Ketamine, despite its efficacy in treating depression, raises concerns regarding safety due to potential abuse, cognitive impairment, and bladder toxicity. Ketamine can affect the locus coeruleus (LC) norepinephrine and attention networks. This study explored the protective effects of electroacupuncture (EA) on the LC of rats exposed to repeated administration of ketamine while investigating the potential role of the Calcium CaM-dependent protein kinase II (CAMK II)/ cAMP response element binding protein (CREB) pathway in mediating EA\'s impact on ketamine-induced neuronal injury in LC.
Rats were repeatedly injected intraperitoneally with ketamine hydrochloride (50 mg/kg) once daily for seven days. Subsequently, EA was performed at the acupoints \"Zusanli\" (ST36) and \"Sanyinjiao\" (SP-6) once daily following ketamine administration. The Morris water maze test was employed to assess behavioral changes in the rats. Neuronal injury was examined using Nissl staining, and the expression of CAMK II, CREB, and phospho-CREB (p-CREB) was evaluated through immunohistochemistry and western blotting.
EA mitigated the cognitive and exploratory impairments and attenuated neuronal injury in the LC induced by repeated administration of ketamine. The expression of CAMK II and p-CREB proteins in the LC increased following 7 days of ketamine administration. However, EA treatment led to a downregulation of CAMK II and p-CREB expression.
Repeated administration of ketamine in male rats can lead to neuronal injury and neurobehavioral dysfunction. However, EA was found to ameliorate neurodegeneration in the LC and enhance neurobehavioral symptoms. This therapeutic effect of EA may be attributed to its modulation of the CAMKII/CREB pathway, thereby mitigating the aforementioned adverse effects.

UNASSIGNED: Self-injurious behavior (SIB) is a clinically challenging problem in the general population and several clinical disorders. However, the precise molecular mechanism of SIB is still not clear. In this paper, the systematic investigation of the genesis and development of SIB is conducted based on behavioral and pathophysiology studies in mink (Neovison vison) models.
UNASSIGNED: The night-vision video was used to observe the mink behavior, and the duration was a month. HE stain was performed to characterize the pathology change in the brain of a mink. IHC assay was performed to conduct the protein level detection of Iba-1, p-CREB, CBP, and p300 in the brain tissues. Elisa assay was used to examine the levels of NfL and NfH in serum and CSF of mink. The qRT-PCR assay was used to detect the expression of Bcl-2, NOR1, FoxO4, c-FOS, CBP, and p300 in brain tissues. Western blot was used to detect the protein levels of p-CREB, CBP, and p300 in brain tissues. We also used Evans Blue as a tracer to detect whether the blood-brain barrier was impaired in the brain of mink.
UNASSIGNED: The behavioral test, histopathological and molecular biology experiments were combined in this paper, and the results showed that CBP was related to SIB. Mechanism analysis showed that the dysregulation of CBP in brain-activated CREB signaling will result in nerve damage of the brain and SIB symptoms in minks. More importantly, the CBP-CREB interaction inhibitor might help relieve SIB and nerve damage in brain tissues.
UNASSIGNED: Our results illustrate that the induction of CBP and the activation of CREB are novel mechanisms in the genesis of SIB. This finding indicates that the CBP-CREB axis is critical for SIB and demonstrates the efficacy of the CBP-CREB interaction inhibitor in treating these behaviors.

