Mechanism Of Fatigue Induced Brain Injury And Protective Effect Of Chang-chih Against Stroke In Shrsps

Stroke, as a major refractory disease in today’s society, seriouslyendangers the health and quality of life, and imposes a heavy burden onindividuals, families and society because of its high incidence, highmorbidity and high recurrence rate. Thus, prevention and treatment ofstroke are of great importance. In addition to the classical risk factors suchas hypertension and diabetes, fatigue is also reported to relate to the onsetof stroke. Previous studies were mainly focused on the increased recurrentrisk of stroke caused by fatigue, whether fatigue can induce the onset ofstroke as an independent risk factor is still unclear.We used a middle cerebral artery occlusion model to study whetherfatigue could increase the susceptibility of ischemic stroke and to explorethe underlined mechanisms related to increased cerebral infarction. MaleSprague-Dawley rats were deprived of rest for5consecutive days in a cagefilled with water to a height of1.5cm as described previously to makefatigue model, and suffered a rat middle cerebral artery occlusion (MCAO)model to be ischemic stroke. As a result, fatigue groups induced by sleepdeprivation significantly increased cerebral infarction area followingMCAO[(8.65±0.015) vs (23.42±0.046), P <0.05].According to the present research, it is generally believed that theoccurrence of stroke is related to the hypercoagulable state and the increaseof the FIB content. In order to explore the internal mechanism ofsignificantly increased cerebral infarction area of fatigue rats, we tested thefatigue rats’ four items of blood coagulation. The results showed thatProthrombin time, Activated partial thrombopalstin time and Thrombin time did not change significantly (P>0.05), but the content of FIB wasincreased significantly [(297.44±7.21)vs (584.75±6.48), P <0.05].According to the report, the promoter region of FIB gene exists in theresponse element of IL-6, IL-6can be combined with the IL-6receptor inthe promoter region, so as to promote FIB transcription and translation. Toexplore how and by what means the body regulates the synthesis of FIBafter fatigue, we measured the content of plasma IL-6and FIB of fatiguerats. The results showed that, with the increase of the degree of fatigue, theplasma levels of FIB and IL-6had an increasing trend. So, we speculatethat IL-6can regulate and can control the FIB synthesis.In order to prove this regulation, we introduced IL-6gene knockoutmice. Compared with the wild-type mice, the content of FIB of IL-6knockout mice is significantly lower(P <0.05), and the content reboundafter treating knockout mice IL-6through tail vein, which indicated that,elevating FIB level during fatigue was probably mediated by IL-6, but it isnot the only regulation fator. In order to further explore the relationshipamong fatigue, cerebral infarction, IL-6and FIB, we used IL-6knockoutmice, and treated mice benzene (Bezafibrate is a kind of drugs to treathypolipidemic, and also can reduce the content of plasma FIB) at the sametime to find the connection. The results showed that, regardless ofdecreasing the content of FIB or eliminating the inhibition of IL-6, cerebralinfarction area was significantly decreased.In conclusion, fatigue can increase the susceptibility to ischemicstroke and it is linked to IL-6induced expression of fibrinogen.Stroke brings serious consequences for society and the individuals. Atpresent, there are few ideal methods to prevent the stoke. We choosespontaneously hypertensive rats (SHRSPs) as our research objects to assessthe protective effect induced by drugs. We treat SHRSPs with Chang-chihfor a long time to study whether Chang-chih can prolong the lifespan ofSHRSPs, and if so, explore the underlying mechanisms with2-DE. As a result, Chang-chih significantly prolonged the lifespan of SHRSPs [(114±2.3)d vs(157±4.72)d, P <0.05], and differentially expressed proteins wereidentified as glutathione S-transferase (GST) and superoxide dismutase(SOD). The expression of GST and SOD was confirmed by western blot aswell. Further study revealed that the items related to oxidative stress werealso changed: the enzyme activity of GST and SOD increased [GST:(40.33±5.24) U·mg-1protein vs (70.50±6.24) U·mg-1protein, P <0.05; SOD:(109.25±23.606) U·mg-1protein vs (192.60±23.95) U·mg-1protein, P<0.05], the level of MDA decreased [(3.96±0.45) nmol·mg-1vs (2.04±0.31) nmol·mg-1, P <0.05] and total anti oxidative capability decreased aswell[T-AOC:(66.48±16.17) U·g-1protein vs (124.75±28.43) U·g-1protein,P <0.05]. Therefore, we believe that long term treatment of Chang-chihcan prolong the lifespan of SHRSPs, this is probably related to increasedactivity of anti oxidative enzymes such as SOD and GST.