Inflammation and Neurogenesis (2004)

Monje and colleagues (Science 302:1760–1765, 2003) recenty evaluated the role of inflammation in delayed neurogenesis. The authors administered bacterial lipopo-lysaccharide (LPS) to adult mice, causing a systemic inflammatory response that was ultimately transmitted to the central nervous system (CNS) via interleukins. The authors found the hippocampi of these mice to have a 35% reduction in neurogenesis and a 240% increase in microglial activation 7 days after LPS administration. To determine whether these inflammatory effects could be countered pharmacologically, animals were concurrently treated with daily doses of the non-steroidal antiinflammatory drug (NSAID) indomethacin and LPS injections. The adverse effects of LPS exposure on neurogenesis were completely blocked in the animals treated with indomethacin. Interestingly, the authors report similar findings in rats treated with cranial irradiation (10 Gy daily) for 2 months, which represents a more chronic model of inflammation. A remarkable negative correlation (r = −0.93) was found between the observed numbers of proliferating neural stem cells and activated microglia. To investigate the extent to which microglial activation may cause neural stem cell dysfunction, microglia were stimulated in vitro with LPS and then co-cultured with hippocampal stem cells. Neurogenesis was reduced by 50% in these conditions. Furthermore, stem cell differentiation was reduced when cultured in conditioned medium derived from activated microglia, indicating that such cells produced soluble anti-neurogenic factors. Of these factors, IL-6 was determined to be the key inhibitory cytokine, as anti IL-6 antibodies were able to completely restore neurogenesis. More specifically, IL-6 exposure is believed to induce both a nonselective decrease in cell survival as well as decreased accumulation of neurons via stimulation of the gp130 receptor and Notch-1 pathway. The conclusion reached is that inflammation within the central nervous system causes neuronal stem cell dysfunction by activating microglia and upregulating IL-6 production within the extracellular milleu. To this effect, administration of NSAIDs has been shown to restore neurogenesis in similar animal model scenarios. These observations raise a number of important questions. Most notably, it had largely been assumed that low-grade chronic inflammation following injury to the CNS served an important function in tissue healing and was beneficial to some degree. However, the observed microglial suppression of endogenous neurogenesis calls this concept into question. Perhaps, in light of these data, this concept must be further explored to more clearly elucidate both the beneficial and deleterious consequences of prolonged inflammation. Additionally, the specific implication of IL-6 in the suppression of neurogenesis forces reconsideration of IL-6 blockade as a therapeutic modality. In addition to its well-characterized proinflammatory role, IL-6 serves a number of critical functions in the CNS, most notably promoting survival of neurons. Because of the complex and opposing effects that were considered likely to occur as the result of IL-6 blockade, it has been largely ignored as a potential therapeutic strategy. However, recent work has shown that IL-6 probably promotes neuronal survival in a low-level paracrine fashion, with its pro-inflammatory effects occurring at more distant targets. These observations suggest the possibility that attenuation of IL-6 secretion at the level of activated microglia could lead to selective attenuation of neuroinflammation and stimulation of neurogenesis, without interfering with the necessary role of IL-6 in promoting neuronal survival. While data supporting this hypothesis are forthcoming, a few potential strategies have been reported. Nakamura et. al. reported attenuation of TNF-α and IL-6 secretion by LPS activated microglial cells treated with isoproterenol in vitro. In this report, the authors describe the use of a common FDA approved NSAID, indomethacin, which might be useful in protecting the cognitive function of patients receiving not only whole brain radiation but perhaps even those undergoing gamma knife treatments where critical memory pathways receive significant doses. RICARDO J. KOMOTAR, M.D. MICHAEL SUGHRUE, B.S. E. SANDER CONNOLLY, JR., M.D. TECHNICAL & CLINICAL RESEARCH