Brain Pharmacokinetics and the Pharmacological Effects on Striatal Neurotransmitter Levels of Pueraria lobata Isoflavonoids in Rat

Abstract

Isoflavonoids are putatively active components of Pueraria lobata and has been demonstrated prominent neuro-protection effect against cerebrovascular disorders, hypertension or Parkinson's disease (PD). However, the molecular basis for the beneficial effect of Pueraria lobata on nervous systems has not been well revealed. The present study aims to assess striatum exposure to main active isoflavonoids and changes of striatal extracellular neurotransmitters levels in rat brain after intravenous administration of Pueraria lobata isoflavonoids extracts (PLF), to further elucidate its' substantial bases for neuro activities. Fifteen rats were divided into 3 groups (five rats in each group) to receive a dose of PLF at 80 or 160 mg/kg or normal saline (vehicle), respectively. An LC-MS/MS method was employed to determine the concentrations of five main isoflavonoids and multiple neurotransmitters in microdialysate from striatal extracellular fluid (ECF) of the rats. The exposed quantities of puerarin (PU), 3′-methoxypuerarin (MPU), daidzein-8-C-apiosyl-(1-6)-glucoside (DAC), and 3′-hydroxypuerarin (HPU) in striatum were dose-dependent. The content of daidzein (DAZ) was too low to be detected in all dialysate samples through the experiment. Optimal dose PLF (80 mg/kg) promoted DA metabolism and inhibited 5-HT metabolism. No obvious change in the level of GLu was determined. The concentration of GABA presented a temporary decline firstly and then a gradual uptrend followed by a further downtrend. Higher dose (160 mg/kg) PLF could enhance the metabolism of both DA and 5-HT, and lower the extracellular level of GLu, without changing GABA concentrations, which might result in alleviation on excitatory toxicity under conditions, such as ischemia. The results infer that different dose of PLF should be chosen to achieve appropriate neurochemical modulation effects under conditions, such as hypertension or ischemia/stroke. These findings may significantly contribute to a better understanding of the neuroprotective effect of Pueraria lobata and provide new insights into its application toward neuro-degenerative diseases in the future.

Differential Influence of Pueraria lobata Root Extract and Its Main Isoflavones on Ghrelin Levels in Alcohol-Treated Rats

“…However, the KU mechanism of action is not obvious, since there were some observations that the isoflavones from KU suppressed alcohol drinking without entering the brain [78] and none of the compounds changed the activities of liver alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) [15]. On the contrary, the data shows that KU (P. lobata root extract produced in a special way called PLF) intravenous administration in doses of 80 and 160 mg/kg resulted in an occurrence (among others) of PUE in the brain, using an LC-MS/MS method in micro dialysate from striatal extracellular fluid of rats [83]. These authors also suggested that KU, especially in a lower dose (so-called optimal), promoted dopamine metabolism and inhibited serotonin metabolism without an influence on glutamine level.…”

Isolation of Mirificin and Other Bioactive Isoflavone Glycosides from the Kudzu Root Lyophilisate Using Centrifugal Partition and Flash Chromatographic Techniques

“…In this group, for many years, puerarin (daidzein-8- C -glucoside) has been considered the predominant bioactive component exhibiting selective estrogen receptor modulating (SERM) effects [ 6 , 7 , 8 ]. The ability to counteract estrogen deficiency demonstrated by this isoflavone has resulted in the use of kudzu preparations in the treatment of age-related disorders especially in postmenopausal women, involving atherosclerotic cardiovascular disease [ 2 , 9 ], neurological dysfunction [ 10 ], osteoporosis [ 11 , 12 ], and metabolic syndrome resulting in obesity and diabetes [ 13 , 14 ]. Puerarin and kudzu extracts are also known as natural antidipsotropic agents recommended for alcohol abuse and alleviating withdrawal syndrome [ 15 , 16 ].…”

“…After intravenous administration of a higher dose of isoflavones (160 mg/kg), a decrease in DA concentration and inhibition of 5-HT metabolism were observed. In addition, a significant neuroprotective effect of isoflavones has been documented due to a decrease in extracellular Glu levels, which may prevent neurocyte damage resulting from Glu excitotoxicity under ischemia/stroke conditions [ 10 ]. Mirificin was also proved to be a potent tyrosinase inhibitor in vitro , showing a stronger pharmacological effect than kojic acid [ 23 ].…”

Astragalus polysaccharides protect renal function and affect the TGF-β/Smad signaling pathway in streptozotocin-induced diabetic rats

“…The mechanism involved in alleviating myocardial damage caused by diabetes may be related to inhibition of the expression of transforming growth factor (TGF)-β1 and tumor necrosis factor-α (TNF-α). 5 However, there are few reports on the effects of Astragalus polysaccharides on DN.…”