Abstract
Dibutyryl cyclic adenosine monophosphate (dBcAMP), a cell-permeable synthetic analog of cAMP, has been shown to induce astrogliosis in culture. However, the exact mechanism underlying how dBcAMP exerts its function in situ is not clear. The objective of this study was to examine the effects of dBcAMP on astrogliosis and survival of neurons in stab wound and kainic acid models of brain injury. Stab wound was done in cerebral cortex of BALB/c male mice. Kainic acid lesion was induced in hippocampus by injecting 1μl kainic acid into the lateral ventricle. Animals in both models of injury were divided into L+dBcAMP and L+PBS groups and treated with dBcAMP or PBS for 3, 5, and 7 days respectively. The brain sections were stained for Cresyl violet and Fluro jade-B to assess the degenerating neurons. Immunostaining for GFAP and Iba-1 was done for assessing the astrogliosis and microglial response respectively. Expression of GFAP and BDNF levels in the tissue were estimated by Western blotting and ELISA respectively. The results showed a gradual increase in the number of both astrocytes and microglia in both injuries with a significant increase in dBcAMP-treated groups. The number of degenerating neurons significantly decreased in dBcAMP treated groups. In addition, it was found that dBcAMP stimulated the expression of GFAP and BDNF in both stab wound and kainic acid injuries. Treatment with BDNF receptor inhibitor AZ-23, showed an increase in the degenerating neurons suggesting the role of BDNF in neuroprotection. This study indicates that dBcAMP protects neurons from degeneration by enhancing the production of BDNF and may be considered for use as therapeutic agent for treatment of brain injuries.
Highlights
Traumatic brain injury has a dynamic pathophysiology that includes progressive neuronal loss by apoptosis and necrosis (Rosenfeld et al, 2012) and excitotoxicity
Fluoro-Jade B (FJ-B) staining showed a significant decrease in the number of degenerating neurons in Dibutyryl cyclic adenosine monophosphate (dBcAMP) treated groups, compared to PBS treated groups at 3, 5, and 7 days after stab wound injury (p < 0.05, Figures 1A,D) and after excitotoxic lesion, both in dentate hilus and CA3 region (p < 0.001, Figures 1B,C,E,F)
DBcAMP significantly increased the number of astrocytes surrounding the cortical injury at 3, 5 and 7 days post stab wound injury compared to the control groups (p < 0.05, 0.01, Figures 3A,B)
Summary
Traumatic brain injury has a dynamic pathophysiology that includes progressive neuronal loss by apoptosis and necrosis (Rosenfeld et al, 2012) and excitotoxicity. In cases of central nervous system (CNS) injuries, astrocytes begin to proliferate and accumulate at the margin of the injury forming a layer that interfaces between the injury and intact tissues, which is known as the glial scar or reactive astrogliosis (McGraw et al, 2001). It has been suggested that the scar inhibits axon/nerve regeneration by acting as a physical barrier that axon cannot penetrate dBcAMP Rescues Neurons in Brain Injury (McGraw et al, 2001; Wanner et al, 2008). The synthesis of many growth factors, cytokines, and neuropeptides that have been turned on in reactive astrocytes suggest that the astrocytic reaction may play an important role in neuronal regeneration (Faulkner et al, 2004; John et al, 2005; Rolls et al, 2009; Colangelo et al, 2014)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
