Browsing by Author "Koskelainen, Anni"

Parkinson’s disease (PD) is a progressive neurodegenerative disorder in which dopaminergic neurons in the substantia nigra (SN) degenerate and die. This causes multiple motor symptoms such as rigidity, bradykinesia and tremor and non-motor symptoms such as depression, hallucinations, and cognitive impairment. At the time of the diagnosis, approximately 60% of the dopaminergic cells can already be lost, which underlines the importance of neurorestorative treatments for PD. Currently used treatments are only symptomatic and mostly based on levodopa, which can lose its effectiveness as the disease progresses and additionally cause significant side effects such as dyskinesia. Neurotrophic factors (NTF) such as glial cell-line derived neurotrophic factor (GDNF) and neurturin (NRTN) have been studied in clinical trials with PD patients but have shown only modest effects on motor function. Additionally, they have been administered with invasive techniques such as intraputamenal or intracerebroventricular injections which includes many risks. Mesencephalic astrocyte-derived neurotrophic factor (MANF) belongs to unconventional NTF’s with unique molecular structure and mode of action. MANF has shown both neuroprotective and neurorestorative properties for nigrostriatal dopamine system in in vivo study in rat model of PD. To enable systemic administration of MANF, the molecule has been modified by retaining only the C-terminal domain to form C-terminal MANF fragment (C-MANF). C-MANF has shown neurorestorative effects when administered intrastriatally in 6-OHDA lesioned rats and when injected subcutaneously (s.c.) in an ALS animal model. The aim of this study was to assess the effect of daily and weekly s.c administered C-MANF in 6-OHDA mouse model of PD. Cylinder and amphetamine-induced rotation tests were performed as behavioural tests and thereafter morphological studies were done by analyzing tyrosine hydroxylase (TH)+ cells in the substantia nigra pars compacta (SNpc) and optical density from TH+ axons in the striatum. Interestingly, weekly C-MANF treatment decreased the number of TH+ cells in SNpc and the density of TH+ fibers in the striatum compared to PBS. However, it decreased ipsilateral rotations and showed some positive effects in the cylinder test. On the other hand, daily C-MANF treatment increased the number of TH+ cells in SNpc and the density of TH+ fibers in the striatum but had a modest effect on ipsilateral rotations and the cylinder test compared to PBS. Although no statistically significant effects were observed in behavioral and morphological studies, s.c administered C-MANF presents a promising treatment option for PD. Particularly, daily administration of C-MANF showed neurorestorative effects in morphological studies; however, further research is required for validation. Additionally, the investigation of higher doses of C-MANF should be considered.