TRPV1 Activation By Capsaicin Afford Neuroprotection In Parkinson's Disease Rats

Background and Objective:The decrease of dopamine(DA)and its metabolites in dopaminergic neurons caused by denatured dopaminergic neurons is the main cause of Parkinson's disease,and the degree of reduction is positively correlated with the degree of dopaminergic neuron loss.Tyrosine hydroxylase(TH)is a DA synthesis rate-limiting enzyme.Studies have shown that the content of TH in PD patients and PD animal model was significantly decreased.Therefore,increasing the level and activity of TH has become an important therapeutic strategy for slowing PD progression.TRPV1(transient receptor potential vanilloid subfamily member 1)is a non-selective cation channel which can be activated by Capsaicin.Traditionally,TRPV1 was considered involving in broad areas of disease,including pain(inflammatory,visceral,cancer,and neuropathic),inflammatory bowel disease,interstitial cystitis,urinary incontinence,airway diseases,pancreatitis and migraine,Its mechanisms include inflammation,immunity,apoptosis,oxidative stress and many other aspects.Recently,research demonstrated that TRPV1 was not only highly expressed in sensory neurons but also presented in various brain zones and contribute to the cellular processes involved in neuronal death.Moreover,evidences proved that TRPV1 significantly reduced markers of oxidative stress,brain infarction,and lessened deficits in motor and cognitive function.Suggesting that it may play a role in the pathogenesis of neurodegenerative diseases.In this study,we used 6-OHDA-induced Parkinson's disease rat model to explore the neuroprotective effect of TRPV1,and provide theoretical basis for its potential as a new target for drug therapy.Research methodsMale Wistar rats weighing 220g-250g(Experimental Animal Center of Shandong University,Ji Nan,China)were used.The animals were randomly allocated to 4 groups as Control(n=20),SOG(sham operating group with stereotaxic injection of saline,n=20),6-OHDA(6-OHDA induced group without capsaicin treated,n=40),and CAP(6-OHDA induced group with capsaicin treated for continual 7 days initially after the operating,n=40).Behavioral testing(Rotational behavior test and Open field test)was performed on rats.Western blot analysis and immunohistochemistry were performed to detected the level of TH.CAT,SOD and MDA in rat brain were also measured.All values are expressed as mean ± SD,Statistical significance(p<0.05 for all analyses)was assessed by t-tests using GraphPad Prism 5.0(GraphPad Software,Inc.).Results1.Unilateral MFB lesions in rats of CAP significantly decreased the number of contralateral rotations when compared to the rats in 6-OHDA(n=10,p<0.01).In the open field test,the CAP rats traveled over a longer total distance(n=10,p<0.05),spent a shorter time(n=10,p<0.05)and got faster average speed(n=10,p<0.05)duration in the center than the 6-OHDA model group.2.Compared with 6-OHDA rats,a higher level of TRPV1 was observed in SN(n=6,p<0.01)and striatum(n=6,p<0.01)of the CAP group.the protein expression of TH in the SN and striatum of the CAP rats was higher than that of the 6-OHDA rats group(n=6,p<0.01).3.The result of immunostaining showed that capsaicin increased the number of TH+ cells and density of TH+ fibers in the SN and striatum at CAP group compared with 6-OHDA rats.4.The results indicated that treatment with capsaicin showed significant(n=6,p<0.01)decrease in MDA level compared to 6-OHDA rats in right SN and striatum.Treatment with capsaicin significantly increased CAT(n=6,p<0.01)and SOD(n=6,p<0.01)activity compared to 6-OHDA rats in right SN and striatum.In the left SN and striatum,these three experiment indexes have no differences between model rats treated with capsaicin and 6-OHDA rats(n=6,p>0.05).ConclusionTRPV1 activation by capsaicin protects against loss of dopamine neurons and provides behavioral recovery in the 6-OHDA rat model of Parkinson's disease via inhibiting oxidative stress.