β-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease

Abstract

Parkinson disease (PD) is a neurodegenerative disease characterized by progressive dopaminergic neurodegeneration in the substantia nigra pars compacta (SNc) area. The present study was undertaken to evaluate the neuroprotective effect of β-caryophyllene (BCP) against rotenone-induced oxidative stress and neuroinflammation in a rat model of PD. In the present study, BCP was administered once daily for 4 weeks at a dose of 50 mg/kg body weight prior to a rotenone (2.5 mg/kg body weight) challenge to mimic the progressive neurodegenerative nature of PD. Rotenone administration results in oxidative stress as evidenced by decreased activities of superoxide dismutase, catalase, and depletion of glutathione with a concomitant rise in lipid peroxidation product, malondialdehyde. Rotenone also significantly increased pro-inflammatory cytokines in the midbrain region and elevated the inflammatory mediators such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the striatum. Further, immunohistochemical analysis revealed loss of dopaminergic neurons in the SNc area and enhanced expression of ionized calcium-binding adaptor molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP), indicators of microglia activation, and astrocyte hypertrophy, respectively, as an index of inflammation. However, treatment with BCP rescued dopaminergic neurons and decreased microglia and astrocyte activation evidenced by reduced Iba-1 and GFAP expression. BCP in addition to attenuation of pro-inflammatory cytokines and inflammatory mediators such as COX-2 and iNOS, also restored antioxidant enzymes and inhibited lipid peroxidation as well as glutathione depletion. The findings demonstrate that BCP provides neuroprotection against rotenone-induced PD and the neuroprotective effects can be ascribed to its potent antioxidant and anti-inflammatory activities.

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Acknowledgments

The research grants support from the United Arab Emirates University and the National Research Foundation, United Arab Emirates to MEH and SO are duly acknowledged. The authors would also like to acknowledge Mahmoud Hag Ali, Animal Research Facility controller for his help in animal care and welfare. The authors also acknowledge the proof read of the manuscript by Dr. Keith M Bagnall, Professor of Anatomy, College of Medicine and Health Sciences, UAE University, UAE.

Author contributions

All the authors provided important intellectual content, reviewed the content, and approved the final version for the manuscript. Contributed significantly, read, and approved the manuscript: HJ, MEH, and SO. Conceived and designed the experiments: HJ, MEH, and SO. Performed the experiments: HJ and AS. Analyzed the data: HJ, MEH, and SO. Contributed reagents/materials/analysis tools: MEH and SO. Wrote the paper: HJ, MEH, and SO.

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Correspondence to M. Emdadul Haque.

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There are no patents, products in development or marketed products to declare. The research grant funding organizations have no role in study design, data collection and analysis, decision to publish, or the preparation of the manuscript.

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Shreesh Ojha and Hayate Javed have contributed equally to this work.

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Ojha, S., Javed, H., Azimullah, S. et al. β-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease. Mol Cell Biochem 418, 59–70 (2016). https://doi.org/10.1007/s11010-016-2733-y

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Keywords

  • β-Caryophyllene
  • Neurodegeneration
  • Neurotoxicity
  • Parkinson disease
  • Rotenone