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The Preventative Effect of Dexmedetomidine on Rats with PTSD and Its Impact of the Expression of ERK and ARC in Hippocampus

Author: ZhangYao
Tutor: LiWeiYan
School: Southern Medical University,
Course: Anesthesiology
Keywords: Posttraumatic stress disorder Dexmedetomidine Extracellular-signal-regulated kinase Activity-regulated-cytoskeletal protein
CLC: R614
Type: Master's thesis
Year: 2013
Downloads: 37
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Abstract


Post-traumatic stress disorder or PTSD is a anxiety disorder that can trigger intense fear, helplessness or offensive severe in anyone who has experienced a life-threatening or catastrophic events. It cause the long-term adverse effects on patients’ social and family life, physical and mental health. PTSD can be categorized into two types of acute and chronic PTSD:if symptoms persist for less than three months, it is termed "acute PTSD," otherwise, it is called "chronic PTSD."60.7%of men and51.2%of women would experience at least one potentially traumatic event in their lifetime. The lifetime prevalence of PTSD is significantly higher in women than men. Lifetime prevalence of PTSD varies from0.3%in China to6.1%in New Zealand and6.8%in America. Thus effective preventions (mainly for surgery patients) and treatments of PTSD have currently been a hotspot of medical research. Three types of symptoms are prevalent in PTSD:reexperiencing, avoidance and hyperarousal. Reminders of the traumatic event usually trigger reexperiencing and avoidance symptoms whereas hyperarousal symptoms might be present more continuously. Although fear learning is an evolutionarily advantageous response mechanism, when fear learning due to a traumatic event becomes generalized to situations that would normally be considered safe and results in autonomic hyperarousal in inappropriate situations.Under conditions of extreme stress/trauma, stressor-induced sensitization of noradrenergic systems and long-term actions of norepinephrine may well prove maladaptive. Beyond long-term alterations in neuronal circuitry induced by NE at the time of a traumatic event, evidence further indicates that noradrenergic systems may be dysregulated in PTSD. Specifically, noradrenergic systems appear to be hyperreactive in PTSD. There is strong evidence for an involvement of noradrenergic systems in PTSD-related hyperarousal, intrusive memories, and sleep disturbances. A large amount human and animal studies and clinical evidence have revealed that NE system and play an important role in the cognitive process involved in behavior, such as the fear memory and learning.Dexmedetomidine is a highly specific and powerful a2-adrenoceptor agonist, it activate central presynaptic alpha2receptors to play as a sedative, analgesic and anaesthetic drug. Dexmedetomidine is began to use as analgesic in recent years, and in1999the U.S. food and drug administration has approved to used it in intensive care unit patients with mechanical ventilation at first24h. Dexmedetomidine mainly inhibit adenylate cyclase activity, decreases the production of inner cyclic adenosine monophosphate(CAMP) and open the K+channel to increase permeability of K+in postsynaptic membrane to produce membrane hyperpolarization. In this way to inhibit the central nervous system from releasing norepinephrine and give play to the role of sedation analgesia. The LC is the major source of brain NE and the target of dexmedetomidine. A previous study of Pavlovian fear conditioning training in mice shows that when administered before training, dexmedetomidine selectively suppressed discrete cue fear conditioning without affecting contextual memory, dexmedetomidine was administered after training, it suppressed contextual memory. Recent studies suggest that pharmacological disruption of noradrenergic neurotransmission may well be efficacious in treating symptoms of PTSD, such as hyperarousal.There are a variety of animal models for PTSD, such as classic Pavlovian fear conditioning and forced swimming. Although animal models for PTSD are limited to the assessment of measurable and observable behavioral parameters and cannot assess complex psychological symptoms such as intrusive thoughts, meaning and dreams, valid and reliable animal models offer a means for researching biomolecular, pathophysiological, and pharmacological features of the disorder in ways that are not feasible in human studies. Trauma/stress-based models were developed in an attempt to induce in the animal a state similar to PTSD by exposing animals to an equivalent of a traumatic experience, testing the changes in animal behavior and physiology, the research mainly focuse on the fear of associative learning process conditions (fear conditioning) and the formation of associative learning sensitization behavior (sensitization). The rat model of PTSD reported by Rau et al is a new fear conditioning model, when animals are given15shocks first in context A then one shocks the following day in context B after observing the basal freezing, the third day observing freezing in context B, a significantly longer freezing can be observed, this longer freezing is called stress-enhanced fear learning (SEFL). SEFL may bear some similarity to sensitized reactions experienced by PTSD patients in which an innocuous stimulus or mild stressor elicits a reaction more appropriate in magnitude to the original raumatizing event. Synaptic plasticity is an important molecular function of learning and memory, Previous studies showed that removal of Arc in knockout (KO) animals results in an unusual phenotype:short-term learning is normal but lasting memories cannot be formed. Arc, therefore, provides a means to understand the cellular processes of memory consolidation. However, Arc has multiple functions and responds differently to different stimuli and signaling