Upregulation of BDNF and hippocampal functions by a hippocampal ligand of PPARα
Dhruv Patel, Avik Roy, Sumita Raha, Madhuchhanda Kundu, Frank J. Gonzalez, Kalipada Pahan
Dhruv Patel, Avik Roy, Sumita Raha, Madhuchhanda Kundu, Frank J. Gonzalez, Kalipada Pahan
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Research Article Neuroscience

Upregulation of BDNF and hippocampal functions by a hippocampal ligand of PPARα

Abstract

Discovery strategies commonly focus on the identification of chemical libraries or natural products, but the modulation of endogenous ligands offers a much better therapeutic strategy due to their low adverse potential. Recently, we found that hexadecanamide (Hex) is present in hippocampal nuclei of normal mice as an endogenous ligand of PPARα. This study underlines the importance of Hex in inducing the expression of brain-derived neurotrophic factor (BDNF) from hippocampal neurons via PPARα. The level of Hex was lower in the hippocampi of 5XFAD mice as compared with that in non-Tg mice. Oral administration of Hex increased the level of this molecule in the hippocampus to stimulate BDNF and its downstream plasticity-associated molecules, promote synaptic functions in the hippocampus, and improve memory and learning in 5XFAD mice. However, oral Hex remained unable to stimulate hippocampal plasticity and improve cognitive behaviors in 5XFADPparα-null and 5XFADPparα-ΔHippo mice, indicating an essential role of hippocampal PPARα in Hex-mediated improvement in hippocampal functions. This is the first demonstration to our knowledge of protection of hippocampal functions by oral administration of a hippocampus-based drug, suggesting that Hex may be explored for therapeutic intervention in AD.

Authors

Dhruv Patel, Avik Roy, Sumita Raha, Madhuchhanda Kundu, Frank J. Gonzalez, Kalipada Pahan

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Figure 6

Hex promotes calcium influx and ameliorates cognitive deficits in 5XFAD mice via hippocampal PPARα.

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Hex promotes calcium influx and ameliorates cognitive deficits in 5XFAD ...
5XFAD, 5XFADPparα-null, and 5XFADPparα-ΔHippo mice (n = 6/group; 6–7 months old) were orally treated with Hex (5 mg/kg body weight) or vehicle (0.1% methyl cellulose) for 30 days. Age-matched non-Tg (NTG) mice without any treatment (n = 6) were used as controls. Following treatment, AMPA- (A) and NMDA-dependent (B) calcium currents were measured in the hippocampal slices of NTG, vehicle-fed or Hex-fed 5XFAD mice, vehicle-fed or Hex-fed 5XFADPparα-null mice, and vehicle-fed or Hex-fed 5XFADPparα-ΔHippo mice. Arrow indicates the application of AMPA and NMDA into the assay. Results represent 3 independent experiments. Following Hex treatment, hippocampus-dependent spatial behavior of mice across all groups was also analyzed using Barnes maze (BM). (C) Representative track plots summarizing the overall activity of mice on the apparatus recorded with a Noldus camera and visualized by Ethovision XT software. (D) Latency and (E) number of errors made by NTG, vehicle-fed or Hex-fed 5XFAD mice, vehicle-fed or Hex-fed 5XFADPparα-null mice, and vehicle-fed or Hex-fed 5XFADPparα-ΔHippo mice. Results are shown as mean ± SEM. One-way ANOVA [BM latency: F(6,35) = 23.28, P < 0.0001 and BM errors: F(6,35) = 16.002, P < 0.001], followed by Bonferroni’s multiple comparisons test, was used to assess the significance of the mean; ***P < 0.001 vs. vehicle-fed 5XFAD, nsP > 0.05 vs. vehicle-fed 5XFAD. Context-dependent hippocampal behavior was analyzed by T-maze test. (F) Number of positive turns and (G) number of errors of NTG, control and Hex-treated 5XFAD, 5XFADPparα-null and 5XFADPparα-ΔHippo mice on an appetitive T maze conditioning task were manually recorded. Results are shown as mean ± SEM. One-way ANOVA [TM positive turns: F(6,35) = 5.361, P = 0.0005 and TM errors: F(6,35) = 5.361, P = 0.0005], followed by Bonferroni’s multiple comparisons test, was used to assess the significance of the mean, *P < 0.05 vs. vehicle-fed 5XFAD, **P < 0.01 vs. vehicle-fed 5XFAD, nsP > 0.05 vs. vehicle-fed 5XFAD.