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

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

A new avenue for treating neuronal diseases: Ceftriaxone, an old antibiotic demonstrating behavioral neuronal effects

“…The Bace1 is involved in the increase of Aβ levels but Ide, Mme, and Ece1 are involved in decrease of Aβ levels. Moreover, CEF treatment increased Epo mRNA levels, which are associated with erythropoietin (EPO) expression, neurodevelopment, neurogenesis, and neuroprotection [41]. This is consistent with our previous data illustrating a synergistic effect of combined treatment with CEF and exogenous EPO on neuroprotection as well as cognitive improvements in the MPTP-induced PDD rat model [42].…”

“…Aβ triggers oxidative stress, which stimulates α-syn aggregation [43] and deteriorates neurotoxicity [44]. Inhibiting α-syn accumulation, enhancing antioxidant activity [45,46], and regulation of Aβ metabolism, decreasing production and increasing degradation [41], may underlie neuronal and behavioral protections of CEF in the neurological diseases. Further studies are needed to provide support for the CEF effects on AD and gene regulations.…”

“…CEFinduced increases of GLT-1 expression in the astrocyte enhances glutamate reuptake and lowers extracellular glutamate [6]. CEF regulates expression of genes related to Aß metabolism, reducing production but increasing clearance of Aß [41]. CEF binds directly to the molecular of α-syn, inhibiting α-syn polymerization and Lewy bodies accumulation [39].…”

Repurposing of the β-Lactam Antibiotic, Ceftriaxone for Neurological Disorders: A Review

“…Besides, CEF might exert its neuroprotective actions through other mechanisms such as by affecting Aβ and tau protein metabolism and clearance in an AD model, prevent polymerization of α-synuclein in DLB (Ho et al, 2018) and PD (Ruzza et al, 2014;Tikhonova et al, 2018) models, which is of course, a call for further research to substantiate that the neuroprotective actions of CEF is also mediated via these important pathological proteins.…”

“…Despite the most commonly underlining protein implicated in the pathology of AD, beta-amyloid (Aβ) protein was not directly affected (Zumkehr et al, 2015), CEF downregulated the messenger RNA (mRNA) expression of Bace1 (a gene that encodes β-secretase involved in Aβ formation), Ace2 (a gene that encodes enzymes play a part in Aβ metabolism), and the expression of gene of β-actin. Furthermore, CEF amplified the gene expression of Mme and Ide (genes that encode enzymes involved in Aβ degradation) as well as the expression of EPO gene (a gene that encodes erythropoietin correlated to endothelial function and removal of Aβ) (Tikhonova et al, 2018). CEF-treated animals also showed improvements in memory impairments and restoration of cognitive function and neuronal density (Tikhonova et al, 2017).…”