Dexmedetomidine Ameliorates Sleep Deprivation-Induced Depressive Behaviors in Mice

Purpose Sleep deprivation induces depressive symptoms. Dexmedetomidine is a α2-adrenoreceptor agonist and this drug possesses sedative, anxiolytic, analgesic, and anesthetic-sparing effect. In this study, the action of dexmedetomidine on sleep deprivation-induced depressive behaviors was investigated using mice. Methods For the inducing of sleep deprivation, the mice were placed inside a water cage containing 15 platforms and filled with water up to 1 cm below the platform surface for 7 days. One day after sleep deprivation, dexmedetomidine at the respective dosage (0.5, 1, and 2 μg/kg) was intraperitoneally treated into the mice, one time per a day during 6 days. Then, forced swimming test and tail suspension test were conducted. Immunohistochemistry for tyrosine hydroxylase (TH), 5-hydroxytryptamine (5-HT; serotonin), tryptophan hydroxylase (TPH) and western blot for D1 dopamine receptor were also performed. Results Sleep deprivation increased the immobility latency in the forced swimming test and tail suspension test. The expressions of TPH, 5-HT, and D1 dopamine receptor were decreased, whereas, TH expression was increased by sleep deprivation. Dexmedetomidine decreased the immobility latency and increased the expressions of TPH, 5-HT, and D1 dopamine receptor, whereas, HT expression was decreased by dexmedetomidine treatment. Conclusions In our results, dexmedetomidine alleviated sleep deprivation-induced depressive behaviors by increasing 5-HT synthesis and by decreasing dopamine production with up-regulation of D1 dopamine receptor

Treadmill Exercise Alleviates Circadian Rhythm Disruption-Induced Memory Deficits by Activation of Glucocorticoid Receptor and Brain-Derived Neurotrophic Factor-Dependent Pathway

Purpose Circadian rhythm affects learning process, memory consolidation, and long-term memory. In this study, the alleviating effect of exercise on circadian rhythm disruption-induced memory deficits was investigated. Methods BMAL1 knockdown transgenic mice (BMAL1 TG) were used as the BMAL1-TG group and the BMAL1-TG with treadmill exercise group. Female C57BL/6J mice of the same age were used as the wildtype group and the wildtype with treadmill exercise group. The mice in the treadmill exercise groups performed running on a motorized treadmill under the dark-dark conditions for 8 weeks. Short-term memory, nonspatial object memory, and spatial learning memory were determined using stepdown avoidance test, novel object-recognition test, and radial 8-arm maze test. Immunohistochemistry for doublecortin and 5-bromo-2’-deoxyuridine was conducted for the determination of hippocampal neurogenesis. Using the western blot analysis, we determined the expressions of glucocorticoid receptor (GR) and factors related to the neurogenesis and memory consolidation, such as brain-derived neurotrophic factor, tyrosine kinase B, p44/42 mitogen-activated protein kinase, cyclic AMP-responsive element binding protein, phosphatidylinositol 3-kinase, protein kinas B, protein kinase C alpha, early-growth-response gene 1. Results Circadian rhythm disruption impaired memory function through inhibiting the expressions of GR and the factors related to neurogenesis and memory consolidation. Treadmill exercise improved memory function via enhancing the expressions of GR and above-mentioned factors. Conclusions Treadmill exercise acts as the zeitgeber that improves memory function under the circadian rhythm disrupted conditions

Add-on Therapy With the α-Blockers Tamsulosin and Naftopidil Improves Voiding Function by Enhancing Neuronal Activity in Prostatic Hyperplasia Rats

Purpose Benign prostatic hyperplasia (BPH) impacts quality of life in men by causing lower urinary tract symptoms. α1-Adrenoceptor (α1-AR) blockers improve lower urinary tract symptoms. We investigated the efficacy of add-on therapy with α1-AR blockers on BPH rats. Methods Rats in the drug-treated groups were orally administered each drug once a day for 30 days after orchiectomy. To induce BPH, rats were castrated and testosterone (20 mg/kg) was injected subcutaneously once per day for 30 days. Cystometry was conducted to measure voiding contraction pressure and the interval contraction time, immunohistochemistry was performed to measure c-Fos and nerve growth factor (NGF) expression in the neuronal voiding centers, and nicotinamide adenine dinucleotide phosphate-diaphorase histochemistry was used to measure nitric oxide synthase (NOS) expression. Results Orchiectomy and testosterone injection decreased voiding contraction pressure and the interval contraction time, suggesting BPH symptoms. Voiding contraction pressure and the interval contraction time were greater in the group that received the combination treatment (tamsulosin with naftopidil) than in the tamsulosin monotherapy or naftopidil monotherapy groups. c-Fos, NGF, and NOS expression in the neuronal voiding centers was enhanced by BPH induction. c-Fos, NGF, and NOS expression was suppressed by the combination treatment (tamsulosin with naftopidil) to a greater extent than was the case for tamsulosin monotherapy or naftopidil monotherapy. Conclusions Combination therapy of tamsulosin and naftopidil showed greater efficacy for the treatment of BPH than tamsulosin monotherapy or naftopidil monotherapy; therefore, combination therapy can be considered as a novel therapeutic method for BPH

Scolopendra subspinipes mutilans Extract Suppresses Inflammatory and Neuropathic Pain In Vitro and In Vivo

