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Roflumilast Reduces Pathological Symptoms of Sporadic Alzheimer’s Disease in Rats Produced by Intracerebroventricular Streptozotocin by Inhibiting NF-κB/BACE-1 Mediated Aβ Production in the Hippocampus and Activating the cAMP/BDNF Signalling Pathway

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Abstract

Alzheimer’s disease (AD) is a neurological disease that gradually causes memory loss and cognitive impairment. The intracellular secondary messenger cyclic nucleotide cAMP helps in memory acquisition and consolidation. In several models of AD, increasing their levels using phosphodiesterase (PDE) inhibitors improved cognitive performance and prevent memory loss. Thus, the current investigation was undertaken to investigate the therapeutic potential of the PDE-4 inhibitor roflumilast (RFM) against intracerebroventricular (ICV) streptozotocin (STZ)-induced sporadic AD in rats. STZ (3 mg/kg) was given to rats via the ICV route on the stereotaxic apparatus, followed by RFM (0.51 mg/kg/oral) treatment for 15 days, and donepezil (5 mg/kg/oral) was employed as a reference standard drug. Subsequently, we observed that RFM dramatically increased rats learning and memory capacities as measured by the Morris water maze and a novel object recognition task. RFM enhanced the levels of cAMP and brain-derived neurotrophic factors (BDNFs) while decreasing the expression of nuclear factor kappa B (NF-κB) and glial fibrillary acidic protein (GFAP) in the hippocampus of ICV-STZ-infused rats. RFM was found to significantly reduce ICV-STZ-induced neuroinflammation, amyloidogenesis, oxidative stress cholinergic impairments, GSK-3β, and phosphorylated tau levels in the rat hippocampus. Supporting these, histopathological study using Cresyl violet and Congo red demonstrated that RFM reduced neuronal alterations and Aβ deposition in the hippocampus of AD rats. These findings suggest that RFM could be a promising candidate for the management of AD by inhibiting NF-κB/BACE-1 mediated Aβ production in the hippocampus and activating the cAMP/BDNF signalling pathway.

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Acknowledgements

This study was supported by Department of Science and Technology Government of India, and the Hamdard National Fellowship (HNF), Jamia Hamdard New Delhi, India. We would like to thank the Neurotoxicology Lab, Department of Medical Elementology and Toxicology, School of Chemical and Life Sciences (SCLS), Jamia Hamdard, New Delhi, India, for providing the essential facilities for this work.

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  1. Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India

    Noorul Hasan, Saima Zameer, Abul Kalam Najmi & Mohd Akhtar

  2. Department of Medical Elementology and Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New DelhI, 110062, India

    Suhel Parvez

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  1. Noorul Hasan
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Correspondence to Mohd Akhtar.

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All of the tests were carried out in accordance with the rules established by the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA). The experimental procedure was approved by Jamia Hamdard Institutional Animal Ethics Committee (IAEC) under protocol number 1815.

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Hasan, N., Zameer, S., Najmi, A.K. et al. Roflumilast Reduces Pathological Symptoms of Sporadic Alzheimer’s Disease in Rats Produced by Intracerebroventricular Streptozotocin by Inhibiting NF-κB/BACE-1 Mediated Aβ Production in the Hippocampus and Activating the cAMP/BDNF Signalling Pathway. Neurotox Res 40, 432–448 (2022). https://doi.org/10.1007/s12640-022-00482-x

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