OBJECTIVE: Cancer-induced bone pain (CIBP) is a kind of pain with complex pathophysiology. Proteinase-activated receptor 2 (PAR-2) is involved in CIBP. This study explored the effects of PAR-2 on CIBP rats.
METHODS: CIBP rat model was established by injecting Walker 256 rat breast cancer cells into the left tibia of female Sprague-Dawley rats and verified by tibial morphology observation, HE staining, and mechanical hyperalgesia assay. CIBP rats were injected with PAR-2 inhibitor, ERK activator, and CREB inhibitor through the spinal cord sheath on the 13th day after operation. CIBP behaviors were measured by mechanical hyperalgesia assay. On the 14th day after operation, L4-5 spinal cord tissues were obtained. PAR-2 expression, co-expression of PAR-2 and astrocyte marker GFAP, GFAP mRNA and protein levels and the ERK pathway-related protein levels were detected by Western blot, immunofluorescence double staining, RT-qPCR, and Western blot.
RESULTS: CIBP rats had obvious mechanical hyperalgesia and thermal hyperalgesia from the 7th day after modeling; mechanical hyperalgesia threshold and thermal threshold were decreased; PAR-2 was increased in spinal cord tissues and was co-expressed with GFAP. PAR-2 silencing alleviated rat CIBP by inhibiting astrocyte activation. p-ERK/t-ERK and p-CREB/t-CREB levels in CIBP spinal cord were elevated, the ERK/CREB pathway was activated, while the ERK/CREB pathway was inhibited by PAR-2 silencing. The alleviating effect of PAR-2 inhibitor on hyperalgesia behaviors in CIBP rats were weakened by ERK activator, while were partially restored by CREB inhibitor.
CONCLUSIONS: PAR-2 knockdown inhibited the ERK/CREB pathway activation and astrocyte activation, thus alleviating CIBP in rats.

Aging induces cellular and molecular changes including gene expression alteration in the brain, which might be associated with aging-induced decrease in stress coping ability. In the present study, we investigate how aging changes the ability to cope with stress and increases sensitivity to stress. Aged mice show decreased expression of SUV39H1 histone methyltransferase and increased expression of Mkp-1 in the hippocampus. The siRNA-mediated knockdown of SUV39H1 increases Mkp-1 expression and suppresses p-CREB and Bdnf expression in HT22 cells and in the hippocampus of mice. Chromatin immunoprecipitation assays indicate that the levels of SUV39H1 and methylated histone-H3 bound to the promoter of the Mkp-1 in the hippocampus are reduced in aged mice. Aged mice exhibit depression-like behavior following weak stress that does not induce depressive behavior in young mice. Rosmarinic acid, a phenolic compound that increases SUV39H1 expression, reverses stress-induced changes of SUV39H1, Mkp-1, and Bdnf expression in the hippocampus via an overlapping but distinct mechanism from those of fluoxetine and imipramine and produces anti-depressive effects. These results suggest that aging increases susceptibility to stress via downregulation of SUV39H1 and resulting changes in SUV39H1-regulated signaling pathways in the hippocampus.

Post-stroke depression(PSD) is a common complication and associates with poor physical recovery, low quality of life and high mortality after cerebral infarction. However, the pathogenesis of PSD have not been elucidated thoroughly now, and there is a lack of effective therapy in clinic. It reported that Saikosaponin A, one of the main constituents from Chinese herb Bupleurum chinense, has pharmacological activity in anti-depression. Thus, this study aimed to elucidate the potential effects and mechanisms of Saikosaponin A on the depression-like behavior after cerebral ischemic injury in rats. The rat model of PSD was induced by middle cerebral artery occlusion(MCAO) combined with chronic unpredictable mild stress(CUMS) and isolation. Behavior tests including open field test, beam-walking test, sucrose preference and forced swimming tests were performed. Western blot and immunohistochemistry were adopted to evaluate expression of phosphorylated cAMP response element binding protein(p-CREB), brain derived neurotrophic factor(BDNF) and apoptosis-related molecules in the dentate gyrus region of rat hippocampus. The TUNEL assay was used to determine neuronal apoptosis. We found that the rats subjected to MCAO combined with CUMS and isolation experienced significant depressive-like behavior. Administration of Saikosaponin A significantly ameliorated depressive-like behavior, and inhibited neuronal apoptosis, enhanced the level of p-CREB, BDNF and Bcl-2, reduced the level of Bax, Caspase-3 in the hippocampus of PSD rats. These results revealed that Saikosaponin A improved depression-like behavior and inhibited hippocampal neuronal apoptosis after cerebral ischemia, presumably through increasing the expression of BDNF, p-CREB and Bcl-2, as well as decreasing the level of Bax, Caspase-3.

