Dibutyryl cAMP Enhances Cognitive Functions in Diabetic Rats by Increasing the Hippocampal Neurogenesis

Abstract

Dibutyryl cyclic adenosine monophosphate (dBcAMP) is a cell‐permeable synthetic analog of cyclic adenosine monophosphate (cAMP) known to acts as an intracellular second messenger for neurotransmitters and hormones. dBcAMP enhances differentiation and survival of neurons from neuronal stem cells, differentiation of mesenchymal stromal cell into neurons and stimulates the differentiation of astrocytes and contribute to neuroprotection in neural tissue injury.Diabetes, a chronic metabolic disease has adverse effects on adult hippocampal neurogenesis and cognitive function. Even though, dBcAMP is used as a therapeutic agent in some disease models, it has not been used in diabetes. Present experiment was aimed to study the effects of dBcAMP on learning and memory and adult neurogenesis, in streptozotocin model of diabetic rats. Diabetes was induced in male Wistar rats (3 months old) by injecting streptozotocin (ip, 50mg/kg) into the peritoneal cavity. After confirming the diabetic condition (hyperglycemia) in these rats after 48hrs of STZ injection, they were grouped into diabetic (DI) and diabetic+dBcAMP (DI+dBcAMP groups. Age matched normal rats served as control group (C). DI+dBcAMP group were treated with dBcAMP (ip,10mg/kg) intraperitoneally for 10 days and C and DI groups were be treated with PBS for the same duration. After treatment, animals in all groups were subjected to learning and memory test in Morris water maze from day21 to day27 of the experiment to assess the cognitive function. After the behavioral test rats (n=6 in all groups) were sacrificed on day 30. Fresh hippocampal tissue were collected for ELISA (for BDNF, brain derived neurotrophic factor), and Western blot (for doublecortin, DCX) analysis. Rats (n=6 in all groups), were be perfused with 4% paraformaldehyde and hippocampi were collected for immunostaining (DCX). Number of DCX positive neurons were quantified in the hippocampal dentate gyrus. Data were analyzed by One/Two –way ANOVA, followed by Bonferroni's multiple comparison test. Results showed a significant memory deficit (decreased time spent and distance traveled in platform quadrant) in DI rats compared to C (p<0.001, One way ANOVA), and memory was significantly increased in DI+ dBcAMP compared to DI group (p<0.001). Analysis of number of DCX positive neurons in the dentate gyrus (neurogenesis) showed a significant decrease in neurogenesis in DI group compared to C group (p<0.001, One‐way ANOVA) and it was significantly increased in DI+dBcAMP (p<0.001, One‐way ANOVA). Western blot analysis for DCX showed significant increase in DI+ dBcAMP group (p<0.01) and hence confirmed the DCX positive neuron count data. Analysis of BDNF levels in the hippocampus of the DI+dBcAMP was found to be significantly increased compared to DI group (p<0.01). We conclude that dBcAMP enhances cognitive functions in diabetic rats by increasing the Hippocampal BDNF levels and hence enhanced neurogenesis. Thus dBcAMP may be a potential molecule to be considered in treatment of diabetic patients to prevent the cognitive deterioration.Support or Funding InformationCollege of Graduate Studies and Research Sector, Kuwait UniversityThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.