| Background:Sepsis is an infectious host reaction characterized by systemic inflammatory response. Sepsis and its complications are the diseases and lethal factors happening most in ICU. There are about 750000 patients in America suffering from sepsis every year and the average mortality is 29%. Septic encephalopathy(SE) is the brain dysfunction happening most in ICU which is caused by sepsis and systemic inflammatory response.Cognitive impairment is a clinical syndrome featured by the abnormal of one or more functions of brain, including memory, learning, attention, the speed of thinking,, visual ability and mentality. A prospective cohort study p ublished on JAMA prove firstly that survivors of severe sepsis are triple as likely to gain cognitive impairment from middle to severity degree than non-sepsis patients. Long-term follow- up study show that most cognitive functions of sepsis survivors can recover in several years, b ut some recover badly, such as learning and memory.IGFs involve IGF-1 and IGF-2. They play a significant role in controlling differentiation and proliferation, growth and development, immunity and metabolism。They can also prevent apoptosis. After birth, most functions of IGF-2 are lost most of its functions, whereas IGF-1 remains keeping various physiological actions. Inflammatory mediators produced in sepsis can decrease the level of IGF-1 in circulation. Besides, the level of IGFBP in circulation or local tissues is increased during sepsis. Then it can bind more IGF-1, resulting in the decrese of level and bioactivity of IGF-1. All these effects of IGF-1 are tightly associated with the reciprocal action between IGF-1 and immunity system.Some studies found that cognitive dysfunctions in old people were not related to the increase of age, whereas they was significantly related to the decreased level of growth hormone(GH). Besides, GH deficiency origining from childhood will impaired patient’s cognitive functions in adulthood, while it can recover when receiving GH replacement treatment for a period of time. They also found that memory improvement was weakly related to the mean daily GH dose, but positive cor related to the GH- induced increase of IGF-I in circulation, indicating that IGF-1 was the direct specific molecule which improved cognitive functions. Moreover, studies found that both the level of IGF-1 in circulation and its expression in neuron were decreased during hypoxia- ischemia brain damage in neonate rats. Intraventricular injection of IGF-1 could protect brain from hypoxia-ischemia impairment in rats. Besides, subcutaneous injection with IGF-1 could not only protect neuron and inhibit its apoptos is, but also improve long-term memory and cognition in hypoxic- ischemic encephalopathy. All these effects indicated that brain injury in hypoxic- ischemic encephalopathy was tightly related to the decreased level of IGF-1 during the process of illness.Although the cognitive ability is injured and the IGF-1 level is decreased in sepsis; and previous studies have found that impairment of cognition is tightly assciated to the IGF-1 decrease on some diseases, whether IGF-1 can improve cognitive function and protect brain in sepsis is still unclear.Our research is to estimate the function and mechanism of IGF-1 in cortex injury andbehaviral, cognitive and emotional change during sepsis. Thus may put forward a new target for the treatment of septic encephalopathy.Aims:1. To evalute the expression and the function of IGF-1 in rat’s cortex during sepsis.2. To explore the role and the mechanism of IGF-1 in rats’ emotional, behaviral and cognitive change.Methods:1. CLP was used to induce Sepsis, some rats were given IGF-1 through lateral ventricle. Then IGF-1’s impact on cortex was studied. The change of the reflection of central nervous system was evaluated by using the neurologic behavior scores. The expression of IGF-1 in cortex of septic rats was evaluated by immunofluorescence and western blot. Cell apoptosis and caspase-3 expression in cortex of septic rats were extimated by TUN EL and western blot respectively.2. Sepsis was induced by CLP and a part of the rats were given IGF-1 through enterocoelia. Ten days later, the change of behavior, cognition and emotion as well as the role of IGF-1 on them were studied. Rat survivors during the 10 days after operation were counted and then making survival analysis. Open field test, The forced swimming test, Morris water maze test and Passive avoidance test were implemented to detect behaviral, cognitive and emotional change and the role of IGF-1 on them.3. CLP were performed and animals were divided into 5 groups. IGF-1 began to be given through abdominal cavity 0hrs, 6hrs, 12 hrs, 24 hrs or 36 hrs after CLP respectively. Behavioral study was conducted10 days later. Open field test, Morris water maze test and Passive avoidance test were implementedto assess the function of IGF-1 on learning and memory at different drug administration time.4. Rats were received CLP operation and parts of the rats were intraperitoneal injected with IGF-1. Then, neuron apoptosis of hippocampus was observed 12 hours after CLP and the expression of apoptosis related proteins was tested 6 and 12 hours after C LP. TUNEL and Nissl’s staining were conducted to observe the apoptosis and the neuron number in rats’ hippocampus respectively. The change of Cyt C, caspase-9, TNFR and caspase-8 expression at 6 hours and 12 hours after CLP were tested by western blot.Results:1. In the cerebral cortex of septic rats, IGF-1 was decreased and cell apoptosis was increased, nervous reflex of septic rats was impaired. When e xogenous IGF – 1 was given, nervous reflex was improved and cell apoptosis in cerebral cortex was decereased, indicating that impairment of cells in cerebral cortex was related to the decreasion of IGF-1 during sepsis.2. IGF-1 could not improve survival rate of rats during sepsis.3. The ability of motor and environment adaption of septic rats were not impaired, but the memory to circumstance and noxious stimulation as well as spatial learning and memory were impaired. Besides, depression mood existed in septic rats. When exogenous IGF – 1 was given, improvement of the memory to circumstance and noxious stimulation as well as spatial learning and memory were observed, but the improved effect was not observed in depression mood.4. The memory to circumstance and noxious stimulation as well as spatial learning and memory were obviously improved when IGF-1 began to give during the first 6hrs after C LP, but the improved effect could not observe as IGF-1 was given for the first time 12 hrs after CLP, indicating that the best time of IGF-1 to protect memory and learning may be the early phase of sepsis(within 12 hours).5. 12 hrs after C LP, neuron apoptosis in hippocampus was increased, and IGF-1 could prevent it. 6hrs after CLP, the increased expression of cytochrome C and caspase-9 was observed, while that was not observed in the expression of TNFR and caspase-8. 12 hrs after CLP, the increased expression was not only observed in cytochrome C and caspase-9, but also in TNFR and caspase-8. IGF-1 could inhibit the increase of all of them.Conclusion:1. In septic rats, IGF-1’s level in cortex was decreased and cell apoptosis in cortex was increased. IGF-1 could inhibit cell apoptosis and caspase-3 expression in cortex, indicating that some molecules in caspase-3 pathway maybe the target of IGF-1 to prevent cell apoptosis in cortex.2. The outcome of behavioral experiments indicated that during sepsis, cognitive ability were injured and depressive- like syndromes were induced. Exogenous IGF-1 could improve cognitive functions instead of depressive emotion, indicating that IGF-1 maybe a potential drug to reduce cognitive sequelae after sepsis.3. The protective effect of IGF-1 on cognitive functions during sepsis had time-dependent characteristics. When IGF-1 was given early, the protective effect is obvious. But when IGF-1 was given 12 hrs after CLP, the protective effect is weak.4. IGF-1 may play an anti-apoptosis role by preventing the Cyt C pathway and TNFR pathway. The increase of C yt C was observed in the early time of sepsis, while the increase of TNFR expression was later than Cyt C expression, that may explained why the protective effect of IGF-1 in sepsis was obviously only when IGF-1 was given in the early phase o f sepsis. |
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