β-asarone and levodopa co-administration increase striatal dopamine level in 6-hydroxydopamine induced rats by modulating P-glycoprotein and tight junction proteins at the blood-brain barrier and promoting levodopa into the brain

Clin Exp Pharmacol Physiol. 2016 Jun;43(6):634-43. doi: 10.1111/1440-1681.12570.

Abstract

Levodopa (L-dopa) is widely considered as one of the most effective drug constituents in the treatment of Parkinson's disease (PD), but the blood-brain barrier (BBB) permeability of L-dopa is <5%, which causes low efficacy. Neuroprotective effects of β-asarone on 6-hydroxydopamine (6-OHDA)-induced PD rats were demonstrated by our previous studies. Co-administration of β-asarone and L-dopa has not been explored until being investigated on PD rats in this study. PD rats were divided into four groups: untreated, L-dopa-treated, β-asarone-treated and co-administered-treated groups. All of the treatments were administered to the rats twice per day for 30 days. The L-dopa, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), S100β and neuron-specific enolase (NSE) levels were subsequently determined. The P-glycoprotein (P-gp), zonula occludens-1 (ZO-1), claudin-5, occludin and actin expression was also assessed in cortex. Changes in BBB ultrastructure were observed using transmission electron microscopy. Our results showed that the co-administered treatment increased levels of L-dopa, DA, DOPAC and HVA in striatum, and S100β in plasma, but down-regulated NSE, P-gp, ZO-1, occludin, actin and claudin-5 in cortex. Crevices were observed between capillary endothelial cells at intercellular tight junction of the striatum in co-administered-treated group, while the endothelial cells in untreated group were tightly jointing each other. In addition, the correlations of L-dopa or DA and P-gp or tight junction proteins respectively were significantly negative in co-administered- and β-asarone-treated groups. These findings suggest that co-administered treatment may enhance the L-dopa BBB permeability and attenuate brain injury, which may be beneficial to PD treatment.

Keywords: P-glycoprotein; actin; claudin-5; occluding; zonula occludens-1; β-asarone.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Allylbenzene Derivatives
  • Animals
  • Anisoles* / administration & dosage
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism*
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism*
  • Dopamine / metabolism*
  • Drug Therapy, Combination
  • Levodopa / administration & dosage
  • Levodopa / metabolism*
  • Oxidopamine / toxicity
  • Parkinsonian Disorders / chemically induced
  • Parkinsonian Disorders / metabolism*
  • Parkinsonian Disorders / prevention & control
  • Rats
  • Tight Junction Proteins / antagonists & inhibitors
  • Tight Junction Proteins / metabolism

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • Allylbenzene Derivatives
  • Anisoles
  • Tight Junction Proteins
  • asarone
  • Levodopa
  • Oxidopamine
  • Dopamine