Neurobehavioral effects of chronic dietary and repeated high-level spike exposure to chlorpyrifos in rats.

This study aimed to model long-term subtoxic human exposure to an organophosphorus pesticide, chlorpyrifos, and to examine the influence of that exposure on the response to intermittent high-dose acute challenges. Adult Long-Evans male rats were maintained at 350 g body weight by limited access to a chlorpyrifos-containing diet to produce an intake of 0, 1, or 5 mg/kg/day chlorpyrifos. During the year-long exposure, half of the rats in each dose group received bi-monthly challenges (spikes) of chlorpyrifos, and the other half received vehicle. Rats were periodically tested using a neurological battery of evaluations and motor activity to evaluate the magnitude of the acute response (spike days) as well as recovery and ongoing chronic effects (non-spike days). Effects of the spikes differed as a function of dietary level for several endpoints (e.g., tremor, lacrimation), and in general, the high-dose feed groups showed greater effects of the spike doses. Animals receiving the spikes also showed some neurobehavioral differences among treatment groups (e.g., hypothermia, sensory and neuromotor differences) in the intervening months. During the eleventh month, rats were tested in a Morris water maze. There were some cognitive deficits observed, demonstrated by slightly longer latency during spatial training, and decreased preference for the correct quadrant on probe trials. A consistent finding in the water maze was one of altered swim patterning, or search strategy. The high-dose feed groups showed more tendency to swim in the outer annulus or to swim very close to the walls of the tank (thigmotaxic behavior). Overall, dietary exposure to chlorpyrifos produced long-lasting neurobehavioral changes and also altered the response to acute challenges.     

东莨菪碱和毒扁豆碱对吗啡处理大鼠Morris水迷宫空间学习能力的影响

目的:研究吗啡及胆碱能系统的药物对大鼠空间学习能力的影响 方法:应用Morris水迷宫学习程序研究吗啡处理大鼠的空间学习能力及其在东莨菪碱和毒扁豆碱作用下的变化.结果:高剂量吗啡(10mg/kg)和低剂量吗啡(3mg/kg)对大鼠学习能力的影响差异有显著性;东莨菪碱(3mg/kg)和吗啡(10mg/kg)联合给药,可以使吗啡时学习能力的损害进一步加重;毒扁豆碱(0.1mg/kg)可以改善吗啡所致的学习能力损害,但不能完全逆转.结论:吗啡损害大鼠空间学习能力,已存在量-效关系;胆碱能系统与吗啡处理大鼠空间学习能力关系密切,有可能影响成瘾的发生及治疗.     

Lack of selective developmental neurotoxicity in rat pups from dams treated by gavage with chlorpyrifos.

Pregnant Sprague-Dawley rats were given chlorpyrifos (O:, O-diethyl-O:-[3,5,6-trichloro-2-pyridinyl] phosphorothioate; CPF) in corn oil by gavage from gestation day 6 (GD 6) through lactation day 10 (LD 10) at dosages of 0, 0.3, 1, or 5 mg/kg/day in a developmental neurotoxicity study that conformed to U.S. Environmental Protection Agency 1991 guidelines. GD 0 was the day when evidence of mating was observed and postnatal day 0 (PND 0) was the day of birth. Toxicity was limited to the highest dosage level (5 mg/kg/day) and, in the dams, consisted of muscle fasciculation, hyperpnea, and hyperreactivity. A nonsignificant overall trend toward weight gain and feed consumption was also observed in the high-dosage dams, with a statistically significant Group x Time interaction for reduced weight gain in the 5-mg/kg/day group near the end of gestation. Although many developmental indices were normal, pups from high-dosage dams had increased mortality soon after birth, gained weight more slowly than controls, and had several indications of slightly delayed maturation. The early deaths and delayed maturation were attributed to maternal toxicity, though a possible contributing role of direct pup toxicity in delayed development cannot be eliminated. In spite of the apparent delay in physical development, high-dosage pups tested just after weaning had normal learning and memory as tested on a T-maze spatial delayed-alternation task. Habituation, a primitive form of learning, was tested in 2 tasks (motor activity and auditory startle) and was not affected. No overt effects were noted in either dams or pups at 1 or 0.3 mg/kg/day. Based on these data, chlorpyrifos produced maternal and developmental toxicity in the 5-mg/kg/day-dosage group. There was no evidence of selective developmental neurotoxicity following exposure to chlorpyrifos.     

