Pegylated granulocyte-colony stimulating factor as a therapeutic option in Parkinson's disease

Abstract

Symptoms of Parkinson's disease (PD) are caused by a slowly progressive degeneration of dopaminergic neurons in the substantia nigra. The hematopoietic granulocyte-colony stimulating factor (G-CSF) plays a crucial role in controlling the number of neutrophil progenitor cells. Its function is mediated via the G-CSF receptor, which is expressed not only on hematopoietic cells but also by dopaminergic neurons of the substantia nigra (SN), suggesting that G-CSF might be neuroprotective for dopaminergic neurons and a candidate molecule for the treatment of PD. Recently, we provided prove-of-principle that daily G-CSF (Filgrastim) application significantly reduces dopaminergic cell death in in vitro and in vivo models of PD. Indicating preservation of dopaminergic terminals in the striatum, G-CSF alleviated striatal dopamine depletion after MPTP application in G-CSF-treated mice. Consequently, we tested pharmacokinetically improved G-CSF variants (Pegfilgrastim), with an extended serum half-life compared to conventional G-CSF. Subcutaneous application of Pegfilgrastim only every 3rd day rescued about 50% of dopaminergic substantia nigra neurons from MPTP – induced apoptosis in vitro and in vivo. Thus, pharmacologically modified forms of G-CSF with a longer half-life could improve patient compliance and acceptance of G-CSF as a neuroprotective therapy for PD.