title: Interactions between nitric oxide and corticosterone in the regulation of progenitor cell proliferation in the dentate gyrus of the adult rat.
abstract: It is well established that L-NAME, a generic NOS inhibitor, stimulates neurogenesis in the dentate gyrus of the adult rat and corticosterone reduces it. These experiments explore the interaction between L-NAME and corticosterone. L-NAME (50 mg/kg), as expected, increased proliferation, but also lowered plasma corticosterone levels. However, the stimulating action of L-NAME depends on the presence of rhythmic changes in plasma corticosterone, as it is abolished in rats treated with a subcutaneous implant of corticosterone, which flattens the diurnal rhythm. Adrenalectomized rats implanted with corticosterone also failed to respond to L-NAME. Giving them a single daily injection of corticosterone (2 mg/kg) in an attempt to replicate the diurnal rhythm restored the sensitivity of the progenitor cells to L-NAME. The mechanism for this result remains to be investigated. Excess corticosterone given by daily injection (40/mg/kg) reduced proliferation but did not alter the response to L-NAME, even though this occurred from a lower baseline. nNOS was demonstrable only in the inner (proliferative) layer of the dentate gyrus in control rats, and did not alter following excess corticosterone treatment. iNOS was detectable at low levels in control rats, but was increased markedly following corticosterone. eNOS was evident throughout the dentate gyrus, and also increased after corticosterone (particularly in the hilus). Aminoguanidine (100 mg/kg/day; an iNOS antagonist) significantly increased proliferation in corticosterone-treated rats (40 mg/kg/day) but not in controls without additional corticosterone, confirming that iNOS plays a role in corticosterone-regulated neurogenesis. Corticosterone may thus act on progenitor cells in part at least through increased nitric oxide (NO) formation. The effects of reduced NO on neurogenesis may rely on a dual mechanism: corresponding reductions in plasma corticosterone and increased induction of iNOS (and/or eNOS) within the dentate gyrus. The possibility that NO acts downstream of glucocorticoids in the dentate gyrus is suggested.
authors.affiliation: Department of Physiology, Development and Neuroscience and Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, UK.
authors.forename: Scarlett B
authors.initials: SB
authors.lastname: Pinnock
authors.forename: Rubika
authors.initials: R
authors.lastname: Balendra
authors.forename: Melanie
authors.initials: M
authors.lastname: Chan
authors.forename: Laurence T
authors.initials: LT
authors.lastname: Hunt
authors.forename: Lauvence T
authors.initials: LT
authors.lastname: Hunt
authors.forename: Tabitha
authors.initials: T
authors.lastname: Turner-Stokes
authors.forename: Joe
authors.initials: J
authors.lastname: Herbert
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology; D003345:Corticosterone / Q000097:blood / Q000494:pharmacology*; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester; D003345:Corticosterone