pathways. ARC is through a variety of mechanisms involved in synaptic plasticity to participate in the regulation of memory formation. The extracellular-signal-regulated kinase (ERK) is a central node of the signaling pathways downstream of these receptors and is required for increases in Arc transcription. So this study intends to observe the behavior of rat preventively given different doses of dexmedetomidine befor training, and analyses the influence of the expression of p-Erk and the Arc, to understand the molecular mechanisms of its effect.Object:Using the existing experimental technology (PTSD rats behavior determination method, central nucleus trace protein analysis method for determination of the molecular biology) to evaluate the effects on prevention of post-traumatic stress disorder (PTSD) in rats and hippocampus extracellular signal regulating kinase (Erk) activity and activity-regulated-cytoskeletal protein (Arc) expression when administered dexmedetomidine before training in different concentrations and the time, and further to explore the influence of dexmedetomidine on prevention of PTSD.Method:Using the rat model of PTSD reported by Rau et al, one hundred adult male Sprague-Dawley rats were randomly divided into four groups. The rats in group NS were injected intraperitioneally (i.p.) with saline (2ml)30min before training in the Context A at the first day, while group D1, D2and D3with dexmedetomidine0.3μg/kg,3.0μg/kg and9.0μg/kg respectively. At the first day sixteen rats (n=4for each point) in each group were euthanized at15min,30min,60min,90min after training in Context A, and hippocampus was taken for western blot analysis to assay the expressions of extracellular signal-regulated kinase42/44(ERK42/44) phosphorylated ERK42/44(p-ERK42/44) and activity-regulated-cytoskeletal protein (ARC). At the second and third day, the rest took behavioral testing, and the ratio of freezing was recorded.PTSD model preparation:Animals are given15shocks (each1mA, last1s, between240~480s) in context A on the first day. Animals are given one shock (1mA, last1s) the following day in context B after observing the basal freezing, rats were removed from the chamber after an additional32s. On day three, animals are transported in their homecages to context A and given an8min32s context test, and record freezing. If day three freezing significantly higher than day two suggests that model successfully set up.The data was analyzed by SPSS13.0statistic software. Values were presented as means±SD. Comparisons among groups were performed by one way ANOVA analysis. If the variance to be equalized, two sets data were analyzed with LSD test. If the variance to be not equalized, two sets data were analyzed with Dunnett’s T3test. P<0.05was considered significant.Result:1. Behavior resultAt the second day there was no significant difference about the ratio of freezing in the Context B among four groups (P>0.05. Compared with the second day, the ratio of freezing of four groups significant increased (P<0.05). Compared with the group NS, only the group D2and D3showed a significant decrease about the ratio (P <0.05). There was no statistically significant difference in group D1(P>0.05) There was no statistically significant difference about the ratio of freezing on third day between group D2and D3(P>0.05)2. Western blot2.1The level of phosphorylation of Erk and Erk in rat hippocampus After the training in the Context A at first day, there was no statistical differences of the expression of total ERK42/44at each time in group NS (P>0.05). The expressions of p-Erk42/44in hippocampus of rats in group NS reached peak at15min after the training in the Context A at first day (P<0.05). There was no significant difference about the expression of total ERK42/44among four groups. After the training in the Context A at first day, compared with group NS, groups D2and D3showed a significant decrease of the expression of p-ERK42/44at15min in a dose-dependent manner (P<0.05), no statistically significant difference in group Di (P>0.05). There was no significant difference about the expression of total ERK42/44between group D2and D3(P>0.05)2.2the level of Arc in rat hippocampusThe expressions of Arc in hippocampus of rats in group NS reached peak at30min after the training in the Context A at first day (P<0.05). After the training in the Context A at first day, compared with group NS, groups D2and D3showed a significant decrease of the expression of Arc at30min in a dose-dependent manner (P <0.05), no statistically significant difference in group Di (P>0.05). There was no significant difference about the expression of Arc between group D2and D3(P>0.05).Conclusion:Fear memory formation for traumatic events is the basis for the development of PTSD. Rau et al pointed out that animals received15shocks in Context A on the first day is the key to appear SEFL in Context B on the third day. Hippocampus is an important neural structures of conditioned fear learning, it provide environmental information for the basolateral amygdala. Arc is specifically required for long-term memory formation and affects all of these forms of synaptic plasticity, recent studies have found that it was also involved in the process of learning and memory. The extracellular-signal-regulated kinase (ERK) is a central node of the signaling pathways downstream of these receptors and is required for increases in Arc transcription. The preventive effects on PTSD of dexmedetomidine probably result from inhibiting the activity of p-ERK in hippocampus and then decreasing the expression of ARC, finally impairing fear memory formation of traumatic events..This experiment for the first time found the dexmedetomidine for PTSD has prevention effect, so it may reduce patients with intraoperative awareness during general anesthesia to develop PTSD.

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