Context: Oxidative imbalance-induced cognitive impairment is among the most urgent clinical concerns. Isoflurane has been demonstrated to impair cognitive function via an increase in oxidative stress. GSP has strong antioxidant capacities, suggesting potential cognitive benefits.Objective: This study investigates whether GSP pre-treatment can alleviate isoflurane-induced cognitive dysfunction in mice.Materials and methods: C57BL/6J mice were pre-treated with either GSP 25-100 mg/kg/d for seven days or GSP 100-400 mg/kg as a single dose before the 6 h isoflurane anaesthesia. Cognitive functioning was examined using the fear conditioning tests. The levels of SOD, p-NR2B and p-CREB in the hippocampus were also analysed.Results: Pre-treatment with either a dose of GSP 50 mg/kg/d for seven days or a single dose of GSP 200 mg/kg significantly increased the % freezing time in contextual tests on the 1st (72.18 ± 12.39% vs. 37.60 ± 8.93%; 78.27 ± 8.46% vs. 52.72 ± 2.64%), 3rd (93.80 ± 7.62% vs. 52.94 ± 14.10%; 87.65 ± 10.86% vs. 52.89 ± 1.73%) and 7th (91.36 ± 5.31% vs. 64.09 ± 14.46%; 93.78 ± 3.92% vs. 79.17 ± 1.79%) day after anaesthesia. In the hippocampus of mice exposed to isoflurane, GSP 200 mg/kg increased the total SOD activity on the 1st and 3rd day and reversed the decreased activity of the NR2B/CREB pathway.Discussion and conclusions: These findings suggest that GSP improves isoflurane-induced cognitive dysfunction by protecting against perturbing antioxidant enzyme activities and NR2B/CREB pathway. Therefore, GSP may possess a potential prophylactic role in isoflurane-induced and other oxidative stress-related cognitive decline.

Methotrexate (MTX) is commonly used to treat several types of cancer and autoimmune diseases. However, there is increasing concern over its organs toxicities particularly liver toxicity. Liraglutide, a glucagon like peptide-1 agonist, possesses antioxidant and anti-inflammatory features. This study aimed to explore the potential protective effect of liraglutide pre-treatment in ameliorating MTX-induced hepatotoxicity and to further investigate the underlying mechanisms. Rats received 1.2 mg/kg liraglutide intraperitoneal twice daily for 7 days before MTX. Results revealed that liraglutide significantly decreased activities of liver enzymes and oxidative stress in hepatocytes. Furthermore, NF-kB expression and related inflammatory markers (TNF-α, COX-2 and IL-6) were reduced in the pre-treatment group of liraglutide. These data validate the advantageous effects of liraglutide in MTX hepatotoxic animals. In addition, liraglutide increased the expression of the antioxidant transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf-2), along with the transcription of downstream phosphorylated cAMP response element-binding protein (pCREB) which increases the activity of Nrf-2. Additionally, caspase-3 expression/activity and BAX/Bcl-2 ratio were decreased following liraglutide pre-treatment. In conclusion, it was confirmed that liraglutide enhanced the antioxidant activity of liver cells by activating the Nrf-2 and pCREB signaling, thereby, reducing liver cell inflammation and apoptosis induced by MTX.

A cellular degeneration of two thalamic nuclei belonging to the \"limbic thalamus\", i.e., the anteroventral (AV) and mediodorsal (MD) nuclei, has been shown in patients suffering from Fatal Familial Insomnia (FFI), a lethal prion disease characterized by autonomic activation and severe insomnia. To better assess the physiological role of these nuclei in autonomic and sleep regulation, c-Fos expression was measured in rats during a prolonged exposure to low ambient temperature (Ta, - 10 °C) and in the first hours of the subsequent recovery period at normal laboratory Ta (25 °C). Under this protocol, the thermoregulatory and autonomic activation led to a tonic increase in waking and to a reciprocal depression in sleep occurrence, which was more evident for REM sleep. These effects were followed by a clear REM sleep rebound and by a rebound of Delta power during non-REM sleep in the following recovery period. In the anterior thalamic nuclei, c-Fos expression was (1) larger during the activity rather than the rest period in the baseline; (2) clamped at a level in-between the normal daily variation during cold exposure; (3) not significantly affected during the recovery period in comparison to the time-matched baseline. No significant changes were observed in either the MD or the paraventricular thalamic nucleus, which is also part of the limbic thalamus. The observed changes in the activity of the anterior thalamic nuclei appear, therefore, to be more specifically related to behavioral activation than to autonomic or sleep regulation.

