Maria Eduarda Rocha França1, Renata Kelly Luna Gomes Ramos2, Wilma Helena Oliveira3, Eduardo Duarte-Silva4, Shyrlene Meyre Rocha Araújo3, Deniele Bezerra Lós5, Christina Alves Peixoto6. 1. Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Recife, Pernambuco, Brazil; Postgraduate Program in Biological Sciences (PPGCB), Federal University of Pernambuco Recife, Pernambuco, Brazil. Electronic address: mariaeduarda.rfranca@gmail.com. 2. Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Recife, Pernambuco, Brazil. 3. Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Recife, Pernambuco, Brazil; Postgraduate Program in Biological Sciences (PPGCB), Federal University of Pernambuco Recife, Pernambuco, Brazil. 4. Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Recife, Pernambuco, Brazil; Postgraduate Program in Biosciences and Biotechnology for Health (PPGBBS), Oswaldo Cruz Foundation (FIOCRUZ-PE)/ Aggeu Magalhães Institute (IAM), Recife, Pernambuco, Brazil. 5. Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Recife, Pernambuco, Brazil; Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil. 6. Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Recife, Pernambuco, Brazil; Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil. Electronic address: cpeixoto@cpqam.fiocruz.br.
Abstract
BACKGROUND AND AIM: Tadalafil displays important neuroprotective effects in experimental models of neurodegenerative diseases, however its mechanisms of action remain poorly understood. The aim of the present study was to investigate the action of Tadalafil on learning and memory, neuroinflammation, glial cell activation and neuroprotection in the experimental model of hepatic encephalopathy (HE) induced by Thioacetamide (TAA) in mice. METHODS: Mice received intraperitoneal injections of TAA, for 3 consecutive days, reaching the final dose of 600 mg/kg. Tadalafil 15 mg/kg body weight was administered by gavage during 15 days after TAA induction. Mice underwent a Barnes maze for learning and memory evaluation. RESULTS: Animals with hepatic encephalopathy showed reduced learning and spatial memory in the Barnes Maze, presented astrocyte and microglia activation and increased neuroinflammatory markers such as TNF-α, IL-1β, IL-6, p-p38, p-ERK and p-NF-kB. In addition, the signaling pathway PKA/PKG/CREB/BDNF/NeuN/synaptophysin and glutamate receptors were deregulated by TAA. Tadalafil treatment regulated the inflammation signaling pathways restoring learning and spatial memory. CONCLUSION: Tadalafil significantly reduced neuroinflammation, promoted neuroprotection and plasticity, regulated the expression of hippocampal glutamate receptor and restored spatial learning ability and memory.
BACKGROUND AND AIM: Tadalafil displays important neuroprotective effects in experimental models of neurodegenerative diseases, however its mechanisms of action remain poorly understood. The aim of the present study was to investigate the action of Tadalafil on learning and memory, neuroinflammation, glial cell activation and neuroprotection in the experimental model of hepatic encephalopathy (HE) induced by Thioacetamide (TAA) in mice. METHODS:Mice received intraperitoneal injections of TAA, for 3 consecutive days, reaching the final dose of 600 mg/kg. Tadalafil 15 mg/kg body weight was administered by gavage during 15 days after TAA induction. Mice underwent a Barnes maze for learning and memory evaluation. RESULTS: Animals with hepatic encephalopathy showed reduced learning and spatial memory in the Barnes Maze, presented astrocyte and microglia activation and increased neuroinflammatory markers such as TNF-α, IL-1β, IL-6, p-p38, p-ERK and p-NF-kB. In addition, the signaling pathway PKA/PKG/CREB/BDNF/NeuN/synaptophysin and glutamate receptors were deregulated by TAA. Tadalafil treatment regulated the inflammation signaling pathways restoring learning and spatial memory. CONCLUSION:Tadalafil significantly reduced neuroinflammation, promoted neuroprotection and plasticity, regulated the expression of hippocampal glutamate receptor and restored spatial learning ability and memory.