丙泊酚对大鼠空间学习记忆能力影响的实验研究

目的研究丙泊酚对于大鼠空间学习记忆能力的影响。方法给予大鼠丙泊酚(10、30和75mg·kg-1)腹腔注射,给予脂肪乳腹腔注射作为对照,然后应用Morris水迷宫评价其对于大鼠空间学习记忆的影响。结果30和75mg·kg-1的丙泊酚腹腔注射可以损害大鼠的空间学习记忆能力,而10mg·kg-1的丙泊酚腹腔注射不影响大鼠的空间学习记忆能力。结论多次给大鼠腹腔注射丙泊酚重复实施麻醉或镇静可以损害其空间学习记忆能力。     

Neurochemical effects of repeated gestational exposure to chlorpyrifos in developing rats.

The neurochemical effects in developing rats exposed during gestation to the anticholinesterase organophosphorus insecticide chlorpyrifos (CPS) were determined. Pregnant rats were dosed daily with CPS (0, 3, or 7 mg/kg) in corn oil from gestation days (GD) 6-20. Pups were euthanized on postnatal days (PND) 1, 3, 6, 9, 12, and 30 for the determination of brain cholinesterase (ChE) and choline acetyltransferase (ChAT) activities, along with muscarinic receptor (mAChR) densities, the levels of the high-affinity choline uptake (HACU) system, and the vesicular acetylcholine transporter (VAChT). ChE activities were inhibited about 15 and 30% on PND 1, in the low- and high-dosage groups, respectively, and were not different from control values by PND 6. mAChR densities on PND 1 were reduced in the high-dosage group by about 18, 21, and 17%, using 3H-N-methylscopolamine, 3H-quinuclidinyl benzilate, and 3H-4-DAMP, respectively, as ligands, and were not different from control levels by PND 6. ChAT activity was decreased by approximately 12% in the high-dosage group on PND 9, 12, and 30. HACU levels, using 3H-hemicholinium-3 as the ligand, were reduced by approximately 25% on PND 6 in the low- and high-dosage groups, and by approximately 14 and 21% on PND 12 and 30, only in the high-dosage group. Levels of the VAChT were reduced by a range of 13-31% on PND 3 through 30 in the high-dosage group, using 3H-AH5183 (vesamicol) as the ligand. These data suggest that gestational exposure to 7 mg/kg/day CPS results in long-term alterations of presynaptic cholinergic neurochemistry.     

Effects of repeated oral postnatal exposure to chlorpyrifos on cholinergic neurochemistry in developing rats.

The neurochemical effects of repeated postnatal exposure to chlorpyrifos (CPS) were studied in developing rats. Rats were gavaged daily from postnatal day (PND) 1-21 with CPS in corn oil starting at 1.5 mg/kg (low dosage group) and increasing gradually to 3 mg/kg and then to 6 mg/kg (high dosage group). Brain cholinesterase (ChE) activity was significantly inhibited on PND 6, 12, 22, and 30, with maximum inhibition on PND 6 of 49 and 59% and recovering to 18 and 33% on PND 30 in the low and high dosage groups, respectively. On PND 22 and 30, 94% or greater of the inhibited ChE could not be reactivated by the oxime TMB-4 in both treatment groups, indicating aging of the phosphorylated ChE. Total muscarinic acetylcholine receptors (mAChR) were reduced in a dose-related manner on PND 12 and 22, with substantial recovery by PND 30. M1/M3 mAChR were significantly reduced on PND 6 and 12 only in the high dosage group, and on PND 22 in both groups, while M2/M4 mAChR were reduced in the high dosage group on PND 22 and 30. On PND 30 choline acetyltransferase activity and vesicular acetylcholine transporter levels were decreased by 12 and 22%, respectively, only in the high dosage group. High-affinity choline transporter levels were decreased at all time points in the high dosage group and on PND 6, 22, and 30 in the low dosage group. The results presented here demonstrate that repeated postnatal exposures to CPS result in transient reductions of mAChR and more persistent alterations of presynaptic cholinergic neurons. In addition, the long-term reduction of brain ChE activity observed following repeated postnatal exposure to CPS is attributable to permanent inactivation or "aging" of the enzyme.     

