Objective: The goal of this study was to characterize the effect of CDNF on motivation, stress and depression-like behavior, because most of the non-motor symptoms, which are related to Parkinson`s disease, are thought not to respond to dopaminergic treatment.

Background: Parkinson’s disease (PD) is progressive neurodegenerative disorder characterized by the motor symptoms as tremor, muscular rigidity and slowness of movements. In addition to motor symptoms, there are non-motor symptoms, which are common in early PD. Non-motor features include mild cognitive impairment, loss of memory, sleep disturbances and pain. Non-motor symptoms can debilitate patients` activities and quality of life. Currently, no effective treatment for PD is yet available. We have discovered a protein and named it Cerebral Dopamine Neurotrophic Factor (CDNF) (1). CDNF is a secreted protein and a member of a novel conserved NTFs family, protecting and repairing mammalian dopaminergic neurons in vivo. CDNF regulates ER stress and UPR intracellularly, secreting from the cells to extracellular space during ER-stress. CDNF has a therapeutic potential in rodent and non-human primates models of PD. CDNF is a potent molecule to protect and restore function of DA neurons. In addition to the prevention of apoptosis, CDNF-treatment also reduces ER stress markers in experimental model of PD (2). It was observed that CDNF affects stressed neurons. Recent data demonstrate that CDNF is possibly able to reduce α-synuclein aggregates. Importantly, CDNF is a stable protein, which diffuses in brain tissue better than any other neurotrophic factor.

Methods: Adult female and male C57BL/6JRccHsd mice received intracerebral injection of CDNF of different doses or vehicle. Forced swim test is applied for assessment of depressive-like behavior. Fear Conditioning assessed contextual and cued memory formation. Moreover, Intellicage system was used for measurements of the motivation, memory and overall activity of animals.

Results: We show that single intracerebral injection of CDNF has an effect on expression of fear by decreasing freezing time in fear condition test. CDNF shows dose-depending decreasing tendency of depression-like behavior in Porsolt forced swimming test. Moreover, CDNF increases the level of motivation is increased. We see no positive effect on learning of näive animals. Interestingly that CDNF decreased the dopamine level in prefrontal cortex and in VTA. CDNF increases the number of c-Fos positive cells in comparison with vehicle.

Conclusions: CDNF has effects on non-motor symptoms and can be a potential new drug candidate for treating these symptoms, which are related to Parkinsonian patients.

References: 1. Lindholm, P., et al. Nature, 2007. 448(7149): 73-7. 2. Voutilainen, M.H., et al., eNeuro, 2017. 4(1). e0117-16.2017.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/effect-of-cdnf-on-non-motor-symptoms-like-motivation-fear-stress-and-depression-like-behavior/