ABSTRACT
Several hypotheses have been raised about the dual role of histamine in neurological disorders, and evidences have shown its crucial involvement in the modulation of microglia-mediated neuroinflammation. Previously, we reported that the administration of histamine induces a deleterious effect by promoting a pro-inflammatory phenotype on microglia that in turn compromises dopaminergic neuronal survival. Contrary, under lipopolysaccharide challenge, histamine inhibits the injurious effect of microglia-mediated inflammation, protecting dopaminergic neurons, suggesting that the modulation of microglial activity is dependent on the environmental context. Thus, histamine and/or histamine receptor agonists may serve to develop new therapeutic approaches to overcome neurodegenerative disorders.
Subject(s)
Dopaminergic Neurons/immunology , Histamine/immunology , Inflammation/immunology , Microglia/immunology , Neurodegenerative Diseases/immunology , Animals , Dopaminergic Neurons/pathology , Humans , Inflammation/pathology , Lipopolysaccharides/immunology , Microglia/pathology , Neurodegenerative Diseases/pathology , Parkinson Disease/immunology , Parkinson Disease/pathologyABSTRACT
Parkinson's disease (PD) is characterised by the preferential loss of dopaminergic neurones from the substantia nigra (SN) that leads to the hallmark motor disturbances. Animal and human studies suggest a beneficial effect of oestrogen to the nigrostriatal system, and the regulation of neurotrophic factor expression by oestrogens has been suggested as a possible mechanism contributing to that neuroprotective effect. The present study was designed to investigate whether the neuroprotection exerted by 17ß-oestradiol on nigrostriatal dopaminergic neurones is mediated through the regulation of glial cell line-derived neurotrophic factor (GDNF) expression. Using an in vivo rat model of PD, we were able to confirm the relevance of 17ß-oestradiol in defending dopaminergic neurones against 6-hydroxydopamine (6-OHDA) toxicity. 17ß-oestradiol, released by micro-osmotic pumps, implanted 10 days before intrastriatal 6-OHDA injection, prevented the loss of dopaminergic neurones induced by 6-OHDA. 17ß-oestradiol treatment also promoted an increase in GDNF protein levels both in the SN and striatum. To explore the relevance of GDNF increases to 17ß-oestradiol neuroprotection, we analysed, in SN neurone-glia cultures, the effect of GDNF antibody neutralisation and RNA interference-mediated GDNF knockdown. The results showed that both GDNF neutralisation and GDNF silencing abolished the dopaminergic protection provided by 17ß-oestradiol against 6-OHDA toxicity. Taken together, these results strongly identify GDNF as an important player in 17ß-oestradiol-mediated dopaminergic neuroprotection.