Neuroprotective effects of xanthone derivative of Garcinia mangostana against lead-induced acetylcholinesterase dysfunction and cognitive impairment.

Lead poisoning is a common environmental toxicity and low level of lead exposure is responsible for neurobehavioral or intelligence defects. This study was designed to investigate the protective effect of a xanthone derivative of Garcinia mangostana against lead-induced acetycholinesterase (AChE) dysfunction and cognitive impairment in mice. ICR mice were exposed to lead acetate (Pb) in drinking water (1%) with or without xanthone co-administration (100 and 200mg/kgBW/day) for 38days. Xanthone possesses a high phenolic content, which is positive correlation with its antioxidant activity (R(2)=0.98). The IC50 of xanthone on scavenging free radical activities, hydroxyl radical, superoxide radical, hydrogen peroxide and nitric oxide in cell-free system were 0.48±0.08, 1.88±0.09, 2.20±0.03 and 0.98±0.40mg/mL, respectively. We found that Pb induced AChE dysfunction and memory deficit in a dose dependent manner, indicated by in vitro and in vivo studies. However, xanthone significantly restored AChE activity in the blood and brains of mice and prevented Pb-induced neurobehavioral defect indicators with Forced Swimming and Morris water maze tests. Xanthone treatment improved all indicators compared to the Pb-treated group. In conclusion, xanthone alleviates Pb-induced neurotoxicity, in part, by suppression of oxidative damage and reversing AChE activity with a reduction in learning deficit and memory loss.

Phyu MP ，Tangpong J 《-》

Protective effect of puerarin on lead-induced mouse cognitive impairment via altering activities of acetyl cholinesterase, monoamine oxidase and nitric oxide synthase.

Puerarin (PU), a natural flavonoid, has been reported to have many benefits and medicinal properties. The present study aimed to investigate the protective effects of puerarin on neurotoxicity in mice exposed to lead. ICR mice were exposed to lead acetate in the drinking water (500 ppm) with or without puerarin coadministration (100 and 200 mgPU/kg intragastrically once daily) for three months. We found puerarin significantly prevented Pb-induced neurotoxicity in a dose-dependent manner, indicated by behavioral indicators. Puerarin also decreased Pb contents in blood and brain. Puerarin increased activities of acetyl cholinesterase (AChE) and monoamine oxidase (MAO) in brain of Pb-treated mice. Moreover, Pb-induced profound elevation of oxidative stress, as evidenced by increasing of lipid peroxidation level and depleting of total antioxidant capacity in brain, were suppressed by treatment with puerarin. Puerarin markedly increased NO production and PKA activity in brain of Pb-treated mice. Western blot analysis showed that puerarin dramatically increased the expression levels of nNOS, eNOS and phosphor-Akt in brains of Pb-treated mice. In conclusion, these results suggested that puerarin can inhibit Pb-induced neurotoxicity, at least in part, by suppressing oxidative stress, reversing the Pb-induced alterations in transmitters and enzymes and modulating the PKA/Akt/NOS signaling pathway.

Liu CM ，Zheng GH ，Ming QL ，Sun JM ，Cheng C ... -  《-》

Xanthone-enriched fraction of Garcinia mangostana and α-mangostin improve the spatial learning and memory of chronic cerebral hypoperfusion rats.

Xanthones isolated from the pericarp of Garcinia mangostana has been reported to exhibit neuroprotective effect. In this study, the effect of xanthone-enriched fraction of Garcinia mangostana (XEFGM) and α-mangostin (α-MG) were investigated on cognitive functions of the chronic cerebral hypoperfusion (CCH) rats. HPLC analysis revealed that XEFGM contained 55.84% of α-MG. Acute oral administration of XEFGM (25, 50 and 100 mg/kg) and α-MG (25 and 50 mg/kg) before locomotor activity and Morris water maze (MWM) tests showed no significant difference between the groups for locomotor activity. However, α-MG (50 mg/kg) and XEFGM (100 mg/kg) reversed the cognitive impairment induced by CCH in MWM test. α-MG (50 mg/kg) was further tested upon sub-acute 14-day treatment in CCH rats. Cognitive improvement was shown in MWM test but not in long-term potentiation (LTP). BDNF but not CaMKII was found to be down-regulated in CCH rats; however, both parameters were not affected by α-MG. In conclusion, α-MG ameliorated learning and memory deficits in both acute and sub-acute treatments in CCH rats by improving the spatial learning but not hippocampal LTP. Hence, α-MG may be a promising lead compound for CCH-associated neurodegenerative diseases, including vascular dementia and Alzheimer's disease.

