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Effect of Neurosteriods on Learning and Memory Ability of Rats and Its Mechanisms

Author: LiShaSha
Tutor: HouYanNing
School: Hebei Medical University
Course: Pharmacology
Keywords: Neurosteroids Progesterone Scopolamine Morris water maze Acetylcholinesterase
CLC: R749.16
Type: Master's thesis
Year: 2010
Downloads: 178
Quote: 1
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Abstract

Objective: cognitive function disorders, especially Alzheimer's disease, vascular dementia and other neuropsychiatric disease is very common in the pre-elderly and senile. Its more prominent clinical features of progressive learning and memory dysfunction, behavioral disorders, mood disorders, etc.. Neurosteroids involved in the regulation of emotional reactions of anxiety, depression, stress, and convulsions, sleep, nerve regeneration and biological circadian rhythm regulation. The study found that neurosteroids regulatory effect on learning and memory. Neurosteroids pregnenolone sulfate (pregnenolone sulfate, PREGS) and DHEA sulfate (dehydroepiandrosterone sulfate, DHEAS) synergistic function of gamma-aminobutyric acid receptor GABAA inhibition of glutamate ionic receptor NMDA function, thus enhancing neuronal excitability and synaptic plasticity promote animal Awakening, the acquisition and consolidation of memory. While the lateral ventricle given allopregnanolone (allopregnanolone, AP) can damage the animal's spatial cognitive ability. Cholinergic system is involved in many activities such as learning, memory, convulsions and attention. Maintain the advanced features of the brain essential for the normal functioning of the balance on the level of acetylcholine in the brain (Acetycholine, Ach). Different brain regions cholinergic damage cholinergic system changes in the level of metabolic enzymes and cholinergic receptor number decreases are related to the occurrence and development of many cognitive disorders. Morris water maze behavioral evaluation can be used for the judgment of the model of the disease. M receptor scopolamine-induced rat model of learning and memory damage has been widely used to understand occurred promote cognitive function in the aging memory impairment and specific pathological state as well as the screening of effective drugs. This study through the preparation of scopolamine-induced memory deficits in a rat model, the determination of animal models of learning and memory abilities as well as changes in the levels of neurosteroids and further determination of ethology and related enzymatic indicators give neurosteroids intervention to investigate neurosteroids of the scopolamine-induced learning and memory impairment in rat models of possible mechanisms, and provide the basis of experimental evidence for the clinical application of the disease mechanisms of learning and memory impairment, articulate and neurosteroids. Methods: Preparation of a packet and drug treatment program 1.1 scopolamine-induced rat model of learning and memory damage and weight 200 ~ 220g male Sprague Dawley (SD) rats 16, were randomly divided into the model group and the saline control group, n = 8 only. 30 minutes before the water maze test model group, each rat was 2.0mg · kg-1 intraperitoneal injection of scopolamine, control group injected with the corresponding volume of saline. Morris water maze behavioral experiments on animal learning and memory abilities test, compared with the control group, the behavior results significantly reduce the representation of models were successfully. 1.2 progesterone learning effects and related mechanisms of memory impairment in rats 40 weighing 200 ~ 220g male SD rats were randomly divided into saline control group, model group, progesterone low dose group (4mg kg-1), pregnant one middle dose group (8mg · kg-1), progesterone high dose group (16mg · kg-1), n ??= 8. Water maze test before 60min, progesterone dose group each rat subcutaneous injection of the appropriate dose progesterone subcutaneous injection in rats of the control group and the model group the corresponding doses blank medicinal injection oil. 30 minutes before the experiment, the model group and progesterone dose group each rat 2.0mg · kg-1 dose intraperitoneal injection of scopolamine control group rat peritoneal injection of the appropriate volume of saline. 2. 1 to 5 days of detection of indicators 2.1 Morris water maze behavioral test navigation test. At a fixed time every day to begin the experiment. Facing the pool wall into the water rat into the water from a fixed point, record the rats to find and climb the escape latency time of the platform, if the rats not find the platform in the 180s recorded escape latency for 180s, and guide their looking to the platform. Whether each rat training after looking to the platform are the place to stay on the platform 10s. Seven days in space exploration experiment. Interval of one day after the end of the navigation test removed platform, the rat into the water facing the pool wall from fixed into the water point, records rats first arrived in the time of the original platform location as well as across the former platform location within its 180s times. The 2.2 sample extraction and determination of neurosteroids space exploration after the end of the experiment, rats were decapitated, take the trunk blood in heparinized tubes and centrifuged supernatant plasma prepared the the neurosteroids detection use. Quickly