Agmatine Improves Hypothermic Response In A Streptozotocin-induced Alzheimer Rat

The main pathological feature of Alzheimer’s disease(AD) is hippocampus and cortical neuron degenerative changes. There are two signs of pathological changes that neurofibrillary tangles and senile plaques, and the hyperphosphorylation of Tau protein in neuron is the structural basis of neurofibrillary tangles inside nerve cells are formed. Tau protein hyperphosphorylation not only associated with aging, cognitive impairment, and memory loss of AD, but also affects the function of the hypothalamus. As is known to all, Hypothalamus plays an important role in thermoregulation. Does AD affect the body temperature regulation function, has not been reported. Therefore, we investigated that the effect of AD on thermoregulation and improving effect of the agmatine on changes in body temperature.PartⅠ Hypothermic response in STZ-induced AD rat model and improving effect of the agmatine on changes in body temperature ObjectiveThe pathological changes of AD accumulate in the hypothalamus. But little is known about the AD whether affect the thermoregulatory function. Intracerebroventricular administration of streptozotocin(STZ) induces pathological and behavioral alterations similar to those observed in AD. Therefore, we established AD model to observe changes in body temperature and activity. At the same time, to investigate the effect of AGM on the body temperature change of AD rats.Main methodsMale SD rats(180g-220g) were randomly divided into three groups: control group, STZ+Saline(Sal) group and AGM Treatment group. The control group was Intracerebroventricular injected with citrate- sodium citrate buffer, and the other two groups were injected with STZ; the control group and the STZ+Sal group were injected with intraperitoneal injection of Sal 14 days after the lateral ventricle injection, while the AGM Treatment group was injected intraperitoneally with AGM. Morris water maze and morphological verification were performed at 2 weeks after operation, after that; continue to carry out other experiments.(1) The circadian rhythm of core temperature and motor activity was measured in undisturbed rats using telemetry at an ambient temperature of 22°C during a 12 h light: 12 h dark photoperiod. To observe the changes of body temperature and activity of AD rats and the effect of AGM on the changes of AD rats;(2) Changes of energy metabolism and the effect of AGM on energy metabolism in AD rats by CLAMS of Columbus Instruments continuous 48 h measurement in AD rats;(3) The discharge frequency of sympathetic nerve of dominated BAT in rats was recorded by BL-420 S Data Acquisition and Analysis System Performance of Chengdu Taimeng Software Co.LTD. To observe the changes of sympathetic nerve discharge in AD rats and the effect of AGM on the changes of sympathetic nerve in AD rats with BAT.(4) Elisa was used to measure the levels of thyroid stimulating hormone, thyroid stimulating hormone and thyroid hormone in the serum of 14 d rats after injection of the lateral ventricles. Main result(1) Core temperature of STZ+Sal group rats was 0.76°C lower than that of control group rats during the light phase(P<0.05);0.64 °C lower than the control group in the dark period of body temperature of rats in the STZ+Sal group(P < 0.05). However, after 14 d continuous intraperitoneal injection of AGM in rats, the body temperature was similar to that in the control group, and was significantly higher than that in the control group(P < 0.05). In the light period, STZ+Sal group and AGM TREATMENT group rats activity was significantly higher than the control group(P < 0.01), while in the dark period. The activity of STZ+Sal group rats was significantly lower than the other two groups(P<0.05).(2) During the dark phase, heat produced in STZ+Sal group rats was significantly lower than that of the control group(P<0.05), For 14 d after administration of AGM, the rats of the dark phase heat production was consistent with the control group and was significantly higher than STZ+Sal group(P<0.05). There was no significant difference between the three groups in the day light period.(3)The frequency of sympathetic nerve discharge in STZ+Sal group was significantly lower than that in control group(P<0.05). The frequency of sympathetic nerve discharge in AGM Treatment group was similar to that in control group, and was significantly higher than that in STZ+Sal group.(4) The levels of TSH, TRH and FT4 and TT4 in STZ+Sal group were significantly lower than those in the control group, Give continuous 14 days after intraperitoneal injection of AGM, serum thyroid hormone levels have risen, similar to the control group, and was significantly higher than in STZ+Sal group. Conclusion(1) The core temperature of AD rat model was significantly lower than control group, and AGM could significantly improve the hypothermic response of AD rat model.(2) AD rat’s model body temperature is lower than the control group relating with decrease of heat production. And AGM can increase the heat production of AD rats.(3) Innervation of BAT sympathetic nerve discharge frequency of AD rats is lower than the control group。It is proved that the reduction of basal body temperature in AD rats is related to the decrease of BAT production, because the heat produced by BAT is controlled by sympathetic nerve. And AGM can improve the basal body temperature of AD rats, which may be related to the frequency of sympathetic nerve discharge.(4) The decrease of body temperature in AD rats may be related to the decrease of thyroid hormone levels, which may be caused by the abnormal function of the hypothalamic-pituitary- thyroid axis due to the pathological changes of AD. AGM can improve the level of thyroid hormone in AD rats.PartⅡ Effect of AGM on stress induced temperature changes in AD rat model ObjectiveStress is the body’s important defensive reaction, through the coordination of the nerve- endocrine system to make reaction of the whole body, when the injury in the central nervous system(CNS), the body will appear abnormal stress response, so that the body cannot tolerate outside or mental stimulation, on the body caused serious damage. AD is neurodegenerative disease, involved in the stress response in multiple brain areas will be affected, Therefore, we take the change of stress temperature as the index of AD stress reaction to observe the stress response of AD rats and the effect of AGM on stress induced temperature changes in AD rats. Main methods(1) Male SD rats(180g-220g) were randomly divided into three groups: control group, STZ+Sal group and AGM Treatment group. The control group was Intracerebroventricular injected with citrate- sodium buffer, and the other two groups were injected with STZ, The control group and the STZ+Sal group were injected with intraperitoneal injection of Sal 14 days after the lateral ventricle injection, while the AGM Treatment group was injected intraperitoneally with AGM. The animal models of stress-induced hyperthermia were duplicated by placing rats in open field chamber, Measurement of body temperature and activity in rats using telemetry.(2) The levels of CRH, ACTH, NA and EP in serum of rats were determined by Elisa, Analysis of the differences between STZ+Sal group and control group, as well as the effect of AGM on the level of CRH, ACTH, NA and EP in serum of AD rat model. Main results(1) In the control group, the body temperature rose rapidly from 37.35±0.11℃ to 38.28 + 0.14℃when placing rats in open filed chamber and then decreased slowly. AGM Treatment group into the open filed chamber, the average decline of 0.58 + 0.17 ℃. the temperature dropped an average of 0.58 + 0.17 ℃. After long-term administration of AGM, the rats were put into the open filed chamber, and the temperature change curve was similar to the normal rats.(2)The levels of CRH, ACTH, NA and EP in the serum of STZ+Sal group were significantly lower than those in the control group(P<0.05). CRH and EP decreased more significantly(P<0.01). After 14 days of intraperitoneal injection of AGM in rats, the levels of serum hormone levels were similar to those in the control group, and were significantly higher than those in the STZ+Sal group, Among them, the level of EP was the most obvious(P<0.01). Conclusion(1) AD rats did not appear stress hypertermic responses, indicating that the stress response of AD rats decreased, and AGM can restore the stress response of AD rats.(2) Involved in the stress response of CRH, ACTH, NA and EP levels decreased significantly, proved that the stress reaction was weakened of AD related to significantly decreased with the levels of CRH, ACTH, NA and EP in vivo. AGM was able to restore the stress response of AD rats and the levels of EP, ACTH, NA and CRH in vivo.