The chronic unpredictable mild stress model of depression has been widely used as an experimental tool to investigate human psychopathology. Our objective was to provide an update on the validity and reliability of the chronic unpredictable mild stress model, by analyzing the interrelationships among the indexes using stepwise discriminant analysis and Pearson correlation coefficient to examine the possible combinations. We evaluated the depressive rats in both the presence and the absence of chronic unpredictable mild stress, using weight change, percentage of sucrose preference, coat state, splash test, open-field test, elevated plus-maze test, forced swimming test, and Morris water maze test. The results showed that 6-week-long chronic unpredictable mild stress produces significant depression and anxiety-like behavior. The combination of body weight change, percentage of sucrose preference, coat state score, open-field score, grooming latency of splash test, immobility time in force swimming test, and platform crossing in the Morris water maze test can effectively discriminate between normal and chronic unpredictable mild stress rats. Strong interrelationships were noted among these indexes in both open-field test and elevated plus-maze test. In conclusion, there might be certain criteria for the combination of behavioral endpoints, which is advantageous to more effectively and reliably assess the chronic unpredictable mild stress induced depression model.
To investigate the mechanism of cyclooxygenase 2 (COX2) in learning and memory impairments in rats subjected to chronic unpredictable mild stress (CUMS), meloxicam was used intragastrically to inhibit the activity of cyclooxygenase 2. Moreover, cyclooxygenase 2 over-expressing or RNA interfere lentivirus was injected intraventricularly to increase or decrease the enzyme's expression, respectively. The body weights and sucrose consumption were used to analyze depressive behaviors, while the Morris water maze and step-down-type passive avoidance tests were carried out to evaluate the learning-memory functions. The levels of inflammatory cytokines were measured to estimate inflammation and the contents of cyclic adenosine monophosphate (cAMP) were used to measure the levels of the second messenger. Changes in cyclooxygenase 2 mRNA levels were analyzed using reverse transcription polymerase chain reaction. Moreover, the expression of cyclooxygenase 2, brain-derived neurotrophic factor (BDNF), prostaglandins receptor 3 (EP3), protein kinase A (PKA), cAMP response element binding protein (CREB), and phosphorylated CREB were estimated using immunohistochemical staining or western blotting. The results showed that CUMS led to significant depressive-like behaviors and learning and memory dysfunctions. Also, the cAMP levels decreased significantly, while levels of inflammatory cytokines and prostaglandins E2 increased significantly. The expressions of PKA, BDNF, phosphorylated CREB/CREB declined and cyclooxygenase 2 was increased. Meloxicam and cyclooxygenase 2 RNA interfere lentivirus reversed the changes caused by CUMS while cyclooxygenase 2-overexpressing lentivirus worsened these abnormalities. The findings also showed that CUMS increased cyclooxygenase 2 expression, which can cause learning and memory impairments, mainly through activating the hippocampal neuronal cAMP/PKA-CREB-BDNF signaling pathways.
Ischemic stroke is a major cause of death and disability all over the world. Ischemic stroke results from a temporary or permanent reduction of cerebral blood flow that leads to functional and structural damage in different brain regions. Despite decades of intense research, the beneficial treatment of stroke remains limited. In light of this, the search for effective means ameliorating cerebral ischemia-reperfusion injury (CIRI) is one of the major problems of experimental medicine and biology. Recently, the 5-Lipoxygenase (5-LO, a key enzyme metabolizing arachidonic acid to produce leukotrienes) inhibitors have been showed to protect brain against ischemic damage in animal model of cerebral ischemia. Caffeic acid, an inhibitor of 5-LO, is a phenolic compound widely distributed in medicinal plants. The aim of this study was to investigate the effect of caffeic acid on global cerebral ischemia-reperfusion injury in rats. The study was carried out on 45 rats that were randomly divided into five groups: the sham group (n = 9), I/R non-treated group (n = 9), I/R-caffeic acid group (10 mg · kg−1) (n = 9), I/R-caffeic acid group (30 mg · kg−1) (n = 9) and I/R-caffeic acid group (50 mg · kg−1) (n = 9). Global cerebral ischemia was induced by bilateral carotid artery occlusion for 20 min followed by reperfusion. Spatial learning and memory was evaluated using Morris water maze. Histopathological changes of hippocampus neurons was observed using HE staining. Superoxide dismutase (SOD, the antioxidant enzyme) activities and malondialdehyde (MDA, an oxidative stress biomarker) contents were detected. NF-κBp65 expression was detected by the methods of immunohistochemistry. Caffeic acid markedly reduced the escape latency, relieved hippocampal neurons injury and increased neuron count compared with those of I/R non-treated rat. NF-κBp65 expression and MDA content decreased significantly, and SOD activities increased significantly in hippocampus. Compared with sham group, 5-LO expression increase significantly in I/R non-treated group rat, and caffeic acid markedly reduced 5-LO expression. The results of the study suggest that caffeic acid has a significant protective effect on global cerebral ischemia-reperfusion injury in rats. The neuroprotective effects is likely to be mediated through the inhibition of 5-LO.
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