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

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-kappa B) 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-3 beta, 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 A beta 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-kappa B/BACE-1 mediated A beta production in the hippocampus and activating the cAMP/BDNF signalling pathway.

Automated summary

This study investigated the therapeutic potential of the PDE-4 inhibitor roflumilast in Alzheimer's disease. The results showed that roflumilast improved learning and memory capacities in rats, reduced neuroinflammation and amyloid deposition, and activated the cAMP/BDNF signaling pathway.