We specifically discuss various signaling cascades that activate several transcription factors involved in the iNOS expression in both astrocytes and microglia. We also discuss the consequences of iNOS-mediated NO production in neuroinflammatory diseases including MS. A complete understanding of the regulation of iNOS expression in glial cells and the mechanisms by which iNOS-mediated NO production is involved in neuroinflammation can provide new insights into the identification of novel targets for therapeutic intervention in NO-mediated neurologic diseases.