Effects of adropin on learning and memory in rats tested in the Morris water maze.

Adropin is a secreted peptide, which is composed of 43 amino acids and shows an effective role in regulating energy metabolism and insulin resistance. Motor coordination and locomotor activity were improved by adropin in the cerebellum. However, it is not known whether adropin administration has an effect on spatial learning and memory. In this study, we investigated the effect of adropin on spatial learning and memory and characterized the biochemical properties of adropin in the hippocampus. Thirty male Sprague-Dawley rats were randomly divided into two groups as control and adropin groups. The control group received 0.9% NaCl intracerebroventricular for 6 days, while the adropin groups received 1 nmol of adropin dissolved in 0.9% NaCl (for 6 days). The Morris water maze, Y maze, and object location recognition tests were performed to evaluate learning and memory. Also, the locomotor activity tests were measured to assess the motor function. The expression of Akt, phospho-Akt, CREB, phospho-CREB, Erk1/2, phospho-Erk1/2, glycogen synthase kinase 3 ß (GSK3ß), phospho-GSK3ß, brain-derived neurotrophic factor (BDNF), and N-methyl-d-aspartate receptor NR2B subunit were determined in the hippocampal tissues by using western blot. Behavior tests showed that adropin significantly increase spatial memory performance. Meanwhile, the western blot analyses revealed that the phosphorylated form of the Akt and CREB were enhanced with adropin administration in the hippocampus. Also, the expression of BDNF showed an enhancement in adropin group in comparison to the control group. In conclusion, we have shown for the first time that adropin exerts its enhancing effect on spatial memory capacity through Akt/CREB/BDNF signaling pathways.

The investigation of the role of sirtuin-1 on embryo implantation in oxidative stress-induced mice.

PURPOSE: Implantation is essential for a successful pregnancy. Despite the increasing number of studies, implantation is still an unknown process. This study aimed to determine whether sirtuin-1 has a role in embryo implantation in oxidative stress-induced mice. METHODS: Pregnant mice were separated into 5 groups: control, vehicle, paraquat, SRT1720, and SRT1720+Paraquat. Paraquat is a herbicide and is used to induce oxidative stress. SRT1720 is a specific sirtuin-1 activator. Implantation and inter-implantation sites were removed in the morning of the 5th day of pregnancy after Chicago blue injection was performed. Sirtuin-1 and Forkhead box O1 (FoxO1) were detected by immunohistochemistry and Western blot while acetylated lysine was evaluated by Western blot analysis. Reactive oxygen and nitrogen species (ROS/RNS) and superoxide dismutase (SOD) activity were determined by fluorometric and spectrometric methods, respectively. RESULTS: Although there was no embryo implantation in paraquat-treated mice, 5 out of 9 SRT1720+Paraquat-treated mice had implantation sites which were significantly higher compared to the paraquat-treated group. Sirtuin-1 and FoxO1 expressions were increased at implantation sites of SRT1720-treated mice. ROS/RNS levels were decreased, while deacetylated FoxO1 levels and SOD activity were increased in SRT1720-treated mice. CONCLUSION: Our findings suggest that sirtuin-1 may play a role in embryo implantation against oxidative stress through FoxO1-SOD signaling.

The effect of chronic neuropeptide-S treatment on non-motor parameters in experimental model of Parkinson's disease.

AIM: Besides motor impairment, non-motor symptoms including cognitive decline, anxiety, and depression are observed in Parkinson's Disease (PD). The aim of this study was to investigate whether chronic administration of central neuropeptide-S (NPS) improves non-motor symptoms in 6-hydroxydopamine (6-OHDA)-induced parkinsonian rats. MATERIAL AND METHODS: Experimental PD was utilized by unilateral stereotaxic injection of the 6-OHDA into the medial forebrain bundle (MFB), while the sham-operated animals underwent the same surgical procedures. NPS (1 nmol) or vehicle was daily administered through an intracerebroventricular (icv) cannula for 7 days. Radial arm maze (RAM) test was used to evaluate the working memory; whereas, elevated plus maze (EPM) test and sucrose preference test were used to monitor the anxiety and depression status, respectively. The levels of dopamine, glutamic acid, and glutamine was determined in harvested striatal and hippocampal tissue samples. The immunoreactivities for tyrosine hydroxylase (TH) was determined using immunohistochemistry. RESULTS: In the RAM test, the 6-OHDA-induced increases in the reference and working memory errors were reduced by the central NPS administration. The decreased sucrose preference in the parkinsonian rats was increased by centrally administered NPS. The levels of dopamine levels in striatum and hippocampus were decreased in the parkinsonian rats, however, they were not altered by the centrally administered NPS. Additionally, NPS treatment significantly attenuated the 6-OHDA-induced loss of TH neuronal number. CONCLUSION: Consequently, NPS appears to be a therapeutic candidate for the treatment of non-motor complications of PD.

Nasal application of kisspeptin-54 mitigates motor deficits by reducing nigrostriatal dopamine loss in hemiparkinsonian rats.

