Neuroprotective effects of roflumilast against quinolinic acid-induced rat model of Huntington’s disease through inhibition of NF-κB mediated neuroinflammatory markers and activation of cAMP/CREB/BDNF signaling pathway

Abstract

Huntington’s disease (HD) is a progressive neurodegenerative and hyperkinetic movement disorder. Decreased activity of cAMP-responsive element-binding protein (CREB) is thought to contribute to the death of striatal medium spiny neurons in HD. The present study has been designed to explore the possible role of roflumilast against qunilonic acid (QA) induced neurotoxicity in rats intending to investigate whether it inhibits the neuroinflammatory response through activation of the cAMP/CREB/BDNF signaling pathway. QA was microinjected (200 nmol/2 µl, bilaterally) through the intrastriatal route in the stereotaxic apparatus. Roflumilast (0.5, 1, and 2 mg/kg, orally) once-daily treatment for 21 days significantly improved locomotor activity in actophotometer, motor coordination in rotarod, and impaired gait performance in narrow beam walk test. Moreover, roflumilast treatment significantly attenuated oxidative and nitrosative stress (p < 0.05) through attenuating lipid peroxidation nitrite concentration and enhancing reduced glutathione, superoxide dismutase, and catalase levels. Furthermore, roflumilast also significantly decreased elevated pro-inflammatory cytokines like TNF-α (p < 0.01), IL-6 (p < 0.01), IFN-γ (p < 0.05), NF-κB (p < 0.05) and significantly increased BDNF(p < 0.05) in the striatum and cortex of rat brain. The results further demonstrated that roflumilast effectively increased the gene expression of cAMP(p < 0.05), CREB(p < 0.05) and decreased the gene expression of PDE4 (p < 0.05) in qRT-PCR. These results conclusively depicted that roflumilast could be a potential candidate as an effective therapeutic agent in the management of HD through the cAMP/CREB/BDNF signaling pathway.

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Acknowledgements

University of grant commission, New Delhi, is acknowledged for granting the funds for the research work. The letter-number is 201314-RGNF-2013-14-SC-UTT-50503 for the same.

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Saroj, P., Bansal, Y., Singh, R. et al. Neuroprotective effects of roflumilast against quinolinic acid-induced rat model of Huntington’s disease through inhibition of NF-κB mediated neuroinflammatory markers and activation of cAMP/CREB/BDNF signaling pathway. Inflammopharmacol (2021). https://doi.org/10.1007/s10787-020-00787-3

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Keywords

  • Huntington’s disease
  • Neuroinflammation
  • Quinilonic acid
  • Oxidative stress
  • NF-κB
  • Roflumilast