丁香酚吸嗅对血管性痴呆模型大鼠学习记忆障碍改善的实验研究

目的研究丁香酚吸嗅对血管性痴呆(vascular dementia,VD)大鼠学习障碍的影响。方法成年雄性SD大鼠32只随机分成4组:VD模型组,丁香酚治疗组,假手术组和正常对照组,每组8只。VD模型组用改良的双侧颈总动脉加扎法造模;丁香酚治疗组大鼠在造模完成后3 d予以1%浓度的丁香酚吸嗅;假手术组除不结扎血管外,余下操作步骤同VD模型组,空白组不做任何处理。在术前和术后60 d时,用Morris水迷宫测定大鼠的空间学习记忆能力。结果 Morris水迷宫实验中,术前各组大鼠的逃避潜伏期及穿台次数差异无统计学意义(P0.05);术后60 d时,VD模型组大鼠的逃避潜伏期明显延长、穿台次数明显减少,与正常对照组和假手术组相比差异有统计学意义(P0.05);丁香酚治疗组大鼠逃避潜伏期明显短于VD模型组,穿台次数多于VD模型组,差异有统计学意义(P0.05)。结论丁香酚吸嗅可改善VD模型大鼠的学习记忆障碍。     

Comparative cholinergic neurotoxicity of oral chlorpyrifos exposures in preweanling and adult rats.

Chlorpyrifos (CPF) is a common organophosphorus (OP) pesticide. Previous studies have demonstrated that neonatal rats are more sensitive than adults to the acute toxicity of high dosages of CPF. The present study examined lethality and age-related differences in neurochemical indicators and functional signs of neurotoxicity following a broad range of acute and repeated oral CPF exposures. There was about a 9-fold difference in sensitivity to the acute-dose lethality of chlorpyrifos among neonatal (7 days-of-age) and adult (90 days-of-age) rats (LD(10): neonates = 15 mg/kg; adults = 136 mg/kg), while juvenile rats (21 days-of-age) exhibited intermediate sensitivity (LD(10) = 47 mg/kg). Neonatal and adult rats (n = 5-7/treatment/age group/time point) were given CPF (0, 0.15, 0.45, 0. 75, 1.5, 4.5, 7.5, or 15 mg/kg/day) for 14 days and sacrificed 4 h after either the first or 14th dose for neurochemical measurements (cholinesterase activity in frontal cortex, plasma and RBC, and muscarinic ([(3)H]QNB) and nicotinic ([(3)H]epibatidine) receptor binding in frontal cortex. No overt signs of functional toxicity (involuntary movements, SLUD signs) were noted in either age group by 4 h after the first dose. With repeated CPF exposures, however, signs of cholinergic toxicity were noted in both age groups at the higher dose levels [no observed effect levels (NOELs): neonate = 4.5 mg/kg/day; adult = 7.5 mg/kg/day]. Similar degrees of ChE inhibition were noted in neonatal brain and blood fractions following acute exposure, but substantial ChE inhibition was only noted in adult plasma and RBC 4 h after the first treatment. Following repeated CPF exposures, similar degrees of ChE inhibition were again noted in tissues from immature animals, but a wide range of sensitivity to inhibition was noted in adult tissues. NOELs based on ChE inhibition for adults were about 1->/=10-fold higher than in neonates with acute exposure but only 0.2-2 times higher with repeated dosing. Moreover, dose-related inhibition of brain ChE was similar between age groups, and similar reductions in both QNB and epibatidine binding were noted between the age groups after repeated dosing, even though by the end of the dosing period young animals (juveniles) were still about 3 times more sensitive than adults, based on acute lethality. We conclude that while immature animals can be markedly more sensitive to lethal effects of high doses of CPF, lesser or no age-related differences are apparent, based on non-lethal endpoints, in particular with repeated exposures.     