Cerebrovascular dysfunction is associated with cognitive impairment in vascular dementia patients. This study aimed to explore augmented improvement of cognition and memory by aripiprazole add-on for cilostazol treatment in vascular dementia model. Male C57BL/6 mice were subjected to BCAS, and spatial probe and memory retention were examined using the Morris water maze (MWM) test. In the present study, the escape latency on the first day after 3rd week was 21.4 ± 4.0 s in sham-operated mice, and 76.3 ± 4.2 s in the vehicle-treated BCAS mice. In the spatial probe tests in the 3rd week, aripiprazole (1 mg/kg/day) showed time-dependently amelioration in spatial learning and memory impairments in contrast to 0.5 mg/kg/day. After treatment with 20 mg/kg/day of cilostazol for 3 weeks, the escape latency significantly decreased to 26.6 ± 5.8 s on the first day and further shortened to 21.6 ± 6.8 s on the fourth day. When the BCAS mice were concurrently treated with 0.5 mg/kg/day aripiprazole plus 20 mg/kg/day of cilostazol for 3 weeks, the escape latency was more shortened from 20.4 ± 1.2 s (1st day) to 14.9 ± 1.7 s on the 4th day of the 3-week trials. Furthermore, decreased spatial memory retention in BCAS mice was significantly alleviated by aripiprazole plus cilostazol cotreatment, indicating the benefit of aripiprazole add-on therapy. In line with these, significantly increased mBDNF and P-CREB levels and reduced apoptosis were identified in the BCAS mouse brain dentate gyrus by cotreatment as contrasted to each monotherapy. These results may provide the synergistic therapeutic avenues for augmented improvement of cognition and memory by cotreatment with aripiprazole plus cilostazol in cases of vascular dementia.

BACKGROUND: Post-stroke depression (PSD) is one of the most prevalent emotional disorders after stroke and often results in poor outcomes. However, the underlying physiopathologic mechanism and effective treatment of PSD remain poorly elucidated.
OBJECTIVE: To investigate whether paeoniflorin has antidepressant-like activity in a rat model of PSD.
METHODS: Rats were randomly divided into four groups: sham-operated control (Sham), PSD, paeoniflorin (with PSD) and fluoxetine group(with PSD). PSD was developed by the right middle cerebral artery occlusion followed 21 days chronic unpredictable mild stress combined (CUMS) with raised alone. Tests of sucrose preference and open field were used to assess the depression-like behavior. Neurological function was evaluated by neurological deficit score and beam balance test. Expression of phosphorylated CREB (p-CREB) and brain-derived neurotrophic factor (BDNF) in the CA1 region of the hippocampal complex was evaluated by western blot and immunofluorescence.
RESULTS: Te depressive-like behaviors markedly improved after paeoniflorin and fluoxetine treatment. Furthermore, paeoniflorin treatment significantly increased BDNF and p-CREB expression in the CA1 region.
CONCLUSIONS: Observed results suggested that paeoniflorin could ameliorate the symptoms and improve the functional capability of PSD rats, similar to the effect of fluoxetine.
BACKGROUND: PSD: post-stroke depression; CUMS: chronic unpredictable mild stress stimulation; MCAO: middle cerebral artery occlusion; OFT: open field test; SPT: sucrose preference test, NDS: neurological deficit score, BBT: beam balance test; BDNF: brain-derived neurotrophic factor protein; p-CREB: phosphorylated Cyclic-AMP responsive element binding protein.