Background. Sciatic nerve injury develops from a variety of pathological causes, including traumatic injury and neuroinflammatory disorders, which are accompanied by pathological changes that have a critical impact on neuropathic pain and locomotor activity. Extracts of Scolopendra subspinipes mutilans (SSM) are used in traditional medicine for the treatment of a wide range of neuropathic diseases, including lower back pain, peripheral neuropathy, and sciatic nerve injury. Although SSM shows anti-inflammatory, antibacterial, and anticonvulsant activities, its diverse mechanisms of action remain unclear. Thus, the present study examined the effects of SSM in vitro and in vivo. Methods. To estimate the anti-inflammatory effects of SSM, inflammatory conditions were induced using lipopolysaccharide (LPS) in RAW 264.7 cells, and inflammatory-related factors were evaluated by enzyme-linked immunosorbent assay (ELISA) and western blotting analyses. Sciatic nerve crush injury (SNCI) was induced in rats using a surgical clip instrument. The effects of SSM in the SNCI model were evaluated in behavioral tests by calculating the sciatic functional index (SFI) and measuring thermal hyperalgesia sensitivity and by monitoring inflammatory factors expression in western blotting analyses. Results. We observed the anti-inflammatory effects of SSM treatment both in vitro and in vivo. The PGE2 and NO production were suppressed by SSM. Protein analyses indicated that expression of NF-κB and degradation of IκBα were suppressed by SSM treatment. In addition, the levels of iNOS, TNF-α, IL-6, and COX-2 expression were reduced by SSM treatment in RAW 264.7 cells and in the SNCI-induced animals. In behavioral studies, SSM treatment enhanced the SFI and improved the thermal sensitivity test results. Conclusions. Our results suggest that SSM suppresses the production of inflammatory factors via the NF-κB pathway and accelerates the morphological and functional recovery of the peripheral nervous system. Hence, SSM may be a useful therapeutic candidate for treatment of neuropathic pain diseases

Adenosine A2A receptor agonist polydeoxyribonucleotide ameliorates short-term memory impairment by suppressing cerebral ischemia-induced inflammation via MAPK pathway.

Cerebral ischemia causes tissue death owing to occlusion of the cerebral blood vessels, and cerebral ischemia activates mitogen-activated protein kinase (MAPK) and induces secretion of pro-inflammatory cytokines. Adenosine A2A receptor agonist, polydeoxyribonucleotide (PDRN), suppresses the secretion of pro-inflammatory cytokines and exhibits anti-inflammatory effect. In the current study, the therapeutic effect of PDRN on cerebral ischemia was evaluated using gerbils. For the induction of cerebral ischemia, the common carotid arteries were exposed, and then aneurysm clips were used to occlude the common carotid arteries bilaterally for 7 minutes. In the PDRN-treated groups, the gerbils were injected intraperitoneally with 0.3 mL of saline containing 8 mg/kg PDRN, per a day for 7 days following cerebral ischemia induction. In order to confirm the participation of the adenosine A2A receptor in the effects mediated by PDRN, 8 mg/kg 7-dimethyl-1-propargylxanthine (DMPX), adenosine A2A receptor antagonist, was treated with PDRN. In the current study, induction of ischemia enhanced the levels of pro-inflammatory cytokines and increased phosphorylation of MAPK signaling factors in the hippocampus and basolateral amygdala. However, treatment with PDRN ameliorated short-term memory impairment by suppressing the production of pro-inflammatory cytokines and inactivation of MAPK signaling factors in cerebral ischemia. Furthermore, PDRN treatment enhanced the concentration of cyclic adenosine-3,5'-monophosphate (cAMP) as well as phosphorylation of cAMP response element-binding protein (p-CREB). Co-treatment of DMPX and PDRN attenuated the therapeutic effect of PDRN on cerebral ischemia. Based on these findings, PDRN may be developed as the primary treatment in cerebral ischemia

Polydeoxyribonucleotide Ameliorates Lipopolysaccharide-Induced Lung Injury by Inhibiting Apoptotic Cell Death in Rats

Lung injury is characterized by diffuse lung inflammation, alveolar-capillary destruction, and alveolar flooding, resulting in respiratory failure. Polydexyribonucleotide (PDRN) has an anti-inflammatory effect, decreasing inflammatory cytokines, and suppressing apoptosis. Thus, we investigated its efficacy in the treatment of lung injury, which was induced in rats using lipopolysaccharide (LPS). Rats were randomly divided into three groups according to sacrifice time, and each group split into control, lung injury-induced, and lung injury-induced + PDRN-treated groups. Rats were sacrificed 24 h and 72 h after PDRN administration, according to each group. Lung injury was induced by intratracheal instillation of LPS (5 mg/kg) in 0.2 mL saline. Rats in PDRN-treated groups received a single intraperitoneal injection of 0.3 mL distilled water including PDRN (8 mg/kg), 1 h after lung injury induction. Percentages of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive, cleaved caspase-3-, -8-, and -9-positive cells, the ratio of Bcl-2-associated X protein (Bax) to B-cell lymphoma 2 (Bcl-2), and expressions of inflammatory cytokines (tumor necrosis factor-α, interleukin-6) were decreased by PDRN treatment in the LPS-induced lung injury rats. Therefore, treatment with PDRN reduced lung injury score. This anti-apoptotic effect of PDRN can be ascribed to the enhancing effect of PDRN on adenosine A2A receptor expression. Based on these results, PDRN might be considered as a new therapeutic agent for the treatment of lung injury