Long-term treatment with roflumilast improves learning of fear extinction memory and anxiety-like response in a type-1 diabetes mellitus animal model

Ana Paula Farias Waltrick, Ana Carolina Felipe da Silva, Bianca Andretto de Mattos, Yane Costa Chaves, Rúbia Maria Weffort de Oliveira, Jos Prickaerts, Janaína Menezes Zanoveli*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Diabetic encephalopathy is related to serious damage to the Central Nervous System leading to several disturbances in memory processing and emotions. It is known that the cyclic adenosine 3',5'-monophosphate (cAMP) responsive element-binding protein (CREB) pathway participates in neuronal plasticity and prevention of neuroinflammation, as well as the mediation of learning/memory processes and emotions in brain areas such as the hippocampus (HIP) and prefrontal cortex (PFC). We aimed to investigate the effect of acute (one injection) and long-term treatment (21 days) with roflumilast (ROF; i.p.; 0, 0.01, 0.03, 0.1 mg/kg), a drug able to inhibit the enzyme phosphodiesterase-4 (PDE-4) responsible for cAMP hydrolysis, on parameters related to the acquisition of fear extinction memory and anxiety-like responses in animals with type-1 diabetes mellitus (T1DM) induced through one injection of streptozotocin (60 mg/kg; ip; STZ animals). When we performed acute treatment, no difference was observed between all the groups when resubmitted to the same context paired with an aversive stimulus (footshock) or to a neutral context. In contrast, long-term treatment was able to improve learning of extinction fear memory and discriminating between a conditioned and neutral context. Moreover, this treatment decreased the pronounced anxiety-like response of STZ animals. In addition, there was an increase in the product of the CREB signaling pathway, the pro brain-derived neurotrophic factor, in the HIP and PFC of these animals. The treatment did not impair glycemic control, whereas it decreased the animal's blood glucose levels. To conclude, these findings suggest that ROF treatment repositioning has potential for future translational investigations involving diabetic patients considering its beneficial effects on emotional processes related to fear memory and anxiety, in addition to improvement of glycemic control.

Original languageEnglish
Article number114217
Number of pages13
JournalBehavioural Brain Research
Issue number1
Early online date15 Nov 2022
Publication statusPublished - 15 Feb 2023


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