Glucocorticoid receptor deficiency increases vulnerability of the nigrostriatal dopaminergic system: critical role of glial nitric oxide

Abstract

Glucocorticoids (GCs) exert via glucocorticoid receptors (GRs) potent anti-inflammatory and immunosuppressive effects. Emerging evidence indicates that an inflammatory process is involved in dopaminergic nigro-striatal neuronal loss in Parkinson's disease. We here report that the GR deficiency of transgenic (Tg) mice expressing GR antisense RNA from early embryonic life has a dramatic impact in "programming" the vulnerability of dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The GR deficiency of Tg mice exacerbates MPTP-induced toxicity to dopaminergic neurons, as revealed by both severe loss of tyrosine hydroxylase positive nigral neurons and sharp decreases in striatal levels of dopamine and its metabolites. In addition, the late increase in dopamine oxidative metabolism and ascorbic acid oxidative status in GR-deficient mice was far greater than in wild-type (Wt) mice. Inducible nitric oxide synthase (iNOS) was sharply increased in activated astrocytes, macrophages/microglia of GR-deficient as compared with Wt mice. Moreover, GR-deficient microglia produced three- to fourfold higher nitrite levels than Wt mice; these increases preceded the loss of dopaminergic function and were resistant to GR the inhibitory effect of GC, pointing to peroxynitrites as candidate neurotoxic effectors. The iNOS inhibitor N6-(1-iminoethyl)-L-lysine normalized vulnerability of Tg mice, thus establishing a novel link between genetic impairment of GR function and vulnerability to MPTP.

β-Amyloid-Stimulated Microglia Induce Neuron Death via Synergistic Stimulation of Tumor Necrosis Factor α and NMDA Receptors

“…Although neuronal iNOS immunoreactivity has been reported previously (Heneka et al, 2003;Grange-Messent et al, 2004;Rodrigo et al, 2004;Small et al, 2004), its expression is certainly well documented in glia as well (Xie et al, 2002;Dehmer et al, 2004;Iravani et al, 2004;Morale et al, 2004;Wang et al, 2004). To confirm that our iNOS-mediated death was occurring via neuronally generated nitric oxide, we performed immunohistochemistry to determine which cell types in our culture were expressing iNOS.…”

“…However, it is probable that several cell types as well as additional molecules contribute to neuronal death in vivo during similar inflammatory events. For example, astrocytes and microglia are also very effective at generating damaging oxidizing/nitrating species (Xie et al, 2002;Dehmer et al, 2004;Iravani et al, 2004;Morale et al, 2004;Wang et al, 2004). In vivo or during glia-neuron coculture paradigms, A␤-activated glia can certainly generate labile oxidizing species that contribute acutely to the resultant neuronal death (Xie et al, 2002).…”

Bilirubin protects astrocytes from its own toxicity by inducing up-regulation and translocation of multidrug resistance-associated protein 1 (Mrp1)

“…Of special interest, astrocytes play crucial roles in the brain response to neuronal injury and plasticity (23,24,26). In particular, functional astrocytes are required to defend neurons against reactive oxygen and nitrogen species, whereas loss of astrocyte function increases neuronal vulnerability to cell death (24,26). The modulation by UCB of the expression and localization of the Mrp1 efflux pump in astrocytes, herein reported, may thus be pivotal for protecting neurons against toxic insults, such as oxidant stress (26) and UCB itself.…”

“…Astrocytes defend neurons against oxidative insults (22,23) by scavenging reactive oxygen species and producing factors that induce antioxidant enzymes (22)(23)(24)(25)(26). Astrocytes also regulate growth, differentiation, and survival of neurons as part of bidirectional neuronal-glial interactions (27)(28)(29).…”

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…In addition to oxidative stress also other mechanisms have been proposed to be involved in selective DA neuron degeneration in PD, including excitotoxicity, intracellular calcium and metal ion rise, neurofibrillary tangle formation and disruption of the cytoskeletal transport [112]. More recently, neuroinflammation and microglial activation have been implicated in the neurodegenerative process in PD, as initially suggested by McGeer et al [155] and then by several authors ( [77,89,95,97,104,102,107,148,168]). In fact, studies accumulated over the last two decades have clearly indicated the presence of an abnormal glial response in postmortem nervous system of PD patients.…”