Nω-硝基-L-精氨酸对大鼠八臂迷宫工作记忆的作用(英文)

目的:研究一氧化氮合成酶抑制剂N_ω-硝基-L-精氨酸(NNA)对大鼠空间工作记忆的作用.方法:采用八臂迷宫延迟插板的程序.结果:腹腔注射NNA 100 mg kg~(-1)对大鼠八臂迷宫选择的准确性没有显著影响,只能增加反应的潜伏期.东莨菪碱0.25 mg kg~(-1)使大鼠延迟后的错误选择显著增加.脑室内注射NNA(10,50,100 nmo1/1 μL)没有影响准确性.结论:急性NNA给予对大鼠空间工作记忆的形成和使用没有显著影响.     

Facilitating effect of histamine on spatial memory deficits induced by dizocilpine as evaluated by 8-arm radial maze in SD rats

AIM: To investigate whether or not histamine is involved in spatial memory deficits induced by dizocilpine (MK-801) as evaluated by 8-arm radial maze of rats. METHODS: 8-Arm (4-arm baited) radial maze was used to measure spatial memory in rats. RESULTS: Bilaterally intrahippocampal (ih) injection of MK-801 (0.3 μg/site) impaired working memory and reference memory in rats. Both histamine (50, 100 ng/site, ih) and intraperitoneal (ip) injection of histidine (100, 200 mg/kg) markedly improved the spatial memory deficits induced by MK-801. On the other hand, the ameliorating effect of histidine (100 mg/kg, ip) was completely antagonized by α-fluoromethylhistidine (α-FMH, 5 μg/site, ih), a potent and selective histidine decarboxylase (HDC) inhibitor, and H_1-antagonist pyrilamine (1 μg/site, ih), but not by H_2-antagonist cimetidine, even at a high dose (2.5 μg/site, ih). CONCLUSION: The hippocampal histamine plays an important role in the ameliorating effect on MK-801-induced spatial memory deficits,     

银杏叶提取物对东莨菪碱所致大鼠空间工作记忆障碍的影响

目的探讨银杏叶提取物对东莨菪碱所致大鼠空间工作记忆障碍的影响。方法大鼠随机分成3组:正常组、东莨菪碱组和银杏叶治疗组。水迷宫试验,东莨菪碱组按0.4mg/kg腹腔注射,以后每天注射等体积生理盐水,连用6d。正常对照组每天注射与东莨菪碱等体积的生理盐水连用6d;银杏叶治疗组按10mg/kg腹腔注射,1次/d,连用6d。1周后进行Morris水迷宫试验,观察3组大鼠平台逃避潜伏期,并与实验后第1天比较。结果两次逃避潜伏期在正常组呈非常显著性差异(46.4±17.7,13.4±8.2,P<0.01)东莨菪碱组无统计学差异(23.6±14.3,18.1±9.8,P>0.05),银杏叶组呈显著性差异(27.9±14.3,9.0±3.8,P<0.05)。结论M-型胆碱能受体阻滞剂东莨菪碱能损害大鼠空间工作记忆,银杏叶提取物能改善这种损害,说明银杏叶提取物是通过影响胆碱能系统来发挥其促智作用的。     

Diazepam impairs place learning in naive but not in maze-experienced rats in the Morris water maze