Tiang N ，Ahad MA ，Murugaiyah V ，Hassan Z ... -  《-》

The memory ameliorating effects of INM-176, an ethanolic extract of Angelica gigas, against scopolamine- or Aβ(1-42)-induced cognitive dysfunction in mice.

Alzheimer's disease is a neurodegenerative disorder associated with cognitive impairment and cholinergic neuronal death. INM-176 is a standardized ethanolic extract of Angelica gigas Nakai that has been traditionally used in herbal medicine in China, Japan, and Korea to treat anemia or as a sedative. We investigated whether INM-176 exhibits anti-amnesic effects. Memory impairment was induced by scopolamine, a cholinergic muscarinic receptor antagonist, or amyloid β(1-42) (Aβ(1-42)) protein. Anti-amnesic effects of INM-176 were measured by the passive avoidance and the Morris water maze tasks in mice. We also examined the effect of INM-176 on the acetylcholinesterase activity, as well as Aβ(1-42) protein-induced astrogliosis or cholinergic neuronal loss in the brain. Scopolamine-induced cognitive dysfunction was significantly attenuated by a single or sub-chronic administration of INM-176 in the passive avoidance and the Morris water maze tasks. A single or sub-chronic administration of INM-176 also ameliorated memory impairments induced by Aβ(1-42) protein. INM-176 inhibited acetylcholinesterase activity in the hippocampal tissue in vitro and ex vivo. In addition, INM-176 attenuated the Aβ(1-42) protein-induced astrocyte activation in the hippocampus as well as cholinergic neuronal damage in the CA3 region of the hippocampus and the nucleus basalis of Meynert. These results suggest that the memory ameliorating effects of INM-176 on scopolamine- or Aβ(1-42) protein-induced memory impairment are mediated, in part, via acetylcholinesterase inhibition and neuroprotective activities.

Park SJ ，Jung JM ，Lee HE ，Lee YW ，Kim DH ，Kim JM ，Hong JG ，Lee CH ，Jung IH ，Cho YB ，Jang DS ，Ryu JH ... -  《-》

Possible neuroprotective mechanisms of curcumin in attenuating 3-nitropropionic acid-induced neurotoxicity.

3-Nitropropionic acid (3-NP) is a well known fungic toxin causing neurotoxicity. Systemic administration of 3-NP causes motor and cognitive deficits that are associated with excessive free radical generation. Recently, curcumin has been implicated as a neuroprotectant in the treatment of various neurological disorders. The present study was designed to investigate the effects of curcumin in 3-NP-induced cognitive impairment and oxidative stress in rats. Curcumin, a potent antioxidant of dietary polyphenol, containing a standardized extract of Curcuma longa root (Zingiberaceae), has been reported to possess free radical scavenging, iron chelating and antiinflammatory activities. Intraperitoneal administration of 3-NP (20 mg/kg for 4 days) showed loss in body weight, declined motor function, poor retention of memory and changes in oxidative stress (lipid peroxidation, reduced glutathione and nitrite level) parameters in brain. Chronic treatment with curcumin (10, 20 and 50 mg/kg, p.o.) once daily for a period of 8 days beginning 4 days prior to 3-NP administration dose-dependently improved the 3-NP-induced motor and cognitive impairment. Biochemical analysis revealed that curcumin administration significantly attenuated 3-NP-induced oxidative stress (lipid peroxidation estimation, reduced glutathione and nitrite activity) in the brains of rats. It also significantly restored the decreased succinate dehydrogenase activity. The results of the present study clearly indicate that curcumin by its antioxidant activity showed neuroprotection against 3-NP-induced behavioral and biochemical alteration.

Kumar P ，Padi SS ，Naidu PS ，Kumar A ... -  《methods and findings in experimental and clinical pharmacology》