Effects of neuroinflammation on the regenerative capacity of brain stem cells.
ABSTRACT In the adult brain, neurogenesis under physiological conditions occurs in the subventricular zone and in the dentate gyrus. Although the exact molecular mechanisms that regulate neural stem cell proliferation and differentiation are largely unknown, several factors have been shown to affect neurogenesis. Decreased neurogenesis in the hippocampus has been recognized as one of the mechanisms of age-related brain dysfunction. Furthermore, in pathological conditions of the central nervous system associated with neuroinflammation, inflammatory mediators such as cytokines and chemokines can affect the capacity of brain stem cells and alter neurogenesis. In this review, we summarize the state of the art on the effects of neuroinflammation on adult neurogenesis and discuss the use of the lipopolysaccharide-model to study the effects of inflammation and reactive-microglia on brain stem cells and neurogenesis. Furthermore, we discuss the possible causes underlying reduced neurogenesis with normal aging and potential anti-inflammatory, pro-neurogenic interventions aimed at improving memory deficits in normal and pathological aging and in neurodegenerative diseases.
[show abstract] [hide abstract]
ABSTRACT: Over expression of inflammatory cytokines in the brain may establish a state that is permissive to the onset of neurodegenerative disease. Because the occurrence of certain neurodegenerative diseases increases with age, in the present study we examined the expression of the inflammatory cytokine, interleukin-6 (IL-6), in the brain of aged mice. In an initial experiment, IL-6 was measured in crude protein extracts from brains of juvenile (1-month-old), adult (3-month-old), and aged (24-month-old) male BALB/c mice. The concentration of IL-6 in crude protein extracts from the cerebellum, cerebral cortex, and hippocampus increased with age. The increase in IL-6 was discrete, as levels in the hypothalamus were not age-dependent. To begin evaluating spontaneous IL-6 production in aging, glial cells were cultured from brains of neonate, adult, and aged mice. An age-associated increase in IL-6 mRNA and supernatant IL-6 concentration was evident, indicating glia from aged mice spontaneously express high levels of IL-6 relative to glia from adult and neonate mice. Flow cytometric analysis revealed that cultures established from aged brain compared to either adult or neonate brain comprised more microglia (i.e., MAC-1-positive cells). Furthermore, the proportion of microglia that was positive for IL-6 increased with age, whereas the proportion of astrocytes that were positive for IL-6 was not age-dependent. The present results suggest that IL-6 increases in the mouse brain with age, and that microglia cultured from aged mice spontaneously produce more IL-6 than those from neonate or adult mice. Therefore, microglia may contribute to the increased level of IL-6 present in aged brain.Journal of Neuroimmunology 02/1999; 93(1-2):139-48. · 2.96 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: Cranial radiation therapy causes a progressive decline in cognitive function that is linked to impaired neurogenesis. Chronic inflammation accompanies radiation injury, suggesting that inflammatory processes may contribute to neural stem cell dysfunction. Here, we show that neuroinflammation alone inhibits neurogenesis and that inflammatory blockade with indomethacin, a common nonsteroidal anti-inflammatory drug, restores neurogenesis after endotoxin-induced inflammation and augments neurogenesis after cranial irradiation.Science 01/2004; 302(5651):1760-5. · 31.20 Impact Factor
Article: Analysis of neurogenesis and programmed cell death reveals a self-renewing capacity in the adult rat brain.[show abstract] [hide abstract]
ABSTRACT: The adult central nervous system was thought to be very limited in its regenerative potential; however, the discovery that stem cell populations produce neurons in the adult brain highlights the dynamics of a previously assumed 'static' organ. The continuous generation of new neurons in the adult brain, nevertheless, leads to the question of whether neurogenesis is counterbalanced by an accompanying cell death in the same regions. The objective of this study was to stereologically analyze neurogenesis and programmed cell death in adult brain regions with known neurogenic activity. Using bromodeoxyuridine (BrdU) to identify newborn cells we find that within a few days of BrdU-labeling the adult dentate gyrus and olfactory bulb generate high numbers of newborn neurons. More importantly, dUTP-nick end labeling (TUNEL) reveals that areas of adult neurogenesis also contain high numbers of apoptotic cells. We conclude that programmed cell death may have an important regulatory function by eliminating supernumerous cells from neurogenic regions and may thus contribute to a self-renewal mechanism in the adult mammalian brain.Neuroscience Letters 10/2000; 291(1):17-20. · 2.11 Impact Factor