Anxiolytic benzodiazepines have been shown to impair place learning in the Morris water maze. However, a clear-cut demonstration of a direct and specific effect on mnemonic processes has not yet been offered. In the present study, the effects of diazepam on place navigation in the Morris water maze were studied in rats. Three conditions were examined: learning, reversal learning and learning after familiarisation of animals with the maze. In view of the anxiolytic and sedative properties of diazepam, appropriate doses of the drug, i.e. those that produced an anxiolytic effect but no major motor impairment, were initially selected in the water-lick conflict and rotarod tests, respectively. Doses of 2.5 and 5 mg/kg PO increased punished drinking in the water-lick conflict test without significantly decreasing rotarod performance. These doses were then used to assess the effects of diazepam on spatial behaviour. Diazepam, at both doses, impaired place learning in behaviourally naive rats. Such an effect appeared to be transient: diazepam-treated rats eventually reached control performance. Moreover, analysis of the probe trial at the end of training revealed adoption of a spatial strategy to locate the submerged platform. Neither reversal learning nor learning after familiarisation was affected. These results do not replicate previous findings in the Morris water maze and provide some evidence that the diazepam-induced place learning deficit may be primarily anxiolytic in nature.     

Biphasic effect of citral, a flavoring and scenting agent, on spatial learning and memory in rats

Although some central effects of citral have been reported, cognitive effects on spatial memory have not been investigated. The evidence showed that citral can regulate the synthesis of retinoic acid (RA), which exerts a vital function in the development and maintenance of spatial memory. In this study, we applied Morris water maze to test the effect of citral on animals' spatial learning and memory. To elucidate the mechanism of this effect, we also measured the retinoic acid concentration in rats' hippocampus by high performance liquid chromatography (HPLC). Our data implied biphasic effects of citral. The low dose (0.1 mg/kg) of citral improved the spatial learning capability, and enhanced the spatial reference memory of rats, whereas the high dose (1.0 mg/kg) was like to produce the opposite effects. Meanwhile, the low dose of citral increased the hippocampal retinoic acid concentration, while the high dose decreased it. Due to the quick elimination and non-bioaccumulation in the body, effects of citral on spatial memory in this study seemed to be indirect actions. The change in hippocampal retinoic acid concentration induced by different doses of citral might be responsible for the biphasic effect of citral on spatial learning and memory.     

神经节苷酯对大鼠脑放射后学习记忆力下降的影响

目的：研究神经节苷酯(GMl)对脑放射后学习记忆能力减退鼠空间学习记忆的影响。方法：60只SD大鼠头部接受^60Coγ射线照射，7Gy/次，1次/天，连续照射6d，总剂量42Gy，照射鼠分3组，每组20只：照射后GMl治疗组；照射后生理盐水(NS)治疗组；照射后未干预组。另设20只鼠为对照组，麻醉后不予照射。照射结束后采用Momis水迷宫测定大鼠的学习记忆能力，迷宫试验结束后断头取脑，观察脑组织病理改变。结果：GMl治疗组大鼠寻找平台潜伏期较照射后未干预组及NS治疗组缩短，但仍长于正常对照组。CMl治疗组大鼠平台象限游泳距离百分比高于照射后未干预组及NS治疗组，但较正常对照组低。组织学检查显示照射后大鼠脑组织神经细胞变性坏死，GMl治疗组病理改变较NS治疗组轻。结论：放射性脑损伤可使鼠的学习记忆能力明显下降，GMl对放射所致的学习记忆能力减退有明显改善作用。     

Effects of 3,3′-iminodipropionitrile on acquisition and performance of spatial tasks in rats

