title: Activin A protects midbrain neurons in the 6-hydroxydopamine mouse model of Parkinson's disease.
abstract: Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by a significant loss of dopaminergic neurons within the substantia nigra pars compacta (SNpc) and a subsequent loss of dopamine (DA) within the striatum. Despite advances in the development of pharmacological therapies that are effective at alleviating the symptoms of PD, the search for therapeutic treatments that halt or slow the underlying nigral degeneration remains a particular challenge. Activin A, a member of the transforming growth factor β superfamily, has been shown to play a role in the neuroprotection of midbrain neurons against 6-hydroxydopamine (6-OHDA) in vitro, suggesting that activin A may offer similar neuroprotective effects in in vivo models of PD. Using robust stereological methods, we found that intrastriatal injections of 6-OHDA results in a significant loss of both TH positive and NeuN positive populations in the SNpc at 1, 2, and 3 weeks post-lesioning in drug naïve mice. Exogenous application of activin A for 7 days, beginning the day prior to 6-OHDA administration, resulted in a significant survival of both dopaminergic and total neuron numbers in the SNpc against 6-OHDA-induced toxicity. However, we found no corresponding protection of striatal DA or dopamine transporter (DAT) expression levels in animals receiving activin A compared to vehicle controls. These results provide the first evidence that activin A exerts potent neuroprotection in a mouse model of PD, however this neuroprotection may be localized to the midbrain.
authors.affiliation: Neuroscience Department, Garvan Institute of Medical Research, Sydney, New South Wales, Australia; Faculty of Medicine, UNSW Australia, Sydney, Australia.
authors.forename: Sandy
authors.initials: S
authors.lastname: Stayte
authors.affiliation: Neuroscience Department, Garvan Institute of Medical Research, Sydney, New South Wales, Australia; School of Biotechnology and Biomolecular Sciences, UNSW Australia, Sydney, Australia.
authors.forename: Peggy
authors.initials: P
authors.lastname: Rentsch
authors.affiliation: Pharmacology Department, Bosch Institute, Sydney Medical School, The University of Sydney, Sydney, Australia.
authors.forename: Kong M
authors.initials: KM
authors.lastname: Li
authors.affiliation: Neuroscience Department, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Bryce
authors.initials: B
authors.lastname: Vissel
mesh_terms: D028341:Activins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000172:deficiency; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D065842:Pars Compacta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013238:Stereotaxic Techniques
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018696:Neuroprotective Agents; C422405:activin A; D028341:Activins; D016627:Oxidopamine; D004298:Dopamine