Modulation of hippocampal neurogenesis by inflammatory and anti-inflammatory agents in adult rats -

Abstract

Background: Constant formation of functional neurons from neural stem and progenitor cells in postnatal stages has been observed in two main neurogenic brain regions: the subgranular zone (SGZ) in the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ) in the lateral ventricles. Adult neurogenesis, however, is prone to alterations by different physiological, pathological and pharmacological stimuli. One flaunting factor is neural inflammation which has been implicated in neurodegenerative disorders. Our aim is to demonstrate that inflammation, induced by intracerebroventricular (icv) injection of Endotoxin (ET) altersthe neurogenic niche of adult rats by decreasing neurogenesis. Methods: Adult Sprague-Dawley male rats (250-300g) received stereotaxic icv injections of ET (6 µg in 1.5 µl) or sterile saline as described previously (Safieh-Garabedian et al., Neuropharmacology, 2011,60:496-504). Rats then received 3 injections (66mg-Kg-injection; ip) of 5’-bromo-2’-deoxyuridine (BrdU) and were perfused at different time intervals (Days 1, 2, 3, 6, and 9). The non-steroidal anti-inflammatory drug (NSAID) Piroxicam was given as daily injections to rats perfused at day 3. Behavioral pain tests were performed and BrdU positive cells were counted in the DG of the hippocampus. Results: ET injection resulted in a significant decrease (p 0.0002) of adult neurogenesis in rats at day 2 (439.75±81.16) and day 3 (479.87±94.69) when compared to sham (966.16±49.60). This was followed by a rebound at day 6 (1124.80±161.18) then recovered the basal levels at day 9 (997±87.23). These alterations were accompanied by thermal hyperalgesia that peaked at day 3. Daily treatment with Piroxicam (12.5 mg-kg; ip) was able to alleviate the ET effects on neurogenesis and reduce hyperalgesia. Conclusion: The current study sheds light on the negative impact of discrete neuro-inflammation on neurogenesis in the hippocampal formation. Thus, understanding the adverse effec