3,3′-Iminodipropionitrile (IDPN) has been reported to disrupt learning and memory in rats (24). The present work addressed the effects of IDPN on tasks requiring the use of spatial information. Separate groups of male rats were dosed with IDPN (IP, in 1 ml/kg saline) for 3 consecutive days and tested in the following procedures: (a) step-through passive avoidance conditioning (0, 100, 150, and 200 mg/kg/day); (b) Morris water maze (MWM) acquisition and retention (0, 125, 150, 175, and 200 mg/kg/day); (c) radial arm maze (RAM) acquisition (0, 100, 200, and 400 mg/kg/day); (d) RAM steady-state performance (0, 200, and 400 mg/kg/day); (e) repeated acquisition in the RAM (0, and 200 mg/kg/day). The vestibular toxicity of IDPN resulted in alterations in spontaneous behavior or swimming deficits in 5 of 8 rats treated with 175 mg/kg/day and in all the animals dosed with 200 or 400 mg/kg/day. IDPN increased step-through PA latencies at 200 mg/kg/day but not at lower doses. In the MWM, no performance deficits were observed at the dose levels preserving the swimming ability of the animals. In both the acquisition and the steady-state RAM tasks, IDPN (400 mg/kg/day) induced an increase in both choice errors and perseverative errors. In the RAM repeated acquisition paradigm, IDPN (200 mg/kg/day) induced performance deficits that included a decreased rate of within-session reduction in errors. The present data show that IDPN disrupts performance of tasks requiring spatial learning and memory and indicate that these deficits can be in part caused by an acquisition deficit.     

Effect of pregabalin on fear-based conditioned avoidance learning and spatial learning in a mouse model of scopolamine-induced amnesia

Objectives: Cognitive deficits are one of the frequent symptoms accompanying epilepsy or its treatment.

Methods: In this study, the effect on cognition of intraperitoneally administered antiepileptic drug, pregabalin (10?mg/kg), was investigated in scopolamine-induced memory-impaired mice in the passive avoidance task and Morris water maze task. The effect of scopolamine and pregabalin on animals’ locomotor activity was also studied.

Results: In the retention phase of the passive avoidance task, pregabalin reversed memory deficits induced by scopolamine (p?p?p?p?Discussion: In passive avoidance task, pregabalin reversed learning deficits induced by scopolamine. In the Morris water maze, pregabalin did not influence spatial learning deficits induced by scopolamine. These results are relevant for epileptic patients treated with pregabalin and those who use it for other therapeutic indications (anxiety, pain).     

Effects of ethylcholine aziridinium,scopolamine and morphine on learning behaviors in morris water maze

To assess the learning behaviors of the various chemicals, such as ethylcholine aziridinium (AF64A), scopolamine and morphine, the chemicals were administered into either rat or mice. And water maze tests were performed before and during drug administration. In AF64A-treated groups (3 nmol/each ventricle), the latencies to escape was significantly increased in both of the pretraining- and posttraining groups. In scopolamine-treatment (2 mg/kg, sc) to the pretrained group, the latency to escape was significantly shortened after the acute administration of scopolamine. However in subacute treatment group with scopolamine, the latency to escape was significantly increased. In morphine-treated groups (10 mg/kg, ip), the latency to escape was significantly increased after the acute administration. However in subacute treatmment with morphine, the latency to escape was not changed. The results indicate that each chemical induces the learning impairment. However the chemical-induced learning impairment may have different characteristics upon the exposed chemical. Also the results suggest that both the motivation and the retrieval of memory might be impaired by AF64A.     

Cocaine self-administration improves performance in a highly demanding water maze task

Rationale Long-term potentiation (LTP) is considered to be a cellular substrate of learning and memory. Indeed, the involvement of LTP-like mechanisms in spatial learning has consistently been demonstrated in the Morris water maze test. We have previously shown that hippocampal LTP in Lewis rats was modulated by cocaine self-administration, although the performance of cocaine-self-administered rats in the Morris water maze was not altered. Objective Given that the ease of the task previously used could have masked any possible effects of the cocaine-induced LTP enhancement on spatial learning, a new and more difficult water maze task was devised to address this issue. Materials and methods Animals self-administered cocaine (1 mg/kg) or saline under a fixed ratio 1 schedule of reinforcement for 22 days. Spatial learning was assessed in a difficult water maze task (four sessions, two trials per session with a 90-min intertrial interval), and spatial memory was also evaluated 48 h after training (a 90-s test). Additionally, reversal learning and perseverance were also studied. Results There was a reduced latency in finding the hidden platform during training, as well as improved memory of the platform location in cocaine-self-administered rats with respect to animals that self-administered saline. No differences were observed in reversal learning or perseverance between groups. Conclusions Our data suggest that cocaine self-administration facilitates learning and memory in the water maze test only when animals are submitted to highly demanding tasks, involving working memory or consolidation-like processes during the intertrial interval. Del Olmo and Higuera-Matas contributed equally to this work.     

