Abstract
Bacopa monniera extract (CDRI-08; BME) has been known to improve learning and memory, and understanding the molecular mechanisms may help to know its specificity. We investigated whether the BME treatment alters the methylation status of reelin and brain-derived neurotropic factor (BDNF) to enhance the memory through the interaction of N-methyl-D-aspartate receptor (NMDAR) with synaptic proteins. Rat pups were subjected to novel object recognition test following daily oral administration of BME (80 mg/kg) in 0.5% gum acacia (per-orally, p.o.; PND 15–29)/three doses of 5-azacytidine (5-azaC; 3.2 mg/kg) in 0.9% saline (intraperitoneally, i.p.) on PND-30. After the behavioral test, methylation status of reelin, BDNF and activation of NMDAR, and its interactions with synaptic proteins were tested. Rat pups treated with BME/5-azaC showed higher discrimination towards novel objects than with old objects during testing. Further, we observed an elevated level of unmethylated DNA in reelin and BDNF promoter region. Up-regulated reelin along with the splice variant of apolipoprotein E receptor 2 (ApoER 2, ex 19) form a cluster and activate NMDAR through disabled adopter protein-1 (DAB1) to enhance BDNF. Observed results suggest that BME regulate reelin epigenetically, which might enhance NMDAR interactions with synaptic proteins and induction of BDNF. These changes may be linked with improved novel object recognition memory.
Highlights
Long-term memory formation requires fine tuned cellular signaling coordination with transcriptional and translational regulations of gene expression (Hawk and Abel, 2010)
Novel object recognition test was performed to examine the effect of BME on hippocampus dependent long-term memory
Demethylation of reelin promoter resulted in significant up-regulation of reelin expression in BME [F(1,11) = 28.79, P < 0.001] and 5-azaC groups [F(1,11) = 17.98, P < 0.01] compared to control group, but there was no significant difference between BME and 5-azaC groups
Summary
Long-term memory formation requires fine tuned cellular signaling coordination with transcriptional and translational regulations of gene expression (Hawk and Abel, 2010). Possible Role of Bacopa monniera in Epigenetic Mechanism This process involves DNA methyltransferases (DNMTs) that mediates de novo methylation within DNA and alters the chromatin structure (Shilatifard, 2006; Lubin, 2011; Nabel and Kohli, 2011); which directly controls transcription. Several studies have reported that DNA methylation/demethylation in a specific promoter region of reelin and brain-derived neurotrophic factor (BDNF) dictates the transcriptional activity thereby critically regulating synaptic plasticity, learning, and memory (Miller and Sweatt, 2007; Levenson et al, 2008; Lubin et al, 2008; Mizuno et al, 2012; Sui et al, 2012). Subunits of NMDA receptor directly interact with post-synaptic density protein-95 (PSD-95 Hoe et al, 2006), and induces LTP and long-term memory (LTM)
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