Pharmacological Activation of GPR55 Improved Cognitive Impairment Induced by Lipopolysaccharide in Mice.

Our previous research found that activation of GPR55 can alleviate cognitive impairment induced by amyloid-beta 1-42 (Aß1-42) and streptozotocin in mice, but the role of GPR55 in the pathogenesis of cognitive impairment remains unknown. Here, we used a lipopolysaccharide (LPS) mouse model to further investigate the role and mechanism of O-1602, a GPR55 agonist, on cognitive dysfunction. ICR mice were treated with an intracerebroventricular (i.c.v.) injection of LPS, followed by cognitive function tests. The expression of GPR55, NF-κB p65, caspase-3, Bax, and Bcl-2 in the hippocampus was examined by Western blotting. Inflammatory cytokines and microglia were detected by ELISA kit and immunohistochemical analyses, respectively. The levels of MDA, GSH, SOD, and CAT were examined by assay kits. Furthermore, TUNEL-staining was used to detect neuronal apoptosis. Our results showed that i.c.v. injection of LPS in mice exhibited impaired performance in the behavior tests, which were ameliorated by O-1602 treatment (2.0 or 4.0 µg/mouse, i.c.v.). Importantly, we found that O-1602 treatment reversed GPR55 downregulation, decreased the expression of NF-κB p65, suppressed the accumulation of proinflammatory cytokines and microglia activation, increased the anti-inflammatory cytokines, and reduced the levels of MDA, increased the levels of GSH, SOD, and CAT in the hippocampus. In addition, O-1602 treatment also significantly reduced Bax and increased Bcl-2 expression as well as decreased caspase-3 activity and TUNEL-positive cells in the hippocampus. These observations indicate that O-1602 may ameliorate LPS-induced cognition deficits via inhibiting neuroinflammation, oxidative stress, and apoptosis mediated by the NF-κB pathway in mice.

Activation of GPR55 attenuates cognitive impairment, oxidative stress, neuroinflammation, and synaptic dysfunction in a streptozotocin-induced Alzheimer's mouse model.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cascading changes in cognition and behavior. G-protein-coupled receptor 55 (GPR55) has been used as a promising target for the treatment of diabetes, but its function in AD is unclear. The objective of this study was to investigate the neuroprotective effects of O-1602, a GPR55 agonist, on the streptozotocin (STZ)-induced AD mouse model. A single intracerebroventricular (i.c.v.) injection of STZ into the brains of mice significantly induced cognitive impairment. In contrast, O-1602 (2.0 or 4.0 µg/mouse, i.c.v.) can improve the cognitive dysfunction caused by STZ in the Morris water maze (MWM) and novel object recognition (NOR) tests. Importantly, O-1602 treatment reversed STZ-induced GPR55 down-regulation, reduced the activity of ß-secretase 1 (BACE1) and the level of Aß1-42, and abolished the up-regulation of acetylcholinesterase (AChE) activity in the hippocampus and frontal cortex. Besides, O-1602 markedly suppressed STZ-induced oxidative stress, characterized by decreased malondialdehyde (MDA) level, and increased the levels of glutathione (GSH), superoxide dismutases (SOD), and catalase (CAT), as well as attenuated neuroinflammation as indicated by decreased series of pro-inflammatory cytokines and microglia activation. O-1602 treatment also ameliorated synaptic dysfunction by promoting the up-regulation of PSD-95 protein in the STZ-treated mice. Our results suggest that O-1602 has potent neuroprotective effects against STZ-induced neurotoxicity. Meanwhile, these findings suggest that GPR55 might be a novel and promising target for the treatment of AD.

Activation of GPR55 attenuates cognitive impairment and neurotoxicity in a mouse model of Alzheimer's disease induced by Aß1-42 through inhibiting RhoA/ROCK2 pathway.

The accumulation of amyloid-ß (Aß) peptides in the brain is considered to be the initial event in the Alzheimer's disease (AD). Neurotoxicity mediated by Aß has been demonstrated to damage the cognitive function. In the present study, we sought to determine the effects of O-1602, a specific G-protein coupled receptor 55 (GPR55) agonist, on the impairment of learning and memory induced by intracerebroventricular (i.c.v.) of Aß1-42 (400 pmol/mouse) in mice. Our results showed that i.c.v. injection of aggregated Aß1-42 into the brain of mice resulted in cognitive impairment and neurotoxicity. In contrast, O-1602 (2.0 or 4.0 µg/mouse, i.c.v.) can improve memory impairment induced by Aß1-42 in the Morris water maze (MWM), and novel object recognition (NOR) tests. Besides, we found that O-1602 reduced the activity of ß-secretase 1 (BACE1) and the level of soluble Aß1-42 in the hippocampus and frontal cortex. Importantly, O-1602 treatment reversed Aß1-42-induced GPR55 down-regulation, decreased pro-inflammatory cytokines, and the level of malondialdehyde (MDA), increased the levels of glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT), as well as suppressed apoptosis as indicated by decreased TUNEL-positive cells, and increased the ratio of Bcl-2/Bax. O-1602 treatment also pronouncedly ameliorated synaptic dysfunction by promoting the upregulation of PSD-95 and synaptophysin (SYN) proteins. Moreover, O-1602 concurrently down regulated the protein levels of RhoA, and ROCK2, the critical proteins in the RhoA/ROCK2 pathway. This study indicates that O-1602 may reverse Aß1-42-induced cognitive impairment and neurotoxicity in mice by inhibiting RhoA/ROCK2 pathway. Taken together, these findings suggest that GPR55 could be a novel and promising target for the treatment of AD.

