Neurogenesis, neural stem cells and nitric oxide in neuroinflammation

Abstract

We investigated whether nitric oxide (NO) is produced in MS patients, determining the concentrations of its oxidation products (NOx) in CSF. The total levels of NOx in CSF were significantly increased in all MS groups as compared to healthy controls and tension headache patients. Since CSF nitrite levels correlated with clinical disease activity the determination of nitrite levels may be used as a surrogate marker for disease activity.

Systemically and intrathecally produced nitric oxide might play different roles in EAE pathogenesis. We therefore administered the NOS inhibitor L-NAME intrathecally or systemically via osmotic minipumps to DA rats with MOG-induced experimental autoimmune encephalomyelitis (EAE). NOS inhibition decreased EAE severity, the extent of CNS inflammation and demyelination. Intrathecal administration was more effective than systemic administration. The observed effect was accompanied by enhanced anti-MOG IgG1 production.

Next we examined if NOS and reactive oxygen species (ROS) inhibition would be beneficial in a traumatic brain injury model (TBI). We administered NOS inhibitor (LNAME) alone and in combination with nitrone radical scavenger (S-PBN) after TBI. NOS inhibition and ROS scavenging significantly reduced neuronal degeneration, possibly via limiting peroxynitrite formation and thus promoting neuronal survival. The combination of LNAME and S-PBN was neuroprotective, but no additive effect was achieved.

We also studied the possible activation and differentiation of central nervous system (CNS) stem cells in EAE lesioned spinal cord. Labelled stem cells from the ependymal layer in the spinal cord respond to the MS-like condition by proliferation and migration into demyelinated areas. Some of the theses cells expressed oligodendrocyte and astrocyte markers. Macrophage attacks on the stem cell population were observed.

We have also addressed the question whether neurogenesis can occur in neuroinflammatory lesions. We found that the progeny of labelled ependymal cells proliferate and migrate to the neuroinflammatory lesions, differentiating into cells expressing neuronal markers. These cells were immunoreactive for markers of cells undergoing cell-proliferation. Freshly isolated DiI labelled cells from spinal cord lesions were able to fire overshooting action potentials comparable to those of immature neurons. We provide the first evidence for neurogenesis in neuroinflammatory lesions in the adult spinal cord.

Accordingly, we investigated the effects of NO exposure on the fate acquisition of neuronal stem cells. Neurogenesis was suppressed and gliogenesis promoted. The suggested mechanisms were related to downregulation of neurogenin-2 and activation of the JAK/STAT- 1 signal transduction pathway.