Browsing by Subject "depression"

This review focuses on neurotrophic factors, especially CDNF, and Amyotropic lateral sclerosis (ALS). This review finds out which neurotrophic factors have been studied in clinical trials of ALS and what kind of results have been got. Neurotrophic factors are important for development and function of neurons because they prevent apoptosis of neurons. They also play role in differentiation, development and migration of neurons. It is also known that many of the neurotrophic factors have protective and restorative properties. ALS is a rare neurodegenerative disease which causes the destruction of motor neurons and leads to death in three years. The disease degenerate the upper and lower motor neurons. Symptoms are muscle weakness, muscle atrophy, cramps and problems with swallowing. At the moment there is no cure for ALS so it is important to study neurotrophic factors that could prevent the progression of the disease and perhaps to protect or repair destroyed motor neurons. This is why it is important to study potential of CDNF in ALS. The experimental part consists of three different parts. The purpose of the first part study was to determine the distribution of CDNF after intraventricular delivery at different time points. CDNF was labeled with 125I (125I-CDNF). The distribution was determined by gammacounter and autoradiography. To determine the stability of the injected 125-I CDNF we performed SDS-PAGE. The second part studied the diffusion volume of CDNF after intraventricular injection with seven wild type mice. After stereotaxic surgery CDNF-immunohistochemistry staining from coronal sections was done. The last experimental part studied the effect of single intracerebral injection of CDNF on motivation, locomotor activity, anxiety and depression with male and female mice. Light-dark box, open field, rotarod, forced swim test (FST), elevated plus maze and fear conditioning were carried out with male mice. After behavioural tests mice were sacrified for HPLC-analysis. Light-dark box and IntelliCage were carried out with female mice before c-fos staining. Gammacounter and autoradiography shows that 125I-CDNF distributes widely after intracerebroventricular injection. It spread throughout to the brain and also all the way to the spinal cord after one and three hours from injection. After 24 hours 125I-CDNF was cleared so the CDNF signal was very weak. SDS-PAGE showed the stability of radioactive CDNF. CDNF increased locomotor activity and decreased anxiety in male mice. But a statistically significant difference appeared in forced swim test and fear conditioning test. HPLC-analysis supported these results partly. CDNF also increased motivation of female mice in IntelliCage experiment. C-fos staining was observed in CDNF group and PBS group so quantitative analysis should be done from these sections so that reliable conclusions could be done. However, because CDNF distributed to spinal cord and it showed some effect on locomotor activity, motivation and depression it might be potential for ALS disease.

Currently, there is an undeniable need for more effective treatments of depression. The efficacy of traditional antidepressant drugs becomes apparent after multiple weeks of treatment. New advancements in depression treatments have been made, as glutamatergic NMDA-receptor antagonist ketamine is seen to ameliorate symptoms rapidly, even only hours after drug administration. Understanding ketamine’s mechanism of action as an antidepressant could enable the development of more effective antidepressant drugs. The critical molecular level component in ketamine’s antidepressant effect is considered to be the activation of TrkB tyrosine receptor kinase B, which subsequently leads to the initiation of signaling pathways, which regulate synaptic plasticity. So far, it has not been examined; whether there is a difference in ketamine’s antidepressant effect based on the dosing-time of day. The aim of the present study was to find out if there is a variation between ketamine’s effect on synaptic plasticity and the circadian phase in which the drug is administered. Ketamine’s (200 or 50 mg/kg, i.p.) effects were studied in C57BL/6J–mice during light phase (mouse’s inactive phase) and dark phase (mouse’s active phase) of the day. The phase of the day didn’t affect the activity of TrkB signaling in its related parts (pTrkBTyr816, pGSK3βSer9, p-p70S6KTyr421/Ser424 and p-p44/42MAPKThr202/Tyr204) in prefrontal cortex samples which were analysed in Western blot assay. Ketamine increased dose-dependently the phosphorylation of GSK3βSer9 and p70S6KTyr421/Ser424 as well as decreased p-p44/42MAPKThr202/Tyr204 at 30 minutes after drug administration in both phases of the day. Ketamine (200 mg/kg, i.p.) also lowered the glucose concentration measured from the trunk blood. To examine the effect of hypoglycemia on the activity of TrkB signaling another experiment was conducted. The hypoglycemia induced by insulin detemir (6 IU/kg, i.p.) didn’t affect any measured protein phosphorylation at 60 minutes after drug administration. The results of this study support the notion of ketamine’s rapid and dosedependent induction of neuroplasticity. The possible role of hypoglycemia in ketamine's neuropharmacology should be investigated in future studies.