Inhibition of GPR17 with cangrelor improves cognitive impairment and synaptic deficits induced by Aß1-42 through Nrf2/HO-1 and NF-κB signaling pathway in mice.

The accumulation of amyloid beta (Aß) in the brain is thought to be associated with cognitive deficits in Alzheimer's disease (AD). However, current methods to combat Aß neurotoxicity are still lacking. G protein-coupled receptor 17 (GPR17) has become a target for treating inflammation in brain diseases, but it is unclear whether it has a role in AD. Here, we investigated the effects of cangrelor, a GPR17 antagonist, on neurotoxicity and memory impairment induced by intracerebroventricular (i.c.v.) injection of Aß1-42 in mice. The behavior results showed that cangrelor (2.0 or 4.0 µg/mouse, i.c.v.) treatment reversed the deficits in memory and learning ability induced by Aß1-42 in mice. Importantly, we demonstrated for the first time that GPR17 expression in the hippocampus and frontal cortex is increased in response to Aß1-42 exposures. We also found that cangrelor treatment reduced the activity of ß-secretase 1 (BACE1) and the levels of soluble Aß1-42 in the hippocampus and frontal cortex. Meanwhile, cangrelor treatment suppressed oxidative stress induced by Aß1-42, as proved by reduced production of malondialdehyde (MDA), and increased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT), and promoted the expression of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1). Furthermore, cangrelor also suppressed Aß1-42-induced neuroinflammation, characterized by suppressed activation of microglia, decreased the levels of pro-inflammatory cytokines, and nuclear translocation of NF-κB p65, as well as ameliorated synaptic deficits by promoting the upregulation of synaptic proteins, and increasing the number of Golgi-Cox stained dendritic spines. These results suggest that cangrelor may reverse Aß1-42-induced cognition deficits via inhibiting oxidative stress, neuroinflammation, and synaptic dysfunction mediated by Nrf2/HO-1 and NF-κB signaling.

Facile preparation and characterization of super tough chitosan/poly(vinyl alcohol) hydrogel with low temperature resistance and anti-swelling property.

Facile preparation of super tough hydrogels with low temperature tolerance and anti-swelling property is still a challenging task for researchers. Meanwhile, the vast majority of tough hydrogels were obtained though chemical crosslinking and complicated synthesis or processing method accompanying a large number of harmful chemical reagents. Herein, the super tough chitosan/poly(vinyl alcohol) (CS/PVA) hydrogels (the maximum compressive strength of 18.97 MPa at a strain of 80% and the maximum tensile strength of 4.02 MPa at a strain of 406.4%) were successfully prepared via a simple post-treatment method. CS/PVA hydrogels were firstly prepared by freezing-thawing process and then soaking in saturated sodium chloride aqueous solution. The resultant hydrogels possess excellent swelling resistance and low temperature tolerance. This work shows that the post-treatment of immersing in saline solution is a feasible way to prepare super tough hydrogels with low temperature tolerance and anti-swelling property. This also would enlarge the application areas of CS.

Facile synthesis of MnO2 nanorods grown on porous carbon for supercapacitor with enhanced electrochemical performance.

Novel MnO2-doped holey carbon materials were obtained by an efficient and facile synthetic method using chitosan, potassium hydroxide and potassium permanganate as the raw materials. The carbon framework with high specific surface area was derived from chitosan by carbonization and activation approach, afterwards, MnO2 nanorods were grown on the surface of porous carbon by one-step agitation method and the MnO2-doped holey carbon material was obtained. The scanning electron microscopy, energy-dispersive X-ray, transmission electron microscopy, X-ray diffraction, N2 adsorption-desorption measurements, Raman spectroscopy and X-ray photoelectron spectroscopy were employed to analyze the physicochemical characteristics of the MnO2-doped holey carbon materials. The electrochemical performance of these materials displayed well through relative tests including cyclic voltammetry, galvanostatic charge-discharge, and electrochemical impedance spectroscopy measurements in 6.0 M KOH solution. Especially, this as-obtained electrode material with the optimum ratio presented a high gravimetric capacitance (460F g-1 at 0.2 A g-1) and exceptional capacitance reservation (91.67% at 10 A g-1 over 10,000 cycles) in the three-electrode system with 6.0 M KOH solution as the electrolyte.

Preparation and characterization of novel magnetic Fe3O4/chitosan/Al(OH)3 beads and its adsorption for fluoride.

A novel magnetic bioadsorbent beads composed of Fe3O4, chitosan, and Al(OH)3 (Fe3O4/CS/Al(OH)3) was synthesized by a modified solvothermal and in-situ reaction. The composite adsorbent was characterized by Fourier-transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, energy dispersive X-ray spectroscopy, and vibrating sample magnetometer, respectively. Adsorption toward F- onto Fe3O4/CS/Al(OH)3 was investigated as a function of Fe3O4 concentration, initial solution pH, adsorbent dosage, initial fluorion concentration, co-existing ions in water and initial temperature. The addition of Fe3O4 could enhance the adsorption properties of CS/Al(OH)3. The saturated adsorption capacity of magnetic Fe3O4/CS/Al(OH)3 calculated from the Langmuir isotherm model was 76.63mg/g at 298K. The adsorption isotherm of F- followed Langmuir isotherm model and the adsorption kinetics fitted better to the pseudo-second order kinetic model. The influence of temperature confirmed that the adsorption was spontaneous and endothermic. The magnetic Fe3O4/CS/Al(OH)3 beads could be easily separated from water under a low magnetic field.