cut open the skull, the reference rat brain stereotaxic atlas, isolated from the cortex and hippocampus in the ice-cold saline, weighed and placed on the use of the neurosteroids detector kept at -70 ℃. Reference in this laboratory has established methods to improve slightly, the two-step method of liquid-liquid extraction and solid phase column using ethyl acetate / hexane (9/1, v / v) extract neurosteroids, using high-performance liquid chromatography - mass spectrometry to the determination of the content of neurosteroids in plasma and brain tissue samples. The 2.3 samples acetylcholinesterase determination of space exploration after the end of the experiment, rats were decapitated, and quickly cut open the skull, the reference rat brain stereotaxic atlas, isolated from the cortex and hippocampus in the ice-cold saline, weighed and physiological brine made of 10% (m / V) homogenates 3500r · min-1 centrifugal 10min, 4 ° C, the supernatant was reference to the kit instructions strictly operating reaction was measured. With UV absorption method for the determination of the protein content in each sample to calculate statistics. Results: 1 neurosteroids measurement methodology corroboration of this experiment DHEA, PREG, AP, PROG and internal standard MT with brain tissue and plasma components used in the method of determination of neurosteroids good separation effect, without interference. DHEA, PREG, AP and PROG has a good linear relationship in the range of 0.015 ~ 4.5ng · ml-1 in the brain tissue samples and plasma samples. DHEA, PREG, AP, PROG days and day coefficient of variation in brain tissue were less than 7.6% and 7.2%, 7.7% and 7.9%, 8.0% and 5.7%, 7.9% and 4.5% (n = 5); plasma DHEA of of PREG, AP, PROG days and day coefficients of variation were less than 8.1% and 7.0%, 6.7% and 12.3%, 8.0% and 6.4%, 8.1% and 6.6% (n = 5). 2 Morris water maze behavioral test results navigation test results show that the model group and the saline control group, two groups of rats to find the hidden platform escape latency with learning the increase of the number of days and render decreasing time required. Compared with the control group rats, the escape latency was significantly prolonged (P lt; 0.05) in the first three days began. Space exploration experiment compared with the control group rats, the time to reach the original platform position time was significantly longer (P lt; 0.05), across a number of original platform Area significantly reduce (P lt; 0.05). Scopolamine-induced memory deficits successful model in rats. Giving progesterone pretreatment, navigation test results show that in the five days of training process with the extension of training time, the rats escape latency showed a decreasing. Compared with the model group, the first three days, progesterone low, middle dose group rats escape latency significantly shorter (P lt; 0.05), starting from the first two days, the escape latency of progesterone high dose group were significantly shorter (P lt; 0.05). Space exploration experiment, compared with the model group, the Progesterone three dose groups 1 to reach the original platform location were significantly reduced (P lt; 0.05). Compared with the model group, low progesterone, middle dose group rats increasing trend across the original platform area times the model group, but the difference was not significant sex (P gt; 0.05), progesterone high dose rats across the former platform Area marked increase (P lt; 0.05). Changes in levels of neurosteroids 3 samples compared with the control group, learning memory impairment induced by scopolamine formation model group rat frontal cortex PREG levels significantly decreased (P lt; 0.05), DHEA, AP, and PROG level without significantly with sex change; model group rat hippocampus within of DHEA, PREG, the AP and PROG levels no significant change; model group rats plasma PROG level significantly with increased (P lt; 0.05) of DHEA, PREG and AP level without significantly with sex changed. 4 samples acetylcholinesterase level changes compared with the saline control group, learning memory impairment induced by scopolamine formed, the the model rats prefrontal cortex and hippocampus AchE activity was significantly higher (P lt; 0.05). Compared with the model group, the the progesterone dose group rat frontal cortex and hippocampus AchE activity were lower (P lt; 0.05). Conclusion: 1 M receptor antagonist scopolamine the alkali induced memory deficits, brain nerve steroidal anabolic changed significantly, PREG was significantly decreased in the frontal cortex of rats. Prompts nerve-steroidal anabolic the M receptor system may be involved in the adjustment process of learning and memory. 2 scopolamine-induced learning and memory damage, peripheral nerve steroidal anabolic significant changes in plasma PROG levels were significantly elevated. Speculated that scopolamine may affect the endocrine system by antagonizing the M receptor, in particular, is closely related to the steroid hormone synthesis activity of the HPA axis regulation of the brain regions involved in learning and memory in rats. 3 exogenous PROG intervention by inhibiting AchE activity in the brain cortex and hippocampus, improve scopolamine-induced injury model of learning and memory in rats in the water maze experimental results. Tip PROG may improve scopolamine induced rat learning and memory damage has a protective effect.

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