Parkinson's Disease is a progressive neurodegenerative disorder characterized by motor symptoms resulting from the loss of nigrostriatal dopaminergic neurons. Kisspeptins (KPs) are a family of neuropeptides that are encoded by the Kiss-1 gene, which exert their physiological effects through interaction with the GPR54 receptor. In the current investigation, we investigated the prospective protective effects of central KP-54 treatments on nigrostriatal dopaminergic neurons and consequent motor performance correlates in 6-hydroxydopamine (6-OHDA)-lesioned rats. Male adult Sprague Dawley rats underwent stereotaxic injection of 6-OHDA into the right medial forebrain bundle to induce hemiparkinsonism. Following surgery, rats received chronic central treatments of nasal or intracerebroventricular KP-54 (logarithmically increasing doses) for seven consecutive days. Motor performance was evaluated seven days post-surgery utilizing the open field test and catalepsy test. The levels of dopamine in the striatum were determined with mass spectrometry. Immunohistochemical analysis was conducted to assess the immunoreactivities of tyrosine hydroxylase (TH) and the GPR54 in the substantia nigra. The dose-response curve revealed a median effective dose value of ≈3 nmol/kg for both central injections. Due to its non-invasive and effective nature, nasal administration was utilized in the second phase of our study. Chronic administration of KP-54 (3nmol/kg, nasally) significantly protected 6-OHDA-induced motor deficits. Nasal KP-54 attenuated the loss of nigrostriatal dopaminergic neurons induced by 6-OHDA. Additionally, significant correlations were observed between motor performance and nigrostriatal dopamine levels. Immunohistochemical analysis demonstrated the localization of the GPR54 within TH-positive nigral cells. These findings suggest the potential efficacy of central KP-54 on motor impairments in hemiparkinsonism.

Adropin increases with swimming exercise and exerts a protective effect on the brain of aged rats.

Adropin is a protein in the brain that decreases with age. Exercise has a protective effect on the endothelium by increasing the level of adropin in circulation. In this study, whether adropin, whose level in the brain decreases with age, may increase with swimming exercise, and exhibit a protective effect was investigated. Young and aged male Sprague Dawley rats were submitted to 1 h of swimming exercise every day for 8 weeks. Motor activity parameters were recorded at the end of the exercise or waiting periods before the animals were euthanized. Increased motor functions were observed in only the young rats that exercised regularly. Adropin levels in the plasma, and the adropin and VEGFR2 immunoreactivities and p-Akt (Ser473) levels in the frontal cortex were significantly increased in the aged rats that exercised regularly. It was also observed that the BAX/Bcl2 ratio and ROS-RNS levels decreased, while the TAC levels increased in the aged rats that exercised regularly. The results of the study indicated that low-moderate chronic swimming exercise had protective effects by increasing the level of adropin in the frontal cortex tissues of the aged rats. Adropin is thought to achieve this effect by increasing the VEGFR2 expression level and causing Akt (Ser473) phosphorylation. These results indicated that an exercise-mediated increase in endogenous adropin may be effective in preventing the destructive effects of aging on the brain.

Central neuropeptide-S treatment improves neurofunctions of 6-OHDA-induced Parkinsonian rats.

Parkinson's disease (PD) is characterized by degeneration of the dopaminergic neurons in substantia nigra (SN). The motor symptoms of PD include tremor, rigidity, bradykinesia and postural impairment. In rodents, central administration of neuropeptide-S (NPS) has been shown to induce locomotor activity, dopamine release and neuronal survival by decreasing lipid peroxidation, additionally, the NPS receptor (NPSR) was detected in SN. Accumulating findings suggest that central NPS may ameliorate the parkinsonian symptoms, however, this has been explored incompletely due to the scarcity of experimental studies. Therefore, the present study was designed to test whether central NPS treatment exerts protective and/or alleviative effects on 6-OHDA-induced rat experimental PD model. Adult male Wistar rats received acute (alleviate; 10 nmol, icv) or chronic (protective; 1 nmol, icv for 7 days) NPS treatment following the central injection of 6-OHDA in medial forebrain bundle. Motor performance tests and in vivo nigral microdialysis were performed before and 7 days after the central 6-OHDA injection. The immunoreactivities for tyrosine hydroxylase (TH), NPSR, 4-hydroxynonenal (4-HNE) and c-Fos were detected by immunohistochemistry in frozen SN sections. Our double immunofluorescence labeling studies demonstrated that NPSR is present in the nigral TH-positive neurons. Central NPS injection caused a remarkable c-Fos expression in SN; whereas, no change was observed following vehicle injection. In both chronic and acute treatment groups, the 6-OHDA-induced motor dysfunction and impaired nigral dopamine release were improved significantly. However, only chronic, but not acute treatment restored the loss of nigral TH-positive cells, while decreasing the 4-HNE immunoreactivity in SN. Our findings demonstrate that central NPS treatment not only exerts a neuroprotective action on nigral dopaminergic neurons, it also improves the striatal dopaminergic signaling. Therefore, the present study candidates the NPSR agonism as a novel therapeutic approach for PD treatment.