Polybrominated diphenyl ether (PBDE) neurotoxicity: a systematic review and meta-analysis of animal evidence

A recent systematic review (SR) and meta-analysis of human studies found an association between prenatal serum polybrominated diphenyl ethers (PBDE) concentrations and a decrease in the IQ of children. A SR of experimental developmental animal PBDE-mediated neurotoxicity studies was performed in the present study. Outcomes assessed included measures related to learning, memory, and attention, which parallel the intelligence-related outcomes evaluated in the human studies SR. PubMed, Embase, and Toxline were searched for relevant experimental non-human mammalian studies. Evaluation of risk of bias (RoB) and overall body of evidence followed guidance developed by the National Toxicology Program. Animal studies using varying designs and outcomes were available for BDEs 47, 99, 153, 203, 206, and 209 and the technical mixture DE-71. Study reporting of methods and results was often incomplete leading to concerns regarding RoB. A meta-analysis of 6 Morris water maze studies showed evidence of a significant increase in last trial latency (effect size of 25.8 [CI, 20.3 to 31.2]) in PBDE-exposed animals with low heterogeneity. For most endpoints, there were unexplained inconsistencies across studies and no consistent evidence of a dose-response relationship. There is a “moderate” level of evidence that exposure to BDEs 47, 99, and 209 affects learning. For other PBDEs and other endpoints, the level of evidence was “low” or “very low”. The meta-analysis led to stronger conclusions than that based upon a qualitative review of the evidence. The SR also identified RoB concerns that might be remedied by better study reporting.     

大黄酚对铅中毒小鼠学习记忆的改善作用及其机制研究

目的研究大黄酚对铅中毒小鼠学习记忆障碍的改善作用,探讨其可能的作用机制。方法采用连续8 d腹腔注射7 mg.kg-1醋酸铅造成铅中毒小鼠模型,应用避暗实验、水迷宫实验,观察腹腔注射大黄酚(10.0、1.0、0.1 mg.kg-1)14 d对铅中毒模型小鼠记忆障碍的改善作用,大黄酚治疗14 d后测定小鼠血铅、脑铅及脑组织中MDA含量SOD,GSH-Px活力,一氧化氮(NO)含量及一氧化氮合酶(NOS)、诱导型一氧化氮合酶(iNOS)的活性。结果连续8 d腹腔注射7 mg.kg-1醋酸铅造成铅中毒小鼠学习记忆障碍,使小鼠脑铅、血铅升高,导致小鼠脑组织内SOD和GSH-Px活性降低,使小鼠脑组织内MDA含量增加,小鼠脑组织内NO含量增加,NOS和iNOS活性升高;连续ip大黄酚14d治疗后,可不同程度改善小鼠铅中毒造成的学习记忆障碍,降低血铅及脑铅水平,大黄酚(0.1 mg.kg-1)可升高铅中毒小鼠脑内SOD和GSH-Px的活性(P<0.01),对MDA含量无影响;大黄酚(10.0、1.0 mg.kg-1)可升高铅中毒小鼠脑内SOD和GSH-Px的活性,降低小鼠脑内MDA含量(P<0.01);大黄酚(0.1 mg.kg-1)可降低小鼠脑内NOS、iNOS的活性(P<0.05),对NO含量无影响;大黄酚10.0,1.0 mg.kg-1治疗组可降低小鼠脑内NO含量和NOS、iNOS的活性(P<0.01)。结论大黄酚通过提高铅中毒小鼠脑组织抗氧化酶活性同时降低NOS、iNOS的活性,抑制脂质过氧化,明显拮抗铅诱导的小鼠学习记忆障碍。