apelin-13-peptide and Memory-Disorders

The present study aimed to evaluate the effects of Apelin-13 on scopolamine-induced memory impairment in rats. Forty male rats were divided into five groups of eight. The control group received no intervention; the scopolamine group underwent stereotaxic surgery and received 3 mg/kg intraperitoneal scopolamine. The treatment groups additionally received 1.25, 2.5 and 5 µg apelin-13 in right lateral ventricles for 7 days. All rats (except the control group) were tested for the passive avoidance reaction, 24 h after the last drug injection. For histological analysis, hippocampal sections were stained with cresyl violet; synaptogenesis biochemical markers were determined by immunoblotting. Apelin-13 alleviated scopolamine-induced passive avoidance memory impairment and neuronal loss in the rats' hippocampus (P<0.001). The reduction observed in mean concentrations of hippocampal synaptic proteins (including neurexin1, neuroligin, and postsynaptic density protein 95) in scopolamine-treated animals was attenuated by apelin-13 treatment. The results demonstrated that apelin-13 can protect against passive avoidance memory deficiency, and neuronal loss, induced by scopolamine in male rats. Further experimental and clinical studies are required to confirm its therapeutic potential in neurodegenerative diseases.

Topics: Animals; Avoidance Learning; Hippocampus; Intercellular Signaling Peptides and Proteins; Male; Memory Disorders; Rats; Scopolamine

It has been shown that alcohol consumption by pregnant women can have detrimental effects on the developing fetus and lead to fetal alcohol spectrum disorders (FASD). Exposure to alcohol in rat pups during this period causes long-term changes in the structure of the animal's hippocampus, leading to impaired hippocampal-related brain functions such as navigation tasks and spatial memory. Apelin-13, a principal neuropeptide with inhibitory effects on neuroinflammation and brain oxidative stress production, has beneficial properties on memory impairment and neuronal injury. The protective effects of apelin-13 have been evaluated on ethanol-related neurotoxicity in the hippocampus of rat pups. Rat pups from 2 until 10 postnatal day, similar to the third trimester of pregnancy in humans, were intubated total daily dose of ethanol (5/27 g/kg/day). Immediately after intubation, 25 and 50 μg/ kg of apelin-13 was injected subcutaneously. By using Morris water maze task, the hippocampus- dependent memory and spatial learning were evaluated 36 days after birth. Then, Immunohistochemical staining was done to determine the levels of GFAP and caspase-3. ELISA assay was also performed to measure both TNF-α and antioxidant enzymes levels. The current study demonstrates that administration of apelin-13 attenuates spatial memory impairment significantly (P < 0.001). After ethanol neurotoxicity, apelin-13 could also increase the catalase level (P < 0.001), activity of total superoxide dismutase as well as glutathione concentration noticeably (P < 0.05). Other impacts of it could be mentioned as attenuating TNF-α production and also preventing lipid peroxidation (P < 0.001). In addition, the results showed that the level of GFAP as a neuroinflammation factor and the number of active caspase-3 positive cells can be decreased by apelin-13 (P < 0.01). Regarding the protective effects of apelin-13 against ethanol-induced neurotoxicity, it is a promising therapeutic choice for FASD; but more studies are needed.

Topics: Animals; Animals, Newborn; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Brain Chemistry; Drug Evaluation, Preclinical; Ethanol; Female; Fetal Alcohol Spectrum Disorders; Glial Fibrillary Acidic Protein; Hippocampus; Inflammation; Intercellular Signaling Peptides and Proteins; Lipid Peroxidation; Male; Memory Disorders; Models, Animal; Morris Water Maze Test; Nerve Tissue Proteins; Oxidative Stress; Pregnancy; Random Allocation; Rats; Rats, Wistar; Spatial Learning; Tumor Necrosis Factor-alpha

Alzheimer's disease (AD) by progressive neurodegenerative pattern is associated with autophagy stress which is suggested as a potential cause of amyloid β (Aβ) aggregation and neural loss. Apelin-13, a neuropeptide with modulatory effect on autophagy, has been shown the beneficial effects on neural cell injuries. We investigated the effect of Apelin-13 on Aβ-induced memory deficit as well as autophagy and apoptosis processes. We performed bilateral intra-CA1 injection of Aβ25-35 alone or in combination with Apelin-13. Spatial reference and working memory was evaluated using the Morris water maze (MWM) and Y-maze tests. Hippocampus was harvested on 2, 5, 10 and 21 days after Aβ injection. The light chain 3 (LC3II/I) ratio, histone deacetylase 6 (HDAC6) level, Caspase-3 cleavage, and mTOR phosphorylation were assessed using western blot technique. Intra-CA1 injection of Aβ caused impairment of working and spatial memory. We observed higher LC3II/I ratio, cleaved caspase-3 and lower HDAC6, and p-mTOR/mTOR ratio in Aβ-treated animals. Apelin-13 provided significant protection against the destructive effects of Aβ on working and spatial memory. Apelin-13 prevented the increase of LC3II/I ratio and cleaved caspase-3 on days 10 and 21 after injection of Aβ. It also limited the Aβ-induced reduction in HDAC6 expression. This implies that Apelin-13 has suppressed both autophagy and apoptosis. Our findings suggested that the neuroprotection of Apelin-13 may be in part related to autophagy and apoptosis inhibition via the mTOR signaling pathway. Apelin-13 may be a promising approach to improve memory impairment and potentially pave the way for new therapeutic plans in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Autophagy; Dose-Response Relationship, Drug; Hippocampus; Histone Deacetylase 6; Intercellular Signaling Peptides and Proteins; Male; Memory; Memory Disorders; Motor Activity; Neuroprotective Agents; Peptide Fragments; Random Allocation; Rats, Wistar; TOR Serine-Threonine Kinases

