NP-6 Rb Fraction Combined with Levodopa Prevent Parkinson Disease by Protecting Neurovascular Unit

Object:Parkinson disease(PD)is the second most common progressive neurodegenerative disorder.The available therapies for PD only treat the symptoms of the disease,without neuroprotective and disease-modifying effects.Drugs that enhance intracerebral dopamine concentrations or stimulate dopamine receptors remain the mainstay of treatment for motor symptoms.Levodopa(L-DOPA)provides the greatest symptomatic benefit,but longterm using not only gradually loses its efficacy but also is associated with motor and non-motor complications,limiting function and reduce quality of life in PD patients,due to the disease progresses and medication.We previously showed that Rb fraction of ginsenosides blocks the PD progression and prevents the development and expression of L-DOPA-induced side effects.Given multiple cell types and impaired blood brain barrier(BBB)involve in the PD’S pathogenesis,this study further explores whether Rb alone or combined with L-DOPA could modify PD and protect neurovascular unit.Methods:Their anti-Parkinsonian activity was evaluated in rotenonelesioned rats.Rb and L-DOPA alone or both combination were given once a day 30 min before rotenone administration until occurrence of impaired motor function in controls,and motor deficits were surveyed at regular intervals.To determine potential persisted effect of treatments,at 3 days after stopping all the medications the last motor performances were tested and then brains were collected for assay of status of neurovascular unit and neuroinflammation.The protective effects of Rb,L-DOPA,and the combination were compared.Results:Rotenone-induced PD model rats displayed a series of motor behavior disorders,such as impaired forelimb grip,and lost balance,as well as reduced spontaneous activity and exploration behavior.Consistently,dopaminergic neuron terminals lost in dorsal-lateral striatum,while the cell bodies in the substantia nigra pars compacta largely spared,indicating dopamine nerve tip injury preceding cell body injury.This feature is highly consistent with clinical neuropathological changes in PD.Moreover,damaged astrocyte,activated microglia,and impaired BBB occurred in the striatum,with abundant infiltration of peripheral immune cells.Strikingly,Rb significantly prevented all those pathological behaviors,and morphological and cellular alterations,whereas L-DOPA only improved the motor performances of the PD rats and even exacerbated the BBB impairment.Interestingly,combination of Rb and L-DOPA showed the better protective effects than Rb alone,nearly completely blocking all the pathological manifestations.Conclusion:Rb,especially its combination with levodopa,can significantly prevent the development of PD.Direct protection of the components of neurovascular unit and consequently maintaining structural and neurochemical homeostasis may contribute to the disease-modifying effect of Rb.Our findings show a favorable application prospect of Rb,especially together with L-DOPA,in treating PD.