Effect of pyrrolo[3,4-d]pyridazinone derivatives in neuroinflammation induced by preincubation with lipopolysaccharide or coculturing with microglia-like cells

Abstract

Alzheimer's disease is one of the most serious disorders of the 21st century. There is still no effective therapy for this condition. The study investigated the potential regenerative effect of four pyrrolo[3,4-d]pyridazinone derivatives in cultures of SH-SY5Y neuron-like cells preincubated with lipopolysaccharide (LPS) or cocultured with microglia-like cells. In addition to the traditional investigation of the effect on viability, the level of free radicals and nitric oxide, the average length of neurites was also measured. Via in silico studies, the possibility of penetration of the blood-brain barrier (BBB) by the tested compounds was assessed. The administration of LPS to the culture of SH-SY5Y cells as well as coculturing with microglia-like cells had a significant negative effect on the results of all the assays performed. The treatment with the tested derivatives in most cases significantly reduced this negative effect. The obtained results suggest that the compound L2 may have a beneficial impact on neuronal damage caused by LPS or proinflammatory cytokines secreted by microglia-like cells. Importantly, tested compounds can pass through the BBB, which allows them to enter the brain.

Keywords: Alzheimer’s disease; Blood–brain barrier; NSAIDs; Neuroinflammation.