PDE-7 Inhibitor BRL-50481 Reduces Neurodegeneration and Long-Term Memory Deficits in Mice Following Sevoflurane Exposure

Abstract

Sevoflurane, one of the most commonly used anesthetic agents, has been demonstrated to induce widespread neurodegeneration in the developing brain. We aimed to evaluate the protective effects of a PDE-7 inhibitor (BRL-50481) against the neurotoxic effects of sevoflurane on the developing nervous system. Spatial learning and memory in sevoflurane-treated mice were examined using the Morris water maze test, and neuroprotective effects of PDE-7 inhibitor (BRL-50481) against sevofluraneinduced impairments were evaluated. Our results showed that sevoflurane treatment markedly induced neurodegeneration and impaired long-term memory in neonatal mice. Notably, BRL-50481 coadministration could significantly attenuate sevofluraneinduced learning and memory defects, prevent deterioration of recognition memory, and protect against neuron apoptosis. Mechanistically, BRL-50481 administration suppressed sevoflurane-induced neurodegenerative disorders through restoring cAMP and activating cAMP/CREB signaling in the hippocampus. PDE7 inhibitor may be a potential therapeutic agent for sevofluraneinduced neurodegeneration and long-term memory deficits.

The effects of BRL-50481 on ovalbumin-induced asthmatic lung inflammation exacerbated by co-exposure to Asian sand dust in the murine model

“…PDE7 inhibitors, such as BRL-50481 (BRL), have pharmacological effects on proinflammatory responses in human blood monocytes, lung macrophages, and CD8 + T-lymphocytes believed to contribute to inflammation (Smith et al 2004 ). Neuroprotective effects of BRL on sevoflurane-induced neurodegeneration have also been reported recently (Chen et al 2020b ).…”

Inhibiting PDE7A Enhances the Protective Effects of Neural Stem Cells on Neurodegeneration and Memory Deficits in Sevoflurane-Exposed Mice

“…For novel object recognition test, a square plastic chamber (0.4 m long, 0.4 m wide, and 0.4 m high) was used. The detailed procedures were conducted with the published papers (Lueptow 2017, Chen, Li et al 2020.…”

“…Immunofluorescence staining was performed as previously described (Chen, Li et al 2020). Briefly, NSCs were fixed with 4% paraformaldehyde and treated with 0.1% Triton X100 for 30 min.…”

“…The phosphodiesterase 7A (PDE7A) is an enzyme responsible for the regulation of intracellular cAMP in the central nervous system (Morales-Garcia, Alonso-Gil et al 2015). It has been revealed that administration of S14, a PDE7 inhibitor, increased NSCs proliferation, and neuronal differentiation (Chen, Li et al 2020). In view of those findings, we aim to investigate the functional roles of PDE7A on the NSCs cell proliferation and differentiation in vitro, and long-term memory and learning ability of sevoflurane-treated mice in vivo using genetic modification strategies.…”

Role of Phosphodiesterase 7 (PDE7) in T Cell Activity. Effects of Selective PDE7 Inhibitors and Dual PDE4/7 Inhibitors on T Cell Functions

“…Benefits of PDE7 inhibitors were reported in the treatment of experimental autoimmune encephalomyelitis (EAE) in mice, as an animal model of human multiple sclerosis [52,55,[57][58][59][60], spinal cord injury [61], a murine model of Alzheimer's disease [62,63], a rodent model of Parkinson's disease [64,65], as well as in sevoflurane-induced long-term memory deficits in mice [66].…”