A large number of studies have demonstrated that the hippocampus has important influences on stress response and memory. The abundant expressions of apelin and its receptor APJ in the hippocampus may imply potential involvement of apelin/APJ signaling in modulating stress-related memory performance deficit. In our previous study, apelin-13 ameliorates memory performance deficit in acute stressed rats. Here, we further examined whether apelin-13 can ameliorate memory performance deficit in chronic stressed rats. Rats were exposed to chronic water-immersion restraint stress (CWIRS) for 4 weeks. After stress withdrawal, apelin-13 was intracerebroventricularly infused once a day for one week. The novel object recognition test (NORT) and Y-maze test (YMT), two hippocampus-dependent memory tasks, were performed to assess memory performance. We found that apelin-13 restored CWIRS-induced decline in the discrimination index and alternation ratio in NORT and YMT, respectively. Furthermore, apelin-13 ameliorated CWIRS-induced hippocampal BDNF expression deficit, and the TrkB receptor antagonist ANA-12 blocked the ameliorative effect of apelin-13 on memory performance deficit in CWIRS rats. The current observations indicate that apelin-13 ameliorates CWIRS-induced memory performance deficit through upregulation of BDNF in rats.

Topics: Animals; Apelin Receptors; Brain-Derived Neurotrophic Factor; Hippocampus; Intercellular Signaling Peptides and Proteins; Male; Memory; Memory Disorders; Rats, Sprague-Dawley; Stress, Physiological; Transcriptional Activation; Up-Regulation

Apelin-13 is known to be one of the predominant neuropeptides with marked protective role in circuits involved in mood disturbances. The most putative hypothesis in pathophysiology of Alzheimer's disease (AD) is Amyloid beta (Aβ) aggregation which interrupt proper function of hypothalamic-pituitary-adrenal (HPA) axis and are associated with anxiety. Here, we assessed the potential anxiolytic effect of Apelin-13 in a rodent cognitive impairment model induced by intrahippocampal Aβ 25-35 administration. We evaluated the memory impairment and anxiogenic behavior using shuttle box and Elevated plus maze apparatuses. We also measured the glucocorticoid receptor (GR) and FK506 binding protein 51 (FKBP5) expression as important markers showing the proper feedback mechanism within the HPA axis. Our findings showed that Aβ 25-35 administration induced memory impairment and anxiety behaviors. Apelin-13 exerted the anxiolytic effects and provided protection against Aβ 25-35 -induced passive avoidance memory impairment. Moreover, Apelin-13 caused an increase in GR and a decrease in FKBP5 expression levels in Aβ 25-35 treated animals. Taken together, these findings showed the anxiolytic effect of Apelin-13. This effect at least in part, may be mediated through the regulation of GR and FKBP5 expression levels which have a pivotal role in the appropriate negative feedback mechanism within the HPA axis. These data suggest that Apelin-13 might be considered as a potential neuropeptide defense that reduces anxiety along with neuroprotective effect against the Aβ 25-35 -induced injury.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anxiety; Blotting, Western; CA1 Region, Hippocampal; Hypothalamo-Hypophyseal System; Intercellular Signaling Peptides and Proteins; Male; Memory Disorders; Peptide Fragments; Pituitary-Adrenal System; Random Allocation; Rats; Rats, Wistar; Receptors, Glucocorticoid; Tacrolimus Binding Proteins

The apelin/APJ signaling is composed of the short peptide apelin usually including apelin-13, apelin-17 and apelin-36, and its receptor APJ. This signaling is abundantly expressed in limbic structures such as the hippocampus, suggesting a potential role in stress response and learning and memory. We recently reported that apelin-13 reverses acute stress-induced memory impairment and depression-like behavior in rats. Here, we further investigate whether apelin-13 reverses memory impairment and depression-like behavior in chronic stressed rats. Rats were subjected to chronic social defeat stress (CSDS), and received intracerebroventricular infusion of apelin-13 for one week after stress withdrawal. Behavioral test battery was performed to assess memory performance and depression-like behavior. Results showed that apelin-13 reversed CSDS-induced decrease in the alternation ratio and discrimination index in the Y-maze and novel object recognition tests, respectively. Apelin-13 also reversed CSDS-induced social avoidance in the social interaction test, and behavioral despair in the forced swimming and tail suspension tests. Additionally, apelin-13 did not influence locomotor activity in the open field test. These observations suggest that apelin-13 reverses memory impairment and depression-like behavior in chronic stressed rats.

Topics: Animals; Depression; Hippocampus; Intercellular Signaling Peptides and Proteins; Male; Memory; Memory Disorders; Rats; Stress, Psychological