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. 2018 Apr 19;19(Suppl 1):13.
doi: 10.1186/s12868-018-0412-5.

Modulation of the expression of genes related to the system of amyloid-beta metabolism in the brain as a novel mechanism of ceftriaxone neuroprotective properties

Maria A Tikhonova  1   2 , Tamara G Amstislavskaya  3   4 , Victor M Belichenko  3 , Larisa A Fedoseeva  3   5 , Sergey P Kovalenko  3 , Ekaterina E Pisareva  3 , Alla S Avdeeva  3 , Nataliya G Kolosova  5 , Nikolai D Belyaev  6 , Lyubomir I Aftanas  3   4
Affiliations

Modulation of the expression of genes related to the system of amyloid-beta metabolism in the brain as a novel mechanism of ceftriaxone neuroprotective properties

Maria A Tikhonova et al. BMC Neurosci. .

Abstract

Background: The dominant hypothesis about the pathogenesis of Alzheimer's disease (AD) is the "amyloid cascade" concept and modulating the expression of proteins involved in the metabolism of amyloid-beta (Aβ) is proposed as an effective strategy for the prevention and therapy of AD. Recently, we found that an antibiotic ceftriaxone (CEF), which possesses neuroprotective activity, reduced cognitive deficits and neurodegenerative changes in OXYS rats, a model of sporadic AD. The molecular mechanisms of this effect are not completely clear, we suggested that the drug might serve as the regulator of the expression of the genes involved in the metabolism of Aβ and the pathogenesis of AD. The study was aimed to determine the effects of CEF on mRNA levels of Bace1 (encoding β-secretase BACE1 involved in Aβ production), Mme, Ide, Ece1, Ace2 (encoding enzymes involved in Aβ degradation), Epo (encoding erythropoietin related to endothelial function and clearance of Aβ across the blood brain barrier) in the frontal cortex, hippocampus, striatum, hypothalamus, and amygdala of OXYS and Wistar (control strain) male rats. Starting from the age of 14 weeks, animals received CEF (100 mg/kg/day, i.p., 36 days) or saline. mRNA levels were evaluated with RT-qPCR method. Biochemical parameters of plasma were measured for control of system effects of the treatment.

Results: To better understand strain variations studied here, we compared the gene expression between untreated OXYS and Wistar rats. This comparison showed a significant decrease in mRNA levels of Ace2 in the frontal cortex and hypothalamus, and of Actb in the amygdala of untreated OXYS rats. Analysis of potential effects of CEF revealed its novel targets. In the compound-treated OXYS cohort, CEF diminished mRNA levels of Bace1 and Ace2 in the hypothalamus, and Aktb in the frontal cortex. Furthermore, CEF augmented Mme, Ide, and Epo mRNA levels in the amygdala as well as the levels of Ece1 and Aktb in the striatum. Finally, CEF also attenuated the activity of ALT and AST in plasma of OXYS rats.

Conclusion: Those findings disclosed novel targets for CEF action that might be involved into neuroprotective mechanisms at early, pre-plaque stages of AD-like pathology development.

Keywords: Alzheimer’s disease; Amyloid metabolism; Ceftriaxone; Gene expression; Neuroprotection; Rats; mRNA.

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Figures

Fig. 1
Fig. 1
Effects of CEF on mRNA levels of Ace2, Bace1, Ece1, Epo, Ide, Mme, and Actb in the amygdala of OXYS and Wistar rats. The data represent the relative mRNA levels of target genes to geometrical mean of B2m, Hprt1, and Mapk6 mRNA levels. The data are expressed as the Mean ± S.E.M. of the values obtained in an independent group of animals (n = 7–10 per group). Statistically significant differences: *P < 0.05 versus “Wistar + saline” group; #P < 0.05; ##P < 0.01 versus “Wistar + CEF” group; $P < 0.05 versus “OXYS + saline” group
Fig. 2
Fig. 2
Effects of CEF on mRNA levels of Ace2, Bace1, Ece1, Epo, Ide, Mme, and Actb in the hypothalamus of OXYS and Wistar rats. The data represent the relative mRNA levels of target genes to geometrical mean of B2m, Hprt1, and Mapk6 mRNA levels. The data are expressed as the Mean ± S.E.M. of the values obtained in an independent group of animals (n = 7–10 per group). Statistically significant differences: *P < 0.05; **P < 0.01; ***P < 0.001 versus “Wistar + saline” group; $P < 0.05 versus “OXYS + saline” group
Fig. 3
Fig. 3
Effects of CEF on mRNA levels of Ace2, Bace1, Ece1, Epo, Ide, Mme, and Actb in the hippocampus of OXYS and Wistar rats. The data represent the relative mRNA levels of target genes to geometrical mean of B2m, Hprt1, and Mapk6 mRNA levels. The data are expressed as the Mean ± S.E.M. of the values obtained in an independent group of animals (n = 6–9 per group). Statistically significant differences: #P < 0.05 versus “Wistar + CEF” group
Fig. 4
Fig. 4
Effects of CEF on mRNA levels of Ace2, Bace1, Ece1, Epo, Ide, Mme, and Actb in the striatum of OXYS and Wistar rats. The data represent the relative mRNA levels of target genes to geometrical mean of B2m, Hprt1, and Mapk6 mRNA levels. The data are expressed as the Mean ± S.E.M. of the values obtained in an independent group of animals (n = 6–9 per group). Statistically significant differences: *P < 0.05 versus “Wistar + saline” group; #P < 0.05 versus “Wistar + CEF” group
Fig. 5
Fig. 5
Effects of CEF on mRNA levels of Ace2, Bace1, Ece1, Epo, Ide, Mme, and Actb in the frontal cerebral cortex of OXYS and Wistar rats. The data represent the relative mRNA levels of target genes to geometrical mean of B2m, Hprt1, and Mapk6 mRNA levels. The data are expressed as the Mean ± S.E.M. of the values obtained in an independent group of animals (n = 6–9 per group). Statistically significant differences: *P < 0.05 versus “Wistar + saline” group; ##P < 0.01 versus “Wistar + CEF” group; $P < 0.05 versus “OXYS + saline” group
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