Therapeutic effects of honokiol on motor impairment in hemiparkinsonian mice are associated with reversing neurodegeneration and targeting PPARγ regulation

Biomed Pharmacother. 2018 Dec;108:254-262. doi: 10.1016/j.biopha.2018.07.095. Epub 2018 Sep 14.

Abstract

Parkinson's disease (PD) is a profound neurodegenerative disorder with gradual loss of dopamine nigrostriatal neurons linked to serious behavioral symptoms. While the current treatment strategies present limitations on halting the progression of PD, this study aimed to investigate the therapeutic potential of honokiol, as a partial peroxisome proliferator-activated receptor-gamma (PPARγ) mimic, on the proceeding behavioral and biochemical alterations in hemiparkinsonian mice. Results showed that unilateral striatal 6-hydroxydopamine (6-OHDA)-lesioned mice exhibited motor impairment, reflecting the contralateral rotation induced by apomorphine at 1-3 weeks post-lesion. Subchronic honokiol administration for 1-2 weeks, beginning 7 days after 6-OHDA-lesion, dose-dependently ameliorated motor dysfunction in hemiparkinsonian mice. Recovery of motor function was correlated with reversal of nigrostriatal dopaminergic neuronal loss, accompanied by higher tyrosine hydroxylase (TH) density, dopamine transporter (DAT) expression and vesicular monoamine transporter-2 (VMAT2) levels. Furthermore, honokiol attenuated oxidative stress and reactive astrocyte induction via decreasing NADPH-oxidase and glial fibrillary acidic protein (GFAP) expressions in 6-OHDA-lesioned striatum. The reversal effects of honokiol on behavioral impairment and striatal PPARγ expression were impeded by PPARγ antagonist GW9662. Notably, subchronic honokiol treatment extended the lifespan of these hemiparkinsonian mice. The present findings demonstrate the therapeutic activities of honokiol in ameliorating motor impairment and progressive dopaminergic damage that could be associated with regulating PPARγ signaling. Therefore, honokiol may potentially exert as a novel therapeutic candidate through PPARγ activation for management of motor symptoms and progressive neurodegeneration in PD.

Keywords: 6-Hydroxydopamine; Honokiol; PPARγ; Parkinson’s disease; Positron-emission tomography.

MeSH terms

  • Animals
  • Biphenyl Compounds / administration & dosage
  • Biphenyl Compounds / pharmacology
  • Biphenyl Compounds / therapeutic use*
  • Gliosis / pathology
  • Lignans / administration & dosage
  • Lignans / pharmacology
  • Lignans / therapeutic use*
  • Longevity / drug effects
  • Male
  • Mice
  • Motor Activity / drug effects*
  • NADPH Oxidases / metabolism
  • Neostriatum / drug effects
  • Neostriatum / pathology
  • Neostriatum / physiopathology
  • Nerve Degeneration / drug therapy*
  • Nerve Degeneration / pathology
  • Oxidation-Reduction
  • Oxidopamine
  • PPAR gamma / metabolism*
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / pathology
  • Parkinson Disease / physiopathology*

Substances

  • Biphenyl Compounds
  • Lignans
  • PPAR gamma
  • honokiol
  • Oxidopamine
  • NADPH Oxidases