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RETRACTED ARTICLE: Roflumilast and tadalafil improve learning and memory deficits in intracerebroventricular Aβ1–42 rat model of Alzheimer’s disease through modulations of hippocampal cAMP/cGMP/BDNF signaling pathway

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Abstract

Background

Alzheimer’s disease (AD) is the most prevalent age-dependent neurodegenerative disease characterized by progressive impairment of memory and cognitive functions. Cyclic nucleotides like cAMP and cGMP are well-known to play an important role in learning and memory functions. Enhancement of cAMP and cGMP levels in the hippocampus by phosphodiesterase (PDE) inhibitors might be a novel therapeutic approach for AD. Thus, the present study was planned to explore the therapeutic potential of roflumilast (RFM) and tadalafil (TDF) phosphodiesterase inhibitors in intracerebroventricular (ICV) Aβ1–42 induced AD in rats.

Methods

ICV Aβ1–42 was administered in rats followed by treatment with RFM (0.05 mg/kg) and TDF (0.51 mg/kg) for 15 days. Novel object recognition (NOR), and Morris water maze (MWM) test were performed during the drug treatment schedule. On the day, 22 rats were sacrificed, and hippocampus was separated for biochemical, neuroinflammation, and histopathological analysis.

Results

Aβ1–42 infused rats were induce behavioral impairment and increased AChE, BACE-1, Aβ1–42, GSK-3β, phosphorylated tau (p-Tau), pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) levels, oxidative stress (increased MDA, Nitrite and decreased GSH), histopathological changes, and reduced cAMP, cGMP, and BDNF levels. RFM and TDF significantly attenuated Aβ1–42 induced memory deficits and neuropathological alterations in the hippocampus.

Conclusion

The outcomes of the current study indicate that RFM and TDF lead to memory enhancement through upregulation of cAMP/cGMP/BDNF pathway, thus they may have a therapeutic potential in cognitive deficits associated with AD.

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Acknowledgements

This study was supported by the DST-PURSE program of the Department of Science and Technology, Government of India. We express our gratitude to Neurotoxicology Lab, Department of Medical Elementology and Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi India, and also to Neurobehavioral Pharmacology Lab, Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard New Delhi India for providing necessary facilities used during this research work.

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

    Suhel Parvez

  3. Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard (Hamdard University), New Delhi, 110062, India

    Mohammad Shahar Yar

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Hasan, N., Zameer, S., Najmi, A.K. et al. RETRACTED ARTICLE: Roflumilast and tadalafil improve learning and memory deficits in intracerebroventricular Aβ1–42 rat model of Alzheimer’s disease through modulations of hippocampal cAMP/cGMP/BDNF signaling pathway. Pharmacol. Rep 73, 1287–1302 (2021). https://doi.org/10.1007/s43440-021-00264-w

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