IL-4 Inhibits IL-1β-Induced Depressive-Like Behavior and Central Neurotransmitter Alterations

It has been known that activation of the central innate immune system or exposure to stress can disrupt balance of anti-/proinflammatory cytokines. The aim of the present study was to investigate the role of pro- and anti-inflammatory cytokines in the modulation of depressive-like behaviors, the hormonal and neurotransmitter systems in rats. We investigated whether centrally administered IL-1β is associated with activation of CNS inflammatory pathways and behavioral changes and whether treatment with IL-4 could modulate IL-1β-induced depressive-like behaviors and central neurotransmitter systems. Infusion of IL-4 significantly decreased IL-1β-induced anhedonic responses and increased social exploration and total activity. Treatment with IL-4 markedly blocked IL-1β-induced increase in PGE2 and CORT levels. Also, IL-4 reduced IL-1β-induced 5-HT levels by inhibiting tryptophan hydroxylase (TPH) mRNA and activating serotonin transporter (SERT) in the hippocampus, and levels of NE were increased by activating tyrosine hydroxylase (TH) mRNA expression. These results demonstrate that IL-4 may locally contribute to the regulation of noradrenergic and serotonergic neurotransmission and may inhibit IL-1β-induced behavioral and immunological changes. The present results suggest that IL-4 modulates IL-1β-induced depressive behavior by inhibiting IL-1β-induced central glial activation and neurotransmitter alterations. IL-4 reduced central and systemic mediatory inflammatory activation, as well as reversing the IL-1β-induced alterations in neurotransmitter levels. The present findings contribute a biochemical pathway regulated by IL-4 that may have therapeutic utility for treatment of IL-1β-induced depressive behavior and neuroinflammation which warrants further study

Decreased Interleukin-4 Release from the Neurons of the Locus Coeruleus in Response to Immobilization Stress

It has been demonstrated that immobilization (IMO) stress affects neuroimmune systems followed by alterations of physiology and behavior. Interleukin-4 (IL-4), an anti-inflammatory cytokine, is known to regulate inflammation caused by immune challenge but the effect of IMO on modulation of IL-4 expression in the brain has not been assessed yet. Here, it was demonstrated that IL-4 was produced by noradrenergic neurons in the locus coeruleus (LC) of the brain and release of IL-4 was reduced in response to IMO. It was observed that IMO groups were more anxious than nontreated groups. Acute IMO (2 h/day, once) stimulated secretion of plasma corticosterone and tyrosine hydroxylase (TH) in the LC whereas these increments were diminished in exposure to chronic stress (2 h/day, 21 consecutive days). Glucocorticoid receptor (GR), TH, and IL-4-expressing cells were localized in identical neurons of the LC, indicating that hypothalamic-pituitary-adrenal- (HPA-) axis and sympathetic-adrenal-medullary- (SAM-) axis might be involved in IL-4 secretion in the stress response. Accordingly, it was concluded that stress-induced decline of IL-4 concentration from LC neurons may be related to anxiety-like behavior and an inverse relationship exists between IL-4 secretion and HPA/SAM-axes activation

Chronic Treatment with Squid Phosphatidylserine Activates Glucose Uptake and Ameliorates TMT-Induced Cognitive Deficit in Rats via Activation of Cholinergic Systems

The present study examined the effects of squid phosphatidylserine (Squid-PS) on the learning and memory function and the neural activity in rats with TMT-induced memory deficits. The rats were administered saline or squid derived Squid-PS (Squid-PS 50 mg kg−1, p.o.) daily for 21 days. The cognitive improving efficacy of Squid-PS on the amnesic rats, which was induced by TMT, was investigated by assessing the passive avoidance task and by performing choline acetyltransferase (ChAT) and acetylcholinesterase (AchE) immunohistochemistry. 18F-Fluorodeoxyglucose and performed a positron emission tomography (PET) scan was also performed. In the passive avoidance test, the control group which were injected with TMT showed a markedly lower latency time than the non-treated normal group (P < 0.05). However, treatment of Squid-PS significantly recovered the impairment of memory compared to the control group (P < 0.05). Consistent with the behavioral data, Squid-PS significantly alleviated the loss of ChAT immunoreactive neurons in the hippocampal CA3 compared to that of the control group (P < 0.01). Also, Squid-PS significantly increased the AchE positive neurons in the hippocampal CA1 and CA3. In the PET analysis, Squid-PS treatment increased the glucose uptake more than twofold in the frontal lobe and the hippocampus (P < 0.05, resp.). These results suggest that Squid-PS may be useful for improving the cognitive function via regulation of cholinergic enzyme activity and neural activity

Acupuncture Stimulation Attenuates Impaired Emotional-Like Behaviors and Activation of the Noradrenergic System during Protracted Abstinence following Chronic Morphine Exposure in Rats

The purpose of this study was to evaluate whether acupuncture stimulation attenuates withdrawal-induced behaviors in the rats during protracted abstinence following chronic morphine exposure. To do this, male rats were first exposed to morphine gradually from 20 to 100 mg/kg for 5 days, and subsequently naloxone was injected once to extend despair-related withdrawal behaviors for 4 weeks. Acupuncture stimulation was performed once at the SP6 (Sanyinjiao) acupoint on rat’s; hind leg for 5 min during protracted abstinence from morphine. The acupuncture stimulation significantly decreased despair-like behavior deficits in the forced swimming test and low sociability in the open-field test as well as increased open-arm exploration in the elevated plus maze test in the last week of 4-week withdrawal period. Also the acupuncture stimulation significantly suppressed the increase in the hypothalamic corticotropin-releasing factor (CRF) expression, the decrease in the tyrosine hydroxylase expression in the locus coeruleus, and the decrease in the hippocampal brain-derived neurotrophic factor mRNA expression, induced by repeated injection of morphine. Taken together, these findings demonstrate that the acupuncture stimulation of SP6 significantly reduces withdrawal-induced behaviors, induced by repeated administration of morphine in rats, possibly through the modulation of hypothalamic CRF and the central noradrenergic system

