Investigations into the Neuroprotective Effects of Osteopontin in In Vitro and In Vivo Models of Parkinsons Disease

Osteopontin (OPN), a glycosylated phosphoprotein found in brain, is reduced in the surviving dopamine-containing neurons in the SN (SN) in Parkinson’s disease (PD). OPN prevents the death of dopaminergic neurons in cell culture and animal models of PD. This effect may be mediated through interactions between the RGD binding domain of OPN and integrin receptors resulting in an attenuation of reactive gliosis and the production glial-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). Therefore, the aim of these studies was to determine the involvement of OPN and an RGD containing peptide in the regulation of glia and neurotrophic factors in the neuroprotective properties of OPN in both in vitro and in vivo models of PD. Treatment of rat El 4 ventral mesencephalic cultures with full-length rat OPN or a peptide fragment of OPN containing the RGD binding domain protected cells from MPP+-induced toxicity. This was accompanied by an attenuation of microglia and macrophage numbers, and an increase in GDNF and BDNF levels. However, blocking GDNF function with a neutralising antibody did not inhibit OPN’s neuroprotective action. These results in vitro prompted the investigation of whether similar therapeutic effects could be found in adult rat brain. It was therefore determined whether the effects of exogenously administered OPN on gliosis and neurotrophic factor levels in rat brain could confirm the trans ferability of the in vitro findings to an in vivo model of dopamine neuron degeneration. OPN and its integrin-binding fragment protected dopaminergic neurons against 6-OHDA toxicity and attenuated 6-OHDA-induced microglial number in vivo, although neither treatment with OPN or the peptide fragment altered levels of GDNF or BDNF in the SN or striatum up to 8 days after the injection.<br/>In summary, both OPN and the RGD-containing peptide were neuroprotective and reduced reactive gliosis in vitro and in vivo and increased neurotrophic factors in embryonic primary cultures. OPN and a smaller RGD containing peptide could thus be a potential treatment for PD.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

King's College London

Year dc:date.issued

2012

Author dc:creator

• Broom, Lauren

Advisors dc:contributor.advisor

• Salvage, Sarah
• Jenner, Peter

Language dc:language

eng

Identifier

oai:kclpure.kcl.ac.uk:studenttheses/5858e8eb-3aa0-4a25-845d-350e19ffc825

OAI identifier oai:identifier

oai:kclpure.kcl.ac.uk:studenttheses/5858e8eb-3aa0-4a25-845d-350e19ffc825