Chronic corticosterone administration dose-dependently modulates A beta((1-42))- and NMDA-induced neurodegeneration in rat magnocellular nucleus basalis

The impact of glucocorticoids on beta-amyloid((1-42)) (A beta((1-42))) and NMDA-induced neurodegeneration was investigated in vivo. A beta((1-42)) or NMDA was injected into the cholinergic magnocellular nucleus basalis in adr enalectomized (ADX) rats, ADX rats supplemented with 25%, 100%, 2 x 100% co rticosterone pellets, or sham-ADX controls. A beta((1-42))- or NMDA-induced damage of cholinergic nucleus basalis neurones was assessed by quantitativ e acetylcholinesterase histochemistry, Plasma concentrations of corticoster one and cholinergic fibre loss after A beta((1-42)) or NMDA injection showe d a clear U-shaped dose-response relationship. ADX and subsequent loss of s erum corticosterone potentiated both the A beta((1-42)) and NMDA-induced ne urodegeneration. ADX + 25% corticosterone resulted in a 1.0-90 nM plasma co rticosterone concentration, which significantly attenuated the A beta((1-42 )) and NMDA neurotoxicity. ADX + 100% corticosterone (corticosterone concen trations of 110-270 nM) potently decreased both A beta((1-42))- and NMDA-in duced neurotoxic brain damage, In contrast, high corticosterone concentrati ons of 310-650 nM potentiated A beta((1-42))- and NMDA-triggered neurodegen eration. In conclusion, chronic low or high corticosterone concentrations i ncrease the vulnerability of cholinergic cells to neurotoxic insult, while slightly elevated corticosterone levels protect against neurotoxic injury. Enhanced neurotoxicity of NMDA in the presence of high concentrations of sp ecific glucocorticoid receptor agonists suggests that the corticosterone ef fects are mediated by glucocorticoid receptors,