30 December 2003. Two recent studies confirm that local inflammation inhibits adult neurogenesis in the hippocampus and, in a promising advance, they find evidence that systemic administration of common nonsteroidal antiinflammatory drugs (NSAIDs) can restore some of the neurogenesis. These findings, from groups working in different disease models, add another angle to the rationale behind the therapeutic use of NSAIDs to protect the brain in Alzheimer's disease and in normal aging.
Already a decade ago, in-vitro data suggested that inflammatory molecules, such as the cytokines released by activated microglia, could regulate the differentiation of dentate gyrus stem cells into neurons and glia (Mehler et al., 1993). In subsequent years, researchers began to link perturbations in hippocampal neurogenesis to cognitive defects in AD and aging, as well as stroke and epilepsy. And in a separate line of research, Theo Palmer, Michelle Monje, and colleagues at Stanford University in California demonstrated last year that the cognitive damage associated with some cancer radiation therapy can be partly blamed on the inhibition of hippocampal neurogenesis (Monje et al., 2002). Monje et al. showed that, rather than damaging the precursors or differentiated neurons directly, radiation therapy disastrously perturbs the “microenvironment” of the stem cells and increases the number of activated microglia.
In the November 11 PNAS, Olle Lindvall, Christine Ekdahl, and their colleagues at Lund University in Sweden implicate inflammation as one of those microenvironment changes. These researchers have been modeling the reduction of hippocampal neurogenesis—which is accompanied by inflammation—in epilepsy. In their recent study, Lindvall and colleagues found that inflammation, whether triggered by status epilepticus or by bacterial lipopolysaccharide (LPS), directly impaired hippocampal neurogenesis in rats. The decreased neurogenesis was accompanied and probably fueled by the activation of microglia, as neurogenesis was tightly correlated with the degree of microglial activation. Minocycline, an NSAID (and an antibiotic) that specifically inhibits microglial activation, was able to significantly boost neurogenesis in spite of status epilepticus- or LPS-induced inflammation (see ARF related news story, Hirsch et al., 2003, Kriz et al., 2002).
Similar findings were reported in the December 5 Science by Monje and colleagues, who found that inflammation associated with both cranial irradiation and LPS treatment substantially reduced hippocampal neurogenesis in vivo. NSAID indomethacin reversed this reduction. The researchers also looked more closely at the possible role of microglia in creating a microenvironment disruptive to neurogenesis. They found that the proinflammatory cytokines interleukin-6 (IL-6) or tumor necrosis factor-α (TNFα) alone, but not IL-1β or interferon-γ, lowered neurogenesis (but not gliogenesis) in vitro by about half. In the presence of conditioned media from astroglia, inhibition of IL-6 alone was sufficient to restore the neurogenesis, suggesting a central role for this cytokine (see also Licastro et al., 2003, Vallieres et al., 2002).
In their editorial accompanying the recent Monje et al. article, Gerd Kempermann of the Max Delbrük Center for Molecular Medicine in Berlin, Germany, and Harald Neumann of the European Neuroscience Institute in Göttingen, Germany, note that "inhibition of neurogenesis by IL-6 might be due to increased production of astrocytes (or perhaps other glial cells) at the expense of neuronal progenitor cells, particularly as astrocytes and neuronal precursor cells seem to share a common stem cell. Alternatively, inhibition of neurogenesis by IL-6 may be a consequence of a decrease in neuronal progenitor cell proliferation or an increase in the number of these cells undergoing apoptosis."
Apropos the question of what indomethacin might be doing to protect neurogenesis, Monje et al. point out that NSAIDs may have effects on the stem cell microenvironment beyond blocking microglial release of IL-6. For example, the drugs have effects via the hypothalamic-pituitary-adrenal axis and may change vascular permeability and reduce the recruitment of proinflammatory endothelial cells.—Hakon Heimer.
Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13632-7. Epub 2003 Oct 27. Abstract
Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003 Dec 5;302(5651):1760-5. Epub 2003 Nov 13. Abstract
Kempermann G, Neumann H. Microglia: the enemy within? Science. 2003 Dec 5;302(5651):1689-90. Abstract