Ginseng Purified Dry Extract, BST204, Improved Cancer Chemotherapy-Related Fatigue and Toxicity in Mice

Cancer related fatigue (CRF) is one of the most common side effects of cancer and its treatments. A large proportion of cancer patients experience cancer-related physical and central fatigue so new strategies are needed for treatment and improved survival of these patients. BST204 was prepared by incubating crude ginseng extract with ginsenoside-β-glucosidase. The purpose of the present study was to examine the effects of BST204, mixture of ginsenosides on 5-fluorouracil (5-FU)-induced CRF, the glycogen synthesis, and biochemical parameters in mice. The mice were randomly divided into the following groups: the naïve normal (normal), the HT-29 cell inoculated (xenograft), xenograft and 5-FU treated (control), xenograft + 5-FU + BST204-treated (100 and 200 mg/kg) (BST204), and xenograft + 5-FU + modafinil (13 mg/kg) treated group (modafinil). Running wheel activity and forced swimming test were used for evaluation of CRF. Muscle glycogen, serum inflammatory cytokines, aspartic aminotransferase (AST), alanine aminotransferase (ALT), creatinine (CRE), white blood cell (WBC), neutrophil (NEUT), red blood cell (RBC), and hemoglobin (HGB) were measured. Treatment with BST204 significantly increased the running wheel activity and forced swimming time compared to the control group. Consistent with the behavioral data, BST204 markedly increased muscle glycogen activity and concentrations of WBC, NEUT, RBC, and HGB. Also, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), AST, ALT, and CRE levels in the serum were significantly reduced in the BST204-treated group compared to the control group. This result suggests that BST204 may improve chemotherapy-related fatigue and adverse toxic side effects

Acori graminei rhizoma Ameliorated Ibotenic Acid-Induced Amnesia in Rats

In the present study, we investigated the effects of Acori graminei rhizoma (AGR) on learning and memory for the Morris water maze task and on the central cholinergic system of the rats with excitotoxic medial septum (MS) lesion. On the water maze test, the rats were trained to find a platform that was in a fixed position during 6 days and then they received a 60 s probe trial in which the platform was removed from the pool on the 7th day. Ibotenic lesioning of the MS impaired the performance on the maze test and it caused degeneration of choline acetyltransferase and acetylcholine esterase in the hippocampus, which are markers of the central cholinergic system. Daily administrations of AGR (100 mg kg−1, i.p.) for 21 consecutive days produced reversals of the ibotenic acid-induced deficit in learning and memory. These treatments also reduced the loss of cholinergic immunoreactivity in the hippocampus that was induced by ibotenic acid. These results demonstrated that AGR ameliorated learning and memory deficits through their effects on the central nervous system, and neuroprotection was partly evaluated through the effect of AGR on the cholinergic system. Our studies suggest that AGR can possibly be used as treatment for Alzheimer's disease

Acupuncture Stimulation Alleviates Corticosterone-Induced Impairments of Spatial Memory and Cholinergic Neurons in Rats

The purpose of this study was to examine whether acupuncture improves spatial cognitive impairment induced by repeated corticosterone (CORT) administration in rats. The effect of acupuncture on the acetylcholinergic system was also investigated in the hippocampus. Male rats were subcutaneously injected with CORT (5 mg/kg) once daily for 21 days. Acupuncture stimulation was performed at the HT7 (Sinmun) acupoint for 5 min before CORT injection. HT7 acupoint is located at the end of transverse crease of ulnar wrist of forepaw. In CORT-treated rats, reduced spatial cognitive function was associated with significant increases in plasma CORT level (+36%) and hippocampal CORT level (+204%) compared with saline-treated rats. Acupuncture stimulation improved the escape latency for finding the platform in the Morris water maze. Consistently, the acupuncture significantly alleviated memory-associated decreases in cholinergic immunoreactivity and mRNA expression of BDNF and CREB in the hippocampus. These findings demonstrate that stimulation of HT7 acupoint produced significant neuroprotective activity against the neuronal impairment and memory dysfunction

The Neuroprotective Effect of Methanol Extract of Gagamjungjihwan and Fructus Euodiae on Ischemia-Induced Neuronal and Cognitive Impairment in the Rat

Gagamjungjihwan (GJ), a decoction consisting of five herbs including ginseng, Acori Graminei Rhizoma, Uncariae Ramulus et Uncus, Polygalae Radic and Frustus Euodiae (FE), has been widely used as herbal treatment for ischemia. In order to investigate the neuroprotective action of this novel prescription, we examined the influence of GJ and FE on learning and memory using the Morris water maze and studied their affects on the central cholinergic system in the hippocampus with neuronal and cognitive impairment. After middle cerebral artery occlusion was applied for 2 h, rats were administered GJ (200 mg kg−1, p.o.) or FE (200 mg kg−1, p.o.) daily for 2 weeks, followed by training and performance of the Morris water maze tasks. Rats with ischemic insults showed impaired learning and memory of the tasks. Pre-treatment with GJ and FE produced improvement in the escape latency to find the platform. Pre-treatments with GJ and FE also reduced the loss of cholinergic immunoreactivity in the hippocampus. The results demonstrated that GJ and FE have a protective effect against ischemia-induced neuronal and cognitive impairment. Our results suggest that GJ and FE might be useful in the treatment of vascular dementia