Study On The Cardio-Cerebrovascular Protective Effect And The Substance Bases Of Cerebralcare Granule~?

Hypertension and dementia are complications.They have become the major threat to human public health.Cerebralcare granule（CG）,a Chinese patent medicine,has been used for the treatment of cardiovascular and cerebrovascular diseases.It has been clinically clear that it has the effects of lowering blood pressure and antidementia.However,there is a lack of research on the modern pharmacology and pharmacological basis of CG.Therefore,this thesis was performed to investigate the antihypertensive and neuroprotective effects as well as the substance bases of CG systematically.Firstly,antihypertensive and neuroprotective effects of CG were studied.（1）The present results suggested that CG induced relaxation in rat aortic rings through endothelium-dependent pathways mediated by the activation of NO/cGMP,CO/HO and H₂S/CSE and endothelium independent pathways involving blockade of Ca²⁺channels,inhibition of Ca²⁺mobilization from intracellular stores,and opening of K_ATP channel.（2）Data in the present study demonstrated that oral administration with CG could induce a potent antihypertensive effect that was partly due to the improvement of endothelial function and the regulation of serum NO and H₂S.In addition,the present results indicated that CG played a critical protective role against pressure overload-induced cardiac hypertrophy.CG not only inhibited the development of cardiac hypertrophy but also improved ventricular function.（3）The present study demonstrated that chronic administration with a high dose of D-galactose（D-gal）could induce significant neurobehavioral and neurochemical deficits.Our findings also showed that CG could protect mice against learning and memory impairment induced by D-gal through the inhibition of the cholinergic deficiency,attenuating oxidative stress,inhibiting inflammation responses,and neurodegeneration.These data clearly demonstrated that CG could protect neuron injured by D-gal and improve memory ability.Secondly,an UPLC-Q-TOF-MS method was established and a total of 47compounds were identified or characterized in CG.In addition,tetrahydropalmatine（THP）was detected in rat plasma after CG oral administration.The pharmacokinetic results revealed that the plasma concentration of THP increased rapidly in the first half hour after a single oral dose of THP to rats.Molecular docking results showed that THP had a good inhibitory activity against enzymes ACE and AChE.Thirdly,cardiovascular protective and neuroprotective effects of THP were studied.（1）Our data demonstrated the endothelium dependent and endothelium independent vasorelaxant effects of THP.The endothelium dependent pathway was the result of activation of NO/cGMP signaling pathway.The endothelium independent pathways were involved in blockading of VDCCs,inhibition of Ca²⁺mobilization from intracellular stores,activation of K_ATP channel,and the stimulation of muscarinic receptor.（2）The present study demonstrated that chronic administration with a high dose of D-gal could induce significant neurobehavioral and neurochemical deficits.Our findings showed that THP could protect rats against memory impairment induced by D-gal through attenuating oxidative damage and reversing the abnormality of ACh level and AChE activity.In addition,treatment with THP could decrease the expression of NF-κB and GFAP which prevented the neuroinflammation triggered by D-gal.These data suggest that THP is beneficial in treatment of aged-related conditions.Taken together,this thesis investigated the antihypertensive effect,antidementia effect,and the substance bases of CG systematically.All these researches provide a theoretical basis for the application of CG.