Effect And Mechanism Of Curcumin On Learning And Memory Dysfunction In Rats Induced By Gp120

American Health Organization presumes that human immunodeficiency virus-1 (HIV-1) causes threaten to public health. There is about 40 million HIV patients over the world, and the number reachs up to 10 million in China, meanwhile with progressively increase of 16000 every day. Due to the exist of progressively infection of HIV, nearely 30% adults and 50% children develop into HIV-1 associated dementia (HAD), known as cognitive,motor dysfunction and behavioral impairments. Learning and memory impairments are frequently observed in patients suffering from HAD. It is reported that HIV-1 is the major Cause of dementia among those people under the age of 60 years, and HAD is the main death cause of acquired immune deficiency syndrome (AIDS). As refer to China which has the largest population in the world, how to deal with the infection and control diseases associated with HIV are the important work to Chinese and people all over the word in the 21 century. The latest statistic reveals that almost 31% patients of HIV have developed into HAD in South Africa, experts claim that if we wouldn't take any measure to control it, HAD will be as common as Alzheimer disease and stroke dementia in the world.A major question underlying the neuropathogenesis of HAD, and a focal point for this investigation is how neuronal dysfunction or injury can occur when viral replication is exclusively limited to brain macrophages and microglia? Most researches reported that the neuronal injury can result from a direct mechanism by interaction with viral proteins, such as gp120, Tat (transcriptional transactivator) and Vpr (viral protein R) produced by infected cells, or by an indirect effect resulting from the inflammatory process involving activated monocytes, macrophages and astrocytes, and the release of neurotoxins include TNF-α, arachidonic acid, platelet activating factors (PAF), nitric oxide (NO) and quinolinic acid (QUIN). gp120, an HIV viral coat glycoprotein, can shed from infective cells, combine and infect CD4⁺ T cell. Learning and memory dysfunction is associated with gp120. The role of CXCR4 in the gp120 mediated neurotoxicity can be direct through the activation of neuronal receptors, or indirect through the stimulation of glial cells, leading to release of neurotoxic factors. Despite the use of highly active antiretroviral therapy (HAART), neuronal cell damage and apoptosis remains a problem that is frequently found in the brains of HIV-1 infected patients. Try to find new and efficient drugs to against HIV and HAD is a focal work. Curcumin has an extensive history as a food additive and herbal medicine and is also a potent polyphenolic antioxidant, antiapoptosis, anti-inflammatory etc. Other researchs found that curcumin disturbed the reproduction of HIV through affecting HIV long terminal repeat directly or indirectly. It was reported that curcumin inhibits the prolease and integrase which were necessary for HIV reproduction. However, the research about curcumin and learning and memory dysfunction induced by gp120 has not been reported. The goal of this study is to investigate the effect of curcumin on learning and memory ability in memory disorder rats induced by gp120 and its possible mechanisms, contributing a new experimental support to the treatment of cognitive dysfunction patients.Materials and Methods:Adult male and female Spraugue-Dawley (SD) rats were used as experimental subjects. The experiment process was designed as followed:control: i.c.v no operation＋dH₂O(ig) 2Wsham: i.c.v operate cannula＋ACSF (5μL×3d)＋dH₂O(ig) 2Wmodel(gp120): i.c.v operate cannula＋gp120(50ng×3d)＋dH₂O(ig) 2Wgp120＋cur(low): i.c.v operate cannula＋gp120 (50ng×3d)＋50mg/kg cur(ig) 2wgp120＋cur(middle): i.c.v operate cannula＋gp 120 (50ng×3d)＋100mg/kg cur(ig)2w gp120＋cur(low): i.c.v operate cannula＋gp120 (50ng×3d)＋200mg/kg cur(ig)2w note: i.c.v-intracerebroventricular, ig-intragastric administration,ACSF-artificial cerebrospinal fluid,After the treatments finished, all rats were tested in Morris water maze (MWM), after the last test day, all rats brain tissues were separated from cranial cavity, and the change of long-term potentiation (LTP) in the CA1 regin of rat hippocampus, oxidative damage index and brain derived neurotrophic factor (BDNF),NMDA_2BR and Nissl stain were observed.Results:1. Morris water maze (MWM) test showed that the rats in model group had longer escape latencies (P＜0.05) compared with rats of control group. Spatial probe test showed that the rats of model group were a bit clumsy, and they spent a significantly longer time to seek the target quadrant (P＜0.05 vs control group). It indicated that gp120 infusion through intracerebroventricular (i.c.v) could cause dysfunction of learning and memory. Application of curcumin could improve the learning and memory ability of rats induced by gp120, MWM test showed that rats in low, middle, high dose curcumin groups had shorter escape latencies, and less time to find target quadrant (P＜0.05 vs model), and low dose curcumin group was better than other two groups of middle (P＜0.05).2. Usage of gp120 inhibited the magnitude of LTP in the CA1 region of hippocampus (P＜0.05 vs control), EPSP initial slope in low, middle, high dose curcumin groups were increased (P＜0.05 vs model), and the low dose curcumin group was more efficient than other two dose curcumin treatment groups (P＜0.01).3. gp120 caused the oxidative damage to organism, the contents of MDA, OH·was higher in model group, wherear SOD, GSH were lower vs control (P＜0.05 vs control). Application of different doses of curcumin alleviated this oxidation effection, SOD and GSH of low dose curcumin group were higer than other two dose curcumin groups, but there were no statistically difference. MDA (P＞0.05) and OH·(P＜0.05)of low dose curcumin group were more lower than other two dose curcumin groups.4. Nissl staining showed that neurons in CA1～CA4 region and dentate gyrus region with reduced amounts of Nissl substance and significantly swelling, lightly stained and arranged abnormally. Neurons of CA1～CA4 region and dentate gyrus region in low, middle, high dose curcumin groups had better condition, and the condition of low dose curcumin group was better than other two dose curcumin groups.5. Immunohistochemical staining showed that the expressions of NMDA_2BR, BDNF and pCREB in model group decreased vs control group, and the expressions of NMDA_2BR, BDNF and pCREB in low, middle and high dose curcumin groups increased, indicated that the mechanism of curcumin could improve the ability of learning and memory maybe related with the upregulation of NMDA_2BR, BDNF and pCREB.Conclusion1. Intracerebroventricular (i.c.v) infusion of gp120 caused dysfunction of learning and memory, which could imitate the model of cognitive dysfunction of HAD efficient.2. Application of low, middle and high dose of curcumin could improve the ability of behavior action,leaning and memory of rats induced by gp120, low dose curcumin has better effect. In addition gp120 inhibited the LTP in the CA1 region of hippocampus, gp120 inhibited the EPSP initial slope significantly, LTP was acknowledged as the basic model in the field of neuro science, this maybe related with dysfunction of cognition induced by gp120. Application of curcumin improved the inhibition of LTP, which was accorded with the behavior consequences, all of those consequences confirmd that curcumin could improve cognition dysfunction.3. Curcumin improved the antioxidative enzyme ability, eliminated the free radical, lessen the lipid peroxidation effect, inhibited oxidative damage effect, improvd the ability of cognition of learning and memory dysfunction rats.4. The mechanism of curcumin against dysfunction of learning and memory induced by gp120 maybe related with regulated the expression of BDNF, NMDA_2BR and pCREB.