Effect Of Hydroxy Safflower Yellow A On Cognitive Function In Ischemic Stroke

ObjectivesStroke is composed of two types,including ischemic stroke and hemorrhagic stroke.The ischemic stroke has a higher morbidity than hemorrhagic stroke and is the most common pathological type of stroke in clinical.Stroke can lead to vascular cognitive impairment(VCI),not only damage the ability of daily life,but also increase the risk of re stroke,and even cause dementia.If the patient can be diagnosed accurately in mild cognitive impairment,and be able to carry out early intervention on the risk factors,it’s likely to delay or even prevent the occurrence of dementia.But at present,there are few effective drugs and methods for the treatment of ischemic stroke。Traditional Chinese medicine believes that the disorder of blood and blood stasis will lead to ischemic stroke.Safflower(Carthamus tinctorius L)is one of the effective drugs in traditional Chinese medicine for improvingthe treatment of blood circulation in traditional Chinese medicine.The main component of safflower is the Safflower yellow(SY)in the petals,while the content of hydroxy safflower yellow A(HSYA)has a high proportion in SY.There have been increasing reports concerning the clinical use of HSYA in the treatment of ischemic stroke,demonstrating promising efficacies and sufficient safety.However,the challenges remain mainly due to the lack of consistency in the effectiveness and the short therapeutic window of HSYA。Furthermore,whether or not the HSYA treatment could also rescure the cognitive impairment induced by ischemia and the neuronal signaling changes underlying this action of HSYA are still not fully understood。In clinical practice,HSYA is commonly given to the ischemic patients via intravenous injection,while animal studies demonstrated that the caudal vein administration of HSYA could take several advantages relevant to improvement of therapeutic efficacy over the intravenous injection.In this study,we investigated the therapeutic effects of HSYA and its relationship with the therapeutic time windows in the MCAO rats following the caudal vein administration,We also examined the modulating effects of HSYA on neuronal JAK2/STAT3/SOCS3(Janus Kinase/Signal Transducer and Activators of Transcription/suppressor of cytokine signaling)signaling pathway responsible for the cognitive improvement role of HSYA.MethodsTransient focal cerebral ischemia and reperfusion rat model was established by unilateral middle cerebral artery occlusion(MCAO)for 1.5 hours.The therapeutic effect of HSYA on ischemic stroke was examined by using carotid artery injection with different concentrations of HSYA(4mg/kg,8mg/kg,16mg/kg)at different time points(3h,6h,9h)after stroke.The efficacy was evaluated by neurological function score,cerebral edema status and the cerebral infarction volume.The effects of HSYA on cognitive function of ischemic rats were tested by several behavioral assays including the open field test,water maze and passive avoidance test.To investiage possible molecular signaling pathway underlying the effectiveness of HSYA,we also examined the expressional changes of JAK2/STAT3/SOCS3 signaling pathway in response to HSYA treatment in the rats.Results(1)when the dose of 8mg/kg or 16mg/kg HSYA was given after 3h of ischemia and reperfusion,the neurological function score was increased,while the cerebral infarct volume and the brain water content were decreased in the ischemic rats.No significant difference was found between the groups when give the same doses of HYSA after 6h or 9h of ischemia and reperfusion.(2)The results of open field test,water maze test and passive avoidance test showed that the treatments of 8mg/kg and 16mg/kg can improve learning and memory to a certain extent.(3)when 8mg/kg or 16mg/kg HSYA was given after 3h of ischemia and reperfusion,the expressions of STAT3,JAK2 and SOCS3 were increased,while phosphorylated forms of these proteins were decreased.However,there was no significant change in the protein expressions when give same doses of HYSA after 6h and 9h of ischemia and reperfusion.ConclusionsHSYA has a protective effect on ischemic stroke as indicated by the reduced cerebral infarction volume,increased neurological function score,and reduced cerebral edema in the MCAO rats treated by HSYA.Moreover,HSYA treatment can activate the JAK2/STAT3/SOCS3 signal pathway,which can protect the cells,reduce apoptosis and improve the cognitive function after ischemic stroke.The effective dose of HSYA is 8mg/kg and 16mg/kg,and the bioavailability of carotid artery injection is greater than that of intravenous injection.Our results suggest that modulation of JAK2/STAT3/SOCS3 signal transduction might be a potential target of HSYA in treatment of cerebral ischemia.