Therapeutic Effects Of BBA In Rodent Model Of Parkinson's Disease And Its Underlying Mechanisms

Aim: To investigate the therapeutic effects of BBA on experimental Parkinson's disease (PD) and its underlying mechanismsMethods: Rodent PD models were produced by unilateral lesion of substantia nigra with stereotaxic microinjection of 6-hydroxydopamine (6-OHDA). Twenty-two days later, L-dopa induced contralateral rotations were used to determine the behavioral deficits of rats. The expression of tyrosine hydroxylase (TH) in SN or striarum was examined by immunohistochemistry. Nissl staining was taken to determine the loss of SN DA neurons. In model animals and animal pretreatment with SN50 (a translocation inhibitor of NF-κB), double immunofluorescence of TUNEL and p65 was used to explore the relationship between apoptosis and NF-κB activation. Twelve or twenty-four hours after 6-OHDA lesion, immunohistochemistry was used to examine the expression of nuclear factor-kappa B (NF-κB) p65 ,inhibitory kappa B alpha (IκBcα), inducible nitroxide synthase (iNOS), p53, Bcl-2, heat shock protein 60 (HSP60). At 3 h, 6h, 12 h, 24 h and 60 h after SN lesion, immunohistochemistry was used to study the effects of intraperitoneal injection of BBA on the expression of NF-κB p65, IκBα, Bcl-2 and iNOS.Result: The results showed that BBA could significantly reduce L-dopa-induced contralatoral rotations (p<0.01, n =6). In 6-OHDA-lesioned SN, most TH-positive neurons disappeared, while in BBA-treated rats there were more survival neurous observed. The neuroprotective action of BBA was most potent at the dose of 10 mg.kg^-1.d^-1 (p<0.01, n=6). In the striatum, more TH expression was found in BBA-treated rats than that of model rats. In lesioned SN, gliosis was obvious, and BBA treatment lessened gliosis. More TUNEL-positive cells were observed in neurons with activated p65 than that with inactivative NF-kB. After SN50 adminstration, TUNEL-positive cells decreased. Compared with model rats, at 3 h> 6 h> 12 h after SN lesion, BBA treatment initially increased the translocation of NF-Kb p65, but decreased its nuclear translocation 24 h and 60 h later. Similarly, in BBA- treated rats degradation of IkBo. was enahnced 3h > 6 h> 12 h% 24, h but reduced 60 h after lesion. At 24 h, BBA blunt the elevated expression of p53. In addition, BBA could increase the expression of HSP60 at 12 h after SN lesion. In contrast with model rats, the protein levels of iNOS decreased in BBA-treated rats while the antiapoptosis protein Bcl-2 increased 3 lu 6 h^ 12 h and 24 h after SN lesion.Conclusion: BBA initially promotes 6-OHDA-induced IkBcc degradation and NF-kB activation but blocks persistant activation of NF-kB, reduces expression of proapoptotic proteins p53 and iNOS, and increases expression of antiapoptotic proteins Bcl-2 and HSP60. These results suggest that BBA may have therapeutic value in treatment of PD.