Abstract
Ceftriaxone (CEF) is a safe and multipotent antimicrobial agent that possesses neuroprotective properties. Earlier, we revealed the restoration of cognitive function in OXYS rats with signs of Alzheimer’s disease (AD)-like pathology by CEF along with its modulating the expression of genes related to the system of amyloid beta (Aβ) metabolism in the brain. The aim of this study was to determine the effects of CEF on behavior, Aβ deposition, and associated neuroinflammation using another model of an early AD-like pathology induced by Aβ. Mice were injected bilaterally i.c.v. with Aβ fragment 25–35 to produce the AD model, while the CEF treatment (100 mg/kg/day, i.p., 36 days) started the next day after the surgery. The open field test, T-maze, Barnes test, IntelliCage, and passive avoidance test were used for behavioral phenotyping. Neuronal density, amyloid accumulation, and the expression of neuroinflammatory markers were measured in the frontal cortex and hippocampus. CEF exhibited beneficial effects on some cognitive features impaired by Aβ neurotoxicity including complete restoration of the fear-induced memory and learning in the passive avoidance test and improved place learning in the IntelliCage. CEF significantly attenuated amyloid deposition and neuroinflammatory response. Thus, CEF could be positioned as a potent multipurpose drug as it simultaneously targets proteostasis network and neuroinflammation, as well as glutamate excitotoxicity, oxidative pathways, and neurotrophic function as reported earlier. Together with previous reports on the positive effects of CEF in AD models, the results confirm the potential of CEF as a promising treatment against cognitive decline from the early stages of AD progression.
Highlights
Drug repurposing is a process of redeveloping a compound for application in a different pathology and finding new therapeutic indications for the existing drugs
Since the glutamate mediated excitotoxicity is one of the essential pathogenic factors involved in various neurodegenerative pathologies including Alzheimer’s disease (AD) (Goncalves-Ribeiro et al, 2019), neuroprotective effects of CEF were studied in AD models as well (Smaga et al, 2020; Kumari and Deshmukh, 2021)
In transgenic murine models of advanced stages of AD-like pathology with highly expressed Aβ plaques (Zumkehr et al, 2015; Hefendehl et al, 2016), CEF neuroprotective effects were attributed to the attenuation of glutamatergic excitotoxicity induced by Aβ deposits, while no pronounced effect on APP processing, overall Aβ species levels, or plaque pathology was observed (Zumkehr et al, 2015)
Summary
Drug repurposing ( called drug repositioning or drug reprofiling) is a process of redeveloping a compound for application in a different pathology and finding new therapeutic indications for the existing drugs. The premise of repositioning is that the drugs that have previously passed clinical trials will minimize the risk of failure in future late-stage clinical trials due to toxicity and lead to faster drug approvals (Li and Jones, 2012). It has been growing in importance in the last few years and becoming mainstream in the drug research area and industry. This strategy appeared to be quite an effective approach in psychopharmacology as well. The present study was focused on another antimicrobial drug with neuroprotective properties